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Soluble amyloid precursor protein-alpha (sAPPα) is a multi-functional brain-derived protein that has neuroprotective, neurogenic and neurotropic properties. Moreover, it is known to facilitate synaptic function and promote neural repair. These properties suggest sAPPα may be useful as a therapeutic agent for the treatment of neurological diseases characterized by synaptic failure and neuronal loss, such as occurs in Alzheimer's disease, and for neural repair following traumatic brain injury and stroke. However, sAPPα's relatively large size and the difficulty of ongoing delivery of therapeutics to the brain mean this is not currently practicable. Importantly, however, sAPPα is composed of several neuroactive domains that each possess properties that collectively are remarkably similar to those of sAPPα itself. Here, we review the molecular structure of sAPPα and identify the domains that contribute to its overall functionality. Four peptide motifs present as possible targets for therapeutic development. We review their physiochemical and neuroactive properties, both within sAPPα and as isolated peptides, and discuss their potential for future development as multipurpose therapeutic agents for the treatment of Alzheimer's disease and other disorders of neuronal function. Further, we discuss the role of heparin binding sites, found within sAPPα's structure and overlapping with the neuroactive domains, as sites for interactions with effector proteins and synaptic receptors. The potential role of the neuroactive peptides known as Cationic Arginine-Rich Peptides (CARPs) as neuroprotective motifs is also reviewed. Mechanisms of peptide delivery to the brain are briefly discussed. Finally, we summarise the potential benefits and pitfalls of using the isolated peptides, either individually or in combination, for the treatment of neurological diseases.

PurposeAlthough high-velocity contractions elicit greater muscle fatigue in older than young adults, the cause of this difference is unclear. We examined the potential roles of resting muscle architecture and baseline contractile properties, as well as changes in voluntary activation and low-frequency fatigue in response to high-velocity knee extensor work.MethodsVastus lateralis muscle architecture was determined in quiescent muscle by ultrasonography in 8 young (23.4±1.8 yrs) and 8 older women (69.6±1.1). Maximal voluntary dynamic (MVDC) and isometric (MVIC), and stimulated (80Hz and 10Hz, 500ms) isometric contractions were performed before and immediately after 120 MVDCs (240°·s−1, one every 2s).ResultsArchitecture variables did not differ between groups (p≥0.209), but the half-time of torque relaxation (T1/2) was longer in older than young women at baseline (151.9±6.0 vs. 118.8±4.4 ms, respectively, p=0.001). Older women fatigued more than young (to 33.6±4.7% vs. 55.2±4.2% initial torque, respectively; p=0.004), with no evidence of voluntary activation failure (ΔMVIC:80Hz torque) in either group (p≥0.317). Low-frequency fatigue (Δ10:80Hz torque) occurred in both groups (p1/2 (p=0.001), with no differences between groups. Baseline T1/2 was inversely associated with fatigue in older (r2=0.584, p=0.045), but not young women (r2=0.147, p=0.348).ConclusionsThese results indicate that differences in muscle architecture, voluntary activation, and low-frequency fatigue do not explain the greater fatigue of older compared with young women during high-velocity contractions. The inverse association between baseline T1/2 and fatigue in older women suggests that factors related to slower muscle contractile properties may be protective against fatigue during fast, repetitive contractions in aging.

Although high-velocity contractions elicit greater muscle fatigue in older than young adults, the cause of this difference is unclear. We examined the potential roles of resting muscle architecture and baseline contractile properties, as well as changes in voluntary activation and low-frequency fatigue in response to high-velocity knee extensor work. Vastus lateralis muscle architecture was determined in quiescent muscle by ultrasonography in 8 young (23.4±1.8 yrs) and 8 older women (69.6±1.1). Maximal voluntary dynamic (MVDC) and isometric (MVIC), and stimulated (80Hz and 10Hz, 500ms) isometric contractions were performed before and immediately after 120 MVDCs (240°.s-1, one every 2s). Architecture variables did not differ between groups (p≥0.209), but the half-time of torque relaxation (T1/2) was longer in older than young women at baseline (151.9±6.0 vs. 118.8±4.4 ms, respectively, p = 0.001). Older women fatigued more than young (to 33.6±4.7% vs. 55.2±4.2% initial torque, respectively; p = 0.004), with no evidence of voluntary activation failure (ΔMVIC:80Hz torque) in either group (p≥0.317). Low-frequency fatigue (Δ10:80Hz torque) occurred in both groups (p

