Postnatal adaptations of phosphatidylcholine metabolism in extremely preterm infants: implications for choline and PUFA metabolism.

BACKGROUND: Lipid metabolism in pregnancy delivers PUFAs from maternal liver to the developing fetus. The transition at birth to diets less enriched in PUFA is especially challenging for immature, extremely preterm infants who are typically supported by total parenteral nutrition. OBJECTIVE: The aim was to characterize phosphatidylcholine (PC) and choline metabolism in preterm infants and demonstrate the molecular specificity of PC synthesis by the immature preterm liver in vivo. METHODS: This MS-based lipidomic study quantified the postnatal adaptations to plasma PC molecular composition in 31 preterm infants <28 weeks' gestational age. Activities of the cytidine diphosphocholine (CDP-choline) and phosphatidylethanolamine-N-methyltransferase (PEMT) pathways for PC synthesis were assessed from incorporations of deuterated methyl-D9-choline chloride. RESULTS: The concentration of plasma PC in these infants increased postnatally from median values of 481 (IQR: 387-798) µM at enrollment to 1046 (IQR: 616-1220) µM 5 d later (P < 0.001). Direct incorporation of methyl-D9-choline demonstrated that this transition was driven by an active CDP-choline pathway that synthesized PC enriched in species containing oleic and linoleic acids. A second infusion of methyl-D9-choline chloride at day 5 clearly indicated continued activity of this pathway. Oxidation of D9-choline through D9-betaine resulted in the transfer of 1 deuterated methyl group to S-adenosylmethionine. A very low subsequent transfer of this labeled methyl group to D3-PC indicated that liver PEMT activity was essentially inactive in these infants. CONCLUSIONS: This study demonstrated that the preterm infant liver soon after birth, and by extension the fetal liver, was metabolically active in lipoprotein metabolism. The low PEMT activity, which is the only pathway for endogenous choline synthesis and is responsible for hormonally regulated export of PUFAs from adult liver, strongly supports increased supplementation of preterm parenteral nutrition with both choline and PUFAs.

Efficacy of oral potassium chloride administration in treating lactating dairy cows with experimentally induced hypokalemia, hypochloremia, and alkalemia.

Hypokalemia occurs commonly in lactating dairy cows. The objectives of this study were to determine (1) whether a 24-h oral KCl dose of 0.4 g/kg of body weight (BW) was effective and safe in hypokalemic cattle; (2) whether potassium was best administered as 2 large doses or multiple smaller doses over a 24-h period; and (3) the effect of oral KCl administration on plasma Mg concentration and urine Mg excretion in fasted lactating dairy cattle. Plasma K and Cl concentrations were decreased, and blood pH increased, in 15 lactating Holstein-Friesian cows by administering 2 intramuscular (i.m.) 10-mg injections of isoflupredone acetate 24h apart followed by 2 i.m. injections of furosemide (1mg/kg of BW) 8h apart and by decreasing feed intake. Cows were randomly assigned to 1 of 3 treatment groups with 5 cows/group: untreated control (group C); oral administration of KCl at 0.05 g/kg of BW 8 times at 3-h intervals (group K3); and oral administration of KCl at 0.2g/kg of BW twice at 12-h intervals (group K12). A 24-h KCl dose rate of 0.4 g/kg of BW increased plasma and milk K concentration and plasma Cl concentration, and corrected the metabolic alkalosis and alkalemia, with no clinically significant difference between 2 large doses (group K12) or multiple small doses (group K3) of KCl over 24 h. Oral KCl administration decreased peripheral fat mobilization in cattle with experimentally induced hypokalemia, as measured by changes in plasma nonesterified fatty acid concentration, and slightly augmented the fasting-induced decrease in plasma Mg concentration. Our findings support recommendations for a 24-h oral KCl dose of 0.4 g/kg of BW for treating moderately hypokalemic cattle. Additional Mg may need to be administered to inappetant lactating dairy cattle being treated with oral KCl to minimize K-induced decreases in magnesium absorption.

Spectral vs. temporal auditory processing in specific language impairment: a developmental ERP study.

Pre-linguistic sensory deficits, especially in "temporal" processing, have been implicated in developmental language impairment (LI). However, recent evidence has been equivocal with data suggesting problems in the spectral domain. The present study examined event-related potential (ERP) measures of auditory sensory temporal and spectral processing, and their interaction, in typical children and those with LI (7-17 years; n=25 per group). The stimuli were three CV syllables and three consonant-to-vowel transitions (spectral sweeps) isolated from the syllables. Each of these six stimuli appeared in three durations (transitions: 20, 50, and 80 ms; syllables: 120, 150, and 180 ms). Behaviorally, the group with LIs showed inferior syllable discrimination both with long and short stimuli. In ERPs, trends were observed in the group with LI for diminished long-latency negativities (the N2-N4 peaks) and a developmentally transient enhancement of the P2 peak. Some, but not all, ERP indices of spectral processing also showed trends to be diminished in the group with LI specifically in responses to syllables. Importantly, measures of the transition N2-N4 peaks correlated with expressive language abilities in the LI children. None of the group differences depended on stimulus duration. Therefore, sound brevity did not account for the diminished spectral resolution in these LI children. Rather, the results suggest a deficit in acoustic feature integration at higher levels of auditory sensory processing. The observed maturational trajectory suggests a non-linear developmental deviance rather than simple delay.