The major yeast phosphatidylinositol/phosphatidylcholine transfer protein Sec14p is the founding member of a large eukaryotic protein superfamily. Functional analyses indicate Sec14p integrates phospholipid metabolism with the membrane trafficking activity of yeast Golgi membranes. In this regard, the ability of Sec14p to rapidly exchange bound phospholipid with phospholipid monomers that reside in stable membrane bilayers is considered to be important for Sec14p function in cells. How Sec14p-like proteins bind phospholipids remains unclear. Herein, we describe the application of EPR spectroscopy to probe the local dynamics and the electrostatic microenvironment of phosphatidylcholine (PtdCho) bound by Sec14p in a soluble protein-PtdCho complex. We demonstrate that PtdCho movement within the Sec14p binding pocket is both anisotropic and highly restricted and that the C5 region of the sn-2 acyl chain of bound PtdCho is highly shielded from solvent, whereas the distal region of that same acyl chain is more accessible. Finally, high field EPR reports on a heterogeneous polarity profile experienced by a phospholipid bound to Sec14p. Taken together, the data suggest a headgroup-out orientation of Sec14p-bound PtdCho. The data further suggest that the Sec14p phospholipid binding pocket provides a polarity gradient that we propose is a primary thermodynamic factor that powers the ability of Sec14p to abstract a phospholipid from a membrane bilayer.

Phospholipase D (PLD) is a PtdCho-hydrolyzing enzyme that plays central signaling functions in eukaryotic cells. We previously demonstrated that action of a set of four nonclassical and membrane-associated Sec14p-like phosphatidylinositol transfer proteins (PITPs) is required for optimal activation of yeast PLD in vegetative cells. Herein, we focus on mechanisms of Sfh2p and Sfh5p function in this regulatory circuit. We describe several independent lines of in vivo evidence to indicate these SFH PITPs regulate PLD by stimulating PtdIns-4,5-P2 synthesis and that this stimulated PtdIns-4,5-P2 synthesis couples to action of the Stt4p PtdIns 4-kinase. Furthermore, we provide genetic evidence to suggest that specific subunits of the yeast exocyst complex (i.e. a component of the plasma membrane vesicle docking machinery) and the Sec9p plasma membrane t-SNARE are regulated by PtdIns(4,5)P2 and that Sfh5p helps regulate this interface in vivo. The collective in vivo and biochemical data suggest SFH-mediated stimulation of Stt4p activity is indirect, most likely via a substrate delivery mechanism.

Studies of the psychological and sexual outcome of hysterectomy have often arrived at conflicting conclusions and this has resulted in some confusion among health professionals as well as among women themselves. This situation should cause concern, since the incidence of this surgery is high in most countries of the western world. The confusion about outcome arises out of the methodological problems that plagued earlier research. Some of the more recent studies using prospective design, standardized measures and appropriate statistical analysis have not implicated hysterectomy with increased psychological or sexual disorders. However, both before and after hysterectomy in samples studied, the rate of psychological disorder was higher than would have been expected in a normal population, although a clearer picture has emerged from the most recent study. In this paper, risk factors are identified, and the need to include women's own evaluation of the procedure is emphasized.

OBJECTIVE To determine the knowledge and attitudes of adolescents with respect to reproductive health, with particular emphasis on their knowledge of the symptoms and transmission of sexually transmitted diseases (STDs), preventive strategies and sources of information. DESIGN Questionnaire survey of a stratified random sample of Year 10 students followed by group interviews with volunteers from the sample. SETTING The study was carried out in 33 Victorian secondary schools. PARTICIPANTS The questionnaire was administered to a stratified random sample of 1351 Year 10 students. Group interviews were conducted with 533 volunteers from the sample. MEASUREMENTS AND MAIN RESULTS Considerable gaps were identified in knowledge of STDs and their short-term and long-term effects on reproductive health. An STD Knowledge Score was constructed based on responses to 46 items. The mean score for the full sample was 22.7 (49.3% correct) with a standard deviation of 6.4. As a group, country students scored better than city students (mean, 23.8 v. 22.2, t = 3.97, P less than 0.001) and females better than males (mean, 23.5 v. 21.9, t = 4.21, P less than 0.001). Medical practitioners were rarely identified as a source of preventive advice. CONCLUSION The deficiencies identified in knowledge about reproductive health suggest that young people need better access to health information. Schools and the medical profession need to work together both to provide information and to help young people develop the confidence to use available information sources.

This paper reports on the results of a survey of the Australian College of Midwives which was concerned with midwives' perceptions of certain aspects of obstetric practice. It raises issues to be addressed in the continuing education activities of The Royal Australian College of Obstetricians and Gynaecologists and in collaborative efforts between the professions involved in maternity care.

Molecular dynamics simulations coupled with functional analyses of the major yeast phosphatidylinositol/phosphatidylcholine transfer protein Sec14p identify structural elements involved in regulating the ability of Sec14p to execute phospholipid exchange. The molecular dynamics simulations suggest large rigid body motions within the Sec14p molecule accompany closing and opening of an A10/T4/A11helical gate, and that “state-of-closure” of this helical gate determines access to the Sec14p phospholipid binding cavity. The data also project that conformational dynamics of the helical gate are controlled by a hinge unit (residues F212, Y213, K239, I240, and I242) that links to the N- and C-terminal ends of the helical gate, and by a novel gating module (composed of the B1LB2and A12LT5substructures) through which conformational information is transduced to the hinge. The114TDKDGR119motif of B1LB2plays an important role in that transduction process. These simulations offer new mechanistic possibilities for an important half-reaction of the Sec14p phospholipid exchange cycle that occurs on membrane surfaces after Sec14p has ejected bound ligand, and is reloading with another phospholipid molecule. These conformational transitions further suggest structural rationales for known disease missense mutations that functionally compromise mammalian members of the Sec14-protein superfamily.

Sec14p promotes the energy-independent transfer of either phosphatidylinositol (PtdIns) or phosphatidylcholine (PtdCho) between lipid bilayers in vitro and represents the major PtdIns/PtdCho transfer protein in the budding yeast Saccharomyces cerevisiae. Herein, we employ multi-frequency high-field electron paramagnetic resonance (EPR) to analyze the electrostatic and hydrogen-bonding microenvironments for series of doxyl-labeled PtdCho molecules bound by Sec14p in a soluble protein-PtdCho complex. A structurally similar compound, 5-doxyl stearic acid dissolved in a series of solvents, was used for experimental calibration. The experiments yielded two-component rigid limit 130- and 220-GHz EPR spectra with excellent resolution in the gx region. Those components were assigned to hydrogen-bonded and nonhydrogen-bonded nitroxide species. Partially resolved 130-GHz EPR spectra from n-doxyl-PtdCho bound to Sec14p were analyzed using this two-component model and allowed quantification of two parameters. First, the fraction of hydrogen-bonded nitroxide species for each n-doxyl-PtdCho was calculated. Second, the proticity profile along the phospholipid-binding cavity of Sec14p was characterized. The data suggest the polarity gradient inside the Sec14p cavity is a significant contributor to the driving molecular forces for extracting a phospholipid from the bilayer. Finally, the enhanced g-factor resolution of EPR at 130 and 220GHz provides researchers with a spectroscopic tool to deconvolute two major contributions to the x-component of the nitroxide g-matrix: hydrogen-bond formation and local electrostatic effects.

The major PI (phosphatidylinositol)/PC (phosphatidylcholine)-transfer protein in yeast, Sec14p, co-ordinates lipid metabolism with protein transport from the Golgi complex. Yeast also express five additional gene products that share 24–65% primary sequence identity with Sec14p. These Sec14p-like proteins are termed SFH (Sec Fourteen Homologue) proteins, and overexpression of certain individual SFH gene products rescues sec14-1 ts -associated growth and secretory defects. SFH proteins are atypical in that these stimulate the transfer of PI, but not PC, between distinct membrane bilayer systems in vitro . Further analysis reveals that SFH proteins functionally interact with the Stt4p phosphoinositide 4-kinase to stimulate PtdIns(4,5) P 2 synthesis which in turn activates phospholipase D. Finally, genetic analyses indicate that Sfh5p interfaces with the function of specific subunits of the exocyst complex as well as the yeast SNAP-25 (25 kDa synaptosome-associated protein) homologue, Sec9p. Our current view is that Sfh5p regulates PtdIns(4,5) P 2 homoeostasis at the plasma membrane, and that Sec9p responds to that regulation. Thus SFH proteins individually regulate specific aspects of lipid metabolism that couple, with exquisite specificity, with key cellular functions.