Event-related potentials reflect spectral differences in speech and non-speech stimuli in children and adults.

OBJECTIVE: Event-related brain potentials (ERP) may provide tools for examining normal and abnormal language development. To clarify functional significance of auditory ERPs, we examined ERP indices of spectral differences in speech and non-speech sounds. METHODS: Three Spectral Items (BA, DA, GA) were presented as three Stimulus Types: syllables, non-phonetics, and consonant-vowel transitions (CVT). Fourteen 7- to 10-year-old children and 14 adults were presented with equiprobable Spectral Item sequences blocked by Stimulus Type. RESULTS: Spectral Item effect appeared as P1, P2, N2, and N4 amplitude variations. The P2 was sensitive to all Stimulus Types in both groups. In adults, the P1 was also sensitive to transitions while the N4 was sensitive to syllables. In children, only the 50-ms CVT stimuli elicited N2 and N4 spectral effects. In both groups, non-phonetic stimuli elicited larger N1-P2 amplitudes while speech stimuli elicited larger N2-N4 amplitudes. CONCLUSIONS: Auditory feature processing is reflected by P1-P2 and N2-N4 peaks and matures earlier than supra-sensory integrative mechanisms, reflected by N1-P2 peaks. Auditory P2 appears to pertain to both processing types. SIGNIFICANCE: These results delineate an orderly processing organization whereby direct feature mapping occurs earlier in processing and, in part, serves sound detection whereas relational mapping occurs later in processing and serves sound identification.

Hospital at home for chronic obstructive pulmonary disease: an integrated hospital and community based generic intermediate care service for prevention and early discharge.

Recent randomized controlled studies have reported success for hospital at home for prevention and early discharge of chronic obstructive pulmonary disease (COPD) patients using hospital based respiratory nurse specialists. This observational study reports results using an integrated hospital and community based generic intermediate care service. The length of care, readmission within 60 days and death within 60 days in the early discharge (9.37 days, 21.1%, 7%) and the prevention of admission (five to six days, 34.1%, 3.8%) are similar to previous studies. We suggest that this generic community model of service may allow hospital at home services for COPD to be introduced in more areas.

Auditory semantic networks for words and natural sounds.

Does lexical processing rely on a specialized semantic network in the brain, or does it draw on more general semantic resources? The primary goal of this study was to compare behavioral and electrophysiological responses evoked during the processing of words, environmental sounds, and non-meaningful sounds in semantically matching or mismatching visual contexts. A secondary goal was to characterize the dynamic relationship between the behavioral and neural activities related to semantic integration using a novel analysis technique, ERP imaging. In matching trials, meaningful-sound ERPs were characterized by an extended positivity (200-600 ms) that in mismatching trials partly overlapped with centro-parietal N400 and frontal N600 negativities. The mismatch word-N400 peaked later than the environmental sound-N400 and was only slightly more posterior in scalp distribution. Single-trial ERP imaging revealed that for meaningful stimuli, the match-positivity consisted of a sensory P2 (200 ms), a semantic positivity (PS, 300 ms), and a parietal response-related positivity (PR, 500-800 ms). The magnitudes (but not the timing) of the N400 and PS activities correlated with subjects' reaction times, whereas both the latency and magnitude of the PR was correlated with subjects' reaction times. These results suggest that largely overlapping neural networks process verbal and non-verbal semantic information. In addition, it appears that semantic integration operates across different time scales: earlier processes (indexed by the PS and N400) utilize the established meaningful, but not necessarily lexical, semantic representations, whereas later processes (indexed by the PR and N600) are involved in the explicit interpretation of stimulus semantics and possibly of the required response.

ERPs differentiate syllable and nonphonetic sound processing in children and adults.

We examined maturation of speech-sound-related indices of auditory event-related brain potentials (ERPs). ERPs were elicited by syllables and nonphonetic correlates in children and adults. Compared with syllables, nonphonetic stimuli elicited larger N1 and P2 in adults and P1 in children. Because the nonphonetics were more perceptually salient, this N1 effect was consistent with known N1 sensitivity to sound onset features. Based on stimulus dependence and independent component structure, children's P1 appeared to contain overlapping P2-like activity. In both subject groups, syllables elicited larger N2/N4 peaks. This might reflect sound content feature processing, more extensive for speech than nonspeech sounds. Therefore, sound detection mechanisms (N1, P2) still develop whereas sound content processing (N2, N4) is largely mature during mid-childhood; in children and adults, speech sounds are processed more extensively than nonspeech sounds 200-400 ms poststimulus.