Phospholipase D (PLD) is a PtdCho-hydrolyzing enzyme that plays central signaling functions in eukaryotic cells. We previously demonstrated that action of a set of four nonclassical and membrane-associated Sec14p-like phosphatidylinositol transfer proteins (PITPs) is required for optimal activation of yeast PLD in vegetative cells. Herein, we focus on mechanisms of Sfh2p and Sfh5p function in this regulatory circuit. We describe several independent lines of in vivo evidence to indicate these SFH PITPs regulate PLD by stimulating PtdIns-4,5-P2 synthesis and that this stimulated PtdIns-4,5-P2 synthesis couples to action of the Stt4p PtdIns 4-kinase. Furthermore, we provide genetic evidence to suggest that specific subunits of the yeast exocyst complex (i.e. a component of the plasma membrane vesicle docking machinery) and the Sec9p plasma membrane t-SNARE are regulated by PtdIns(4,5)P2 and that Sfh5p helps regulate this interface in vivo. The collective in vivo and biochemical data suggest SFH-mediated stimulation of Stt4p activity is indirect, most likely via a substrate delivery mechanism.

OBJECTIVE To evaluate the role of voluntary antenatal testing in HIV surveillance and prevention by examining antenatal HIV antibody testing practice and policy in Australia. DESIGN Cross-sectional study using a self-administered questionnaire. SUBJECTS AND SETTING Specialist obstetricians and gynaecologists and general practitioners (GPs) affiliated with the Royal Australian College of Obstetricians and Gynaecologists and Australian public hospital antenatal clinics, August-November 1992. MAIN OUTCOME MEASURES The percentage of public hospital antenatal clinics and specialist and GP obstetricians in Australia who tested pregnant women for HIV antibody as part of their antenatal care, and the proportion of pregnant women in Australia who had an antenatal HIV antibody test in the 1991-92 financial year. RESULTS Questionnaires concerning antenatal HIV antibody testing were completed by 90% (993/1108) of specialists, 87% (2134/2461) of GPs and 93% (215/230) of public hospitals surveyed. Of the 706 specialists and 1503 GPs who reported that they were currently engaged in obstetric care, approximately 60% (430/706) and 935/1503, respectively) offered antenatal HIV testing either to all pregnant women or to selected groups at risk. There were significant differences in testing patterns between States and Territories. For the 95 public hospitals with antenatal clinics, 81% (77) offered the HIV antibody test to all or selected groups of pregnant women; these percentages did not differ significantly between States and Territories. It was estimated that 25% of pregnant women seen by specialists, 29% seen by GPs and 9% seen in public hospital clinics were tested for HIV antibody as part of their antenatal care in 1991-92. CONCLUSIONS In Australia approximately one in five pregnant women were tested for HIV antibody as part of their antenatal care in 1991-92. Voluntary HIV testing in pregnancy may provide unrepresentative data for measuring the prevalence of HIV infection in pregnant women.

OBJECTIVE To determine what proportion of Australian neonatologists and obstetricians report using systematic reviews of randomised trials. DESIGN Cross-sectional survey using structured telephone interviews. SETTING Australian clinical practice in 1995. PARTICIPANTS 103 of the 104 neonatologists in Australia (defined as clinicians holding a position in a neonatal intensive care unit); a random sample of 145 members of the Royal Australian College of Obstetricians and Gynaecologists currently practising in Australia. MAIN OUTCOME MEASURES Information sources used in clinical practice; reported awareness of, access to and use of systematic reviews, and consequent practice changes. RESULTS Response rates were 95% (neonatologists) and 87% (obstetricians); 71 neonatologists (72%) and 55 obstetricians (44%) reported using systematic reviews, primarily for individual patient care. Databases of systematic reviews were used with a median frequency of once per month. Among neonatologists, systematic reviews were used more commonly by those who were familiar with computers, attended professional meetings, and had authored research papers. Among obstetricians, they were used more commonly by those who were familiar with computers, had less than 10 years' clinical experience, attended more deliveries, and were full-time staff specialists in public hospitals. Of neonatologists who reported using systematic reviews, 58% attributed some practice change to this use. For obstetricians, the corresponding figure was 80%. CONCLUSIONS There is evidence that Australian neonatologists and obstetricians use systematic reviews and modify their practice accordingly. Dissemination efforts can benefit from knowledge of factors that predict use of systematic reviews.

There were 257 liveborn infants of birthweight 500–999 g born in one tertiary centre in the 5 1 4 years commencing January 1977; 86 (33.5%) survived to 2 years of age, corrected for prematurity and 83 86 (96.5%) were fully assessed. The prevalence of cerebral palsy was 10 83 (12%) and 17 83 (20%) had a major impairment. The distribution of weights and heights for 2-year-old boys and girls was significantly lower than for the standard population, as was the head circumference distribution for boys; the distribution of the Mental Developmental Index (Bayley Scales) was not related to the head circumference or body weight at two years or to head-circumference/bodyweight or height ratios. At birth measurements of weight, length and head circumference were under the 3rd percentile for 13 86 (15%), 9 86 (10.5%) and 9 86 (10.5%) respectively. By 2 years of age, weight, length and head circumference were under the 3rd percentile in 23 83 (27.7%), 26 83 (31.3%) and 4 83 (4.8%) respectively. 12 children who were SGA at birth were fully assessed at 2 years; the group of 6, who continued with poor postnatal weight gains (under the 3rd percentile) had the highest rate of major impairment but included were the only extremely SGA twins and the only two major malformations in the study. We found no association of other health problems or unfavourable social factors with poor postnatal growth or impaired outcome.

A cohort of 678 consecutive very low birth weight infants, liveborn in one tertiary institution during a 63-month period, was studied to investigate whether antenatal steroid therapy had any beneficial or harmful effects on mortality or morbidity over the first 2 years of life. Comparing the 244 babies who received treatment with the 434 controls, 195 (79.9%) and 265 (61.1%), respectively, were discharged home (P less than 0.001). Mortality in the treated group remained substantially lower and was almost halved after adjustment for birth weight, extreme immaturity, lethal malformations, and confounding obstetric variables (P = 0.001). Fatal cases of respiratory distress syndrome were less common in the treated group (P = 0.044). Of in-hospital survivors, those in the treated group required less positive pressure respiratory support (P = 0.003) and fewer days in oxygen (P = 0.018), and the incidences of bronchopulmonary dysplasia (P = 0.003) and patent ductus arteriosus (P = 0.002) were lower. Two-year survivors who had received treatment were heavier (P = 0.016) and had larger head circumferences (P = 0.029). These beneficial associations in the treated group were not at the expense of increased rates of infection or adverse neurologic outcome. We did not detect any adverse effects of antenatal steroid therapy on any relevant aspect of mortality or morbidity in infancy under circumstances in which the chances of finding substantial differences were high.

Fifty-nine infants of birthweight 500 to 999 g born in 1977 to 1980 and 132 infants of birthweight 1000 to 1500 g born in 1977 to 1978 were reviewed at two years corrected age. For the whole cohort, cerebral palsy was found in 12.6%, bilateral deafness in 1%, blindness in 1% and severe developmental delay in 12%. There was no significant difference in these disabilities between the groups of larger and smaller infants; 37.7% of the cohort was readmitted to hospital on at least one occasion, 35.6% of children had wheezing episodes and/or lower respiratory tract infections which together accounted for 51% of hospitalizations. The infants of birthweight 500 to 999 g tended to require more frequent and prolonged hospitalizations. Dolicocephalic head shape, chest deformities, iatrogenic sequelae from intensive care, poor growth and cicatricial retrolental fibroplasia were significantly more frequent in children of birthweight 500 to 999 g. Parents reported that 39% of their children had ‘colic’, 31.6% had sleep disturbance and 25% had multiple behavioural problems. Low frustration tolerance, inability to wait, hypo- or hyperactivity and an inappropriate relationship with the mother as measured by the psychologist all occurred significantly more frequently in children of birthweight of less than 1000 g. This report confirms the belief that a comprehensive follow-up is required for very low birthweight (VLBW) children because significant health problems continue after primary hospitalization.

Of 55 consecutive long-term survivors of birth weight 500 to 999 g, complete psychologic and pediatric data were available for 54 children at 2 years corrected age and for 50 at age at least 5 1/2 years. At the latter age, 60% (30 of 50) were not impaired, 10% (five of 50) had severe sensorineural or intellectual impairments, 10% (five of 50) had mild to moderately impairment, and 20% (10 of 50) had minor neurobehavioural abnormalities. Sensorineural deafness in one child and bilateral blindness in one remained stable over time, but of six children with spastic cerebral palsy at 2 years, only three retained this diagnosis at 5 1/2 years. The mean Mental Developmental Index (MDI) on the Bayley Scales at 2 years was 91.1, significantly below the test mean; by 5 1/2 years the mean full scale of the Wechsler Preschool and Primary Scales of Intelligence (WPPSI) was 101.8. The MDI correlated highly with the full-scale WPPSI (r = 0.7), but for individual children it was not always an accurate predictor of 5-year ability. Between 2 and 5 1/2 years there was a substantial reordering within four categories of impairment: findings in 27 children were improved, four were judged to become more severely impaired over time, and 19 did not change. We conclude that our 2-year assessment often underrated the potential of the children as expressed at 5 1/2 years, and that 2 years is too early for reliable classification of children of birth weight 500 to 999 g.