Toxic potential of dietary genistein isoflavone and beta-lapachone on capacitation and acrosome reaction of epididymal spermatozoa.

We determined if acrosomal reaction was influenced by exposure of sperm cells to two dietary phytochemicals, genistein isoflavone and beta-lapachone, using the rat model. Spermatozoa were capacitated in capacitating medium with or without genistein isoflavone and beta-lapachone, and the percentage of posttreatment acrosome reaction compared with controls was assessed with two fluorescent probes, chlortetracycline (CTC) and fluorescein isothiocyanate- Pisum sativum ag-glutinin conjugate (FITC-PSA). Spermatozoa were permeabilized in ethanol and labeled with the FITC-PSA or CTC to determine the acrosome status. The results revealed that calcium ionophore could induce acrosome reaction in spermatozoa and that acrosome-reacted sperm cells showed obvious darkness in the head region, whereas acrosome-intact sperm displayed bright fluorescence over the entire sperm head. The basic response and pattern of acrosome reaction status were significantly similar in both CTC and FITC assays and in both treatment (genistein and beta-lapachone) groups. It was observed that higher doses of both genistein and beta-lapachone significantly suppressed acrosome reaction and that this inhibitory effect was both dose- and time-dependent. It was stipulated that the observed genistein inhibition of acrosome reaction could be due to suppression of protein kinase C, and that beta-lapachone could inhibit acrosome reaction through direct cytotoxic effects on sperm cell membrane at higher doses. However, light microscopic examination indicated that both phytochemicals had no significant effect on sperm morphology. It is concluded that, in view of the fact that acrosome reaction is a physiological prerequisite for fertilization of most mammalian eggs, both genistein and beta-lapachone could potentially suppress male fertility via suppression of acrosome reaction at higher doses, but could enhance fertility by promoting acrosome reaction at lower doses. This bimodal mode of action of both phytochemicals could offer a potentially new dimension in the search for causes of male infertility and possibly for male contraceptive development.

The quality of routine examinations of the newborn performed by midwives and SHOs; an evaluation using video recordings.

OBJECTIVE: To evaluate the quality of the routine examination of the newborn as carried out by senior house officers (SHOs) and midwives. DESIGN: Randomised controlled trial set in a district general hospital in Southeast England. Eligible babies were randomised to a midwife (11) or an SHO (8) who were then video recorded undertaking the routine newborn examination. MAIN OUTCOME MEASURES: Quality of 62 observed technical and communication components of the newborn examination, as agreed between independent consultant paediatrician and senior midwife raters. RESULTS: Major differences were found in the rated quality of examinations between midwives and SHOs for the examinations of the heart and lungs, for the overall quality of the examination, and in areas of communication skills. Quality of examination of the hips was assessed as poor for both professional groups. Where there were significant differences between examiners, the quality of the midwives' examinations was higher. Inter-rater agreement between the consultant paediatricians and senior midwives ranged from excellent to poor for different items of the examination with a mean kappa value of 0.42 across all items indicating moderate agreement. CONCLUSIONS: The quality of midwife examinations exceeded that of SHOs. All midwives who examine receive formalized training in the examination of the newborn; SHOs may benefit from similar specific training. Training for both professional groups may need to be reviewed, particularly in relation to agreement on 'gold standards' for the screening of developmental dysplasia of the hip.

Amelanotic choroidal nevus and melanoma: cytology, tumor size, and pigmentation as prognostic indicators.

BACKGROUND: Choroidal nevi are fairly common lesions of the posterior pole that can sometimes transform into melanoma, and it is thought that most choroidal melanomas arise from preexisting nevi. Occasionally, these lesions present as nonpigmented or amelanotic variations of their pigmented counterparts. Recent studies suggest a relationship between tumor pigmentation and risk of growth and metastasis, with a better prognosis for lightly pigmented or amelanotic lesions. CASE REPORTS: A case of an amelanotic choroidal nevus and melanoma are presented. In Case 1, a 26-year-old white female was found to have a large amelanotic nevus in the right eye. After 7 years of periodic observation, the lesion has not changed. In Case 2, a 51-year-old white male was diagnosed with a large amelanotic melanoma in the left eye. Due to extensive involvement of the optic nerve, the patient underwent enucleation. Histological evaluation confirmed the lesion as a mixed-cell type malignant amelanotic melanoma. CONCLUSION: Management of choroidal nevi generally consists of periodic observation, and the most widely accepted management of choroidal melanoma is observation, radiotherapy, and transpupillary thermotherapy or enucleation. The therapeutic modality of choice for melanoma will vary depending on the size, growth, and location of the lesion