In a collaborative study involving two hospitals with large maternity services, 166 liveborn infants of gestational age from 24 to 28 weeks were born in the calendar years 1977 and 1978. Of these infants, 75 (45.2%) died either in hospital or after discharge home. At the age of 2 years, 16 (9.6%) of the cohort had a major handicap [cerebral palsy, Mental Developmental Index (MDI) under 69, deafness or blindness]. An additional 20 children (12.0%) had significant developmental delay (MDI 69 to 84, -2 to -1 SD below mean) and 53 (31.9%) were considered to be free of these handicaps. Psychological assessments were not performed on two survivors (1.2%) but reliable reports indicated that they were free of major handicaps. Long-term survival increased in a stepwise fashion from 9.1% at 24 weeks to 68.5% at 28 weeks gestation, and there was a trend for major handicap and significant developmental delay to decrease in incidence with increasing maturity. Of the 58 children who had presented by the vertex 42 (72.4%) were free of significant handicap; however, of the 31 children in whom there had been either a breech presentation or a transverse lie, only 11 (35.5%) were free of significant handicap (chi 2 = 9.69, P less than 0.01). The mode of delivery (vaginal or caesarean section) did not significantly affect the handicap rate in the survivors.

The rate of cerebral palsy and factors associated with its occurrence were determined in surviving 2-year-old very low birthweight (VLBW) infants born during an era of modern perinatal intensive care. Of the survivors, 12.5% (52/416) of those traced had spastic cerebral palsy. Motor handicaps were mild in 42%, moderate in 25%, and severe in 33% of children with cerebral palsy. The prevalence of cerebral palsy was similar in all birthweight groups up to the upper limit of 1500 gm, and was considerably higher than in survivors born in the same hospital a decade earlier. Although several perinatal variables were associated with the occurrence of cerebral palsy, either singly or in combination, little statistical or clinical confidence would be placed in these associations. Moreover, although 77% of children with cerebral palsy had one or more commonly recognized perinatal risk factors, almost identical rates of risk factors were present in normal children. The advent of cranial ultrasonography during the time of the study was associated with an increase in mortality but no effect on the prevalence of cerebral palsy. Cerebroventricular hemorrhage correlated poorly with the presence of cerebral palsy. The prevalence of cerebral palsy in surviving VLBW infants is unacceptably high; however, no obvious preventable factors in its etiology could be identified.

Cranial ultrasounds were performed on 218 (96%) of 227 liveborn infants of birthweight 500-1500 g delivered in the Royal Women's Hospital, Melbourne, Australia, in an 18-month period concluding in March 1982. Seventy-two (31.7%) of the children died; 28 children (38.9%) had cerebroventricular haemorrhage, 35 (48.6%) showed no bleeding and there were nine (12.5%) with no data. Paired necropsy and ultrasound data were congruent in 22 (88%) of 25 children. One hundred and forty-eight (95.5%) of 155 survivors were seen at 2 years of age. Forty-one (28%) had cerebroventricular haemorrhage; nine children (6%) had both ventricular dilatation and haemorrhage and two had ventricular dilatation alone. Apart from a marginal advance in gestation and higher number of immigrant and less educated mothers in children without cerebroventricular haemorrhage, all other perinatal, biographical and social variables between those with haemorrhage and those without were similar. The major handicap rate overall was 14.2% (21 patients). The children with cerebroventricular haemorrhage had a trend for greater prevalence of handicap and lower mean Bayley psychological scores. This was even more evident with ventricular dilatation being present. Of children with major handicap 57.1% (12/21) had normal serial ultrasound findings during their primary hospitalization. Major handicap occurred in 15% (3/20) of children with grade 1 haemorrhage, 23.5% (4/17) with grade 2 or 3 bleeds and 25% (1/4) of those with grade 4 haemorrhage. Laterality of cerebral palsy did not correlate with ultrasound findings. Ultrasound findings did not improve statistical prediction of deaths or major handicap.

The cognitive development at 2 and 5 years of a cohort of extremely low birthweight (ELBW) children (birthweight 500-999 g) was compared with that of cohorts of larger very low birthweight (VLBW) children (birthweight 1000-1500 g) and normal birthweight (NBW) children (birthweight greater than 2500 g) to determine whether the improvements in cognitive function of ELBW infants between 2 and 5 years are apparent or real. At 2 years of age, ELBW children had a mean Mental Developmental Index (MDI) on the Bayley Scales of 90.4, significantly lower than the means of 100.3 for the larger VLBW children (P = 0.006), and 107.8 for the NBW children (P = 0.0002). However by 5 years the mean scores on the Wechsler Preschool and Primary Scales of Intelligence (WPPSI) full-scale for the ELBW and larger VLBW children were virtually identical (105.9 and 106.0 respectively)--but still lower than the mean WPPSI full-scale of 114.6 for the NBW children. After standardizing the MDI and WPPSI scores relative to the NBW children, the ELBW children improved between 2 and 5 years (paired t-test, t = 3.2, P = 0.004) whereas the larger VLBW infants did not. We postulate that ELBW children require more time than larger VLBW children after birth to compensate for perinatal and other stresses, and that developmental delay at 2 years may not always persist to 5 years.

ObjectiveTo determine risk factors during neonatal hospital stay and follow‐up associated with failure to thrive in the first year of life of very low birth weight newborns.MethodsStudy of preterm very low birth weight newborns followed from 2006 to 2013 in a public institutional hospital program. The study included newborns that attended at least one appointment in each of the three periods: Period I, up to 3 months of corrected age (CA); Period II, 4–6 months of CA; and Period III, 7–12 months of CA. The variables were analyzed by logistic regression with XLSTAT 2014 software (Microsoft®, WA, USA). Failure to thrive (Z‐score below −2 SD) was classified as a dichotomous dependent variable (0 – failure/1 – success), while the other variables were classified as explanatory variables for the hospitalization periods and for each of the follow‐up periods (I, II, and III).ResultsChildren born adequate for gestational age increased the chance of Z‐score for weight at discharge>−2 SD (OR=10.217; 95% CI: 1.117–93.436). Metabolic bone disease and retinopathy of prematurity in Period I, as well as hospital readmissions in Periods II and III during follow‐up increased the chance of Z‐score

SUMMARY In 1966-70, the survival rate for very low-birthweight (VLBW) children born in a tertiary perinatal centre was 37–1 per cent but by 1980-82 it had increased to 68-3 per cent. The latter cohort had a significantly reduced prevalence of strabismus, myopia and a head circumference under the 10th percentile, but a significantly increased prevalence of cerebral palsy compared with the 1966-70 VLBW children. Survivors born in 1980-82 had a significantly increased mean Mental Development Index (MDI) on the Bayley Scales compared with the sub-group of survivors born in 1968-70 but there was also a significant improvement in mean MDI over time for a group of normal-birthweight children. No improvement of MDI scores of VLBW survivors in the 1980-82 cohort could be attributed solely to perinatal care. The two-year-old VLBW children in the 1980-82 cohort had similar rates of sensorineural impairments, disabilities and mean MDI to those who would have survived with the care available in 1966-70. It is concluded that survival of VLBW infants has improved in recent times but that neurodevelopmental outcome still lags behind that of normal-birthweight peers. RESUME Amelioration du devenir a deux ans des nourrissons de tres faible poids de naissance: realite ou artifice? En 1966-70, le taux de survie des enfants de tres faible poids de naissance (VLBW) nes dans un centre perinatal tertiaire etait de 37-1 pour cent mais en 1980-82 il s'etait relevea 68.3 pour cent. Dans le groupe ne recemment on notait une reduction significative de la prevalence du strabisme, de la myopie et d'un tour de tete au-dessous du dixeme percentile mais une prevalence significativement accrue de l'IMC par comparaison avec les enfants VLBW nes dans la periode 1966-70. Les survivants de la periode 1980-82 presentaient un Index de Developpement Mental (MDI) a l'echelle de Bayley significativement majore par comparaison avec le sous-groupe des survivants nes en 1968-70, mais il y avait egalement une majoration significative de la moyenne MDI avec le temps pour un groupe d'enfants de poids de naissance normal. Aucune amelioration des scores MDI des survivants VLBW du groupe 1980-82 ne saurait etre attribuee seulement aux soins perinataux. Les enfants VLBW de deux ans du groupe 1980-82 presentaient un taux similaire de troubles sensori-neuraux, d'incapacite et de MDI moyens par rapport a ceux qui auraient survecu avec les methodes de soins disponibles en 1966-70. Les auteurs concluent que la survie des nourrissons VLBW s'est amelioree recemment mais que le devenir neurodeveloppemental demeure loin derriere celui de nourrissons correspondants avec poids de naissance normal. ZUSAMMENFASSUNG Verbesserte klinische Ergebnisse bis zum zweiten Lebensjahr bei sehr hypotrophen Kindern: Tatsache Oder Artefakt? Von 1966-70 betrug die Uberlevensrate von Kindern mit sehr niedrigem Geburtsgewicht (VLBW-very low birthweight), die in einem perinatologischen Zentrum geboren wurder 37.1 Prozent, aber bis 1980-82 hatte sie sich auf 68.3 Prozent erhoht. Bei der letzteren Gruppe fand sich eine geringere Haufigkeit von Strabismus, Myopie und Kopfumfang unter der 10. Perzentile, aber eine erholte Anzahl von Cerebralparese verglichen mit den VLBW Kindern aus den Jahren 1966-70. Die Kinder aus den Jahrgangen 1980-82 hatten einen signifikant hoheren mittleren Mental Development Index (MD1) bei den Bayley Skalen verglichen mit einer Untergruppe von Kindern aus den Jahrgangen 1968-70, aber es fand sich auch ein signifikanter Anstieg des mittleren MDI bei einer Gruppe normalgewichtiger Kinder in diesem Zeitraum. Die Verbesserung der MDI Scores der VLBW Kinder von 1980-82 konnte nicht nur der perinatalen Pflege zugeschrieben werden. Die zweijahrigen VLBW Kinder der Gruppe von 1980-82 hatten ahnliche Befunde von sensoneuralen Storungen, Behinderungen und mittleren MDI wie die Kinder, die mit den 1966-70 zur Verfugung stehenden Mitteln uberlebt hatten. RESUMEN Mejoria de la realization a los dos anos de lactantes con muy bajo peso al nacer: un hecho o un artefacto? En 1966-70 la proporcion de supervivencia para los nifios con muy bajo peso al nacer (MBPN) nacidos en el centra perinatal terciario era de 47.1 por ciento, pero en 1980-82 habia aumentado a 68.3 por ciento. El ultimo grupo tenia una prevalencia significativamente reducida de estrabismo, miopia y una circunferencia craneal por debajo del 10° percentil, pero una prevalencia significativamente aumentada de paralisis cerebral en comparacion con el grupo de 1966-70. Los supervivientes nacidos en 1980-82 tenian un aumento significativo en el Indice de Desarrollo Mental (IDM) en las escalas de Bayley en comparacion con el subgrupo de supervivientes nacidos en 1968-70; pero habia tambien una mejoria significativa en el IDM promedio a lo largo del tiempo en un grupo de nifios con peso normal al nacer. Ninguna mejora en los puntajes del IDM de los supervivientes MBPN en el grupo 1980-82 pudo ser atribuida unicamente al cuidado perinatal. Los ninos MBPN de los anos de edad del grupo 1980-82 tenian una misma proporcion de alteraciones sensoneuronales, dishabilidades y IDM promedio, en comparacion con los que hubiesesn sobrevivido con los cuidados posibles en 1966-70. Se concluye que la supervivencia de los lactantes MBPN ha mejorado en los ultimos tiempos, pero la realization neuro-evolutiva todavia esta con retraso con respecto a sus homologos normales.

Sixty women aged between 30 and 55 years, having hysterectomy for benign conditions, were prospectively studied to investigate psychological adjustment to operation, and to explore social, psychological and physical factors associated with psychological outcome. A further 30 women were included for prospective research on psychological outcome. Investigations took place within two weeks of operation and after four months and 14 months. The findings indicated a high prevalence of pre-operative psychological morbidity (55%), which reduced to 31.7% afterwards. There was no evidence that hysterectomy led to a greater psychological distress. The principal risk factors of poor psychological outcome were the previous scores on the mental health measures and personality inventory. Involvement in the research process did not appear to affect psychological outcome.

Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHO's 'Priority 1: Critical' list. By targeting outer membrane YaiW, cationic lacritin peptide 'N-104' translocates into the periplasm where it ligates outer loops 4 and 2 of the inner membrane transporters FeoB and PotH, respectively, to suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExbB1. The mechanism is innate to the surface of the eye and is enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters., Competing Interests: DECLARATION OF INTERESTS GWL is cofounder and CSO of TearSolutions, Inc; and cofounder and CTO of IsletRegen, LLC. Other authors declare no competing interests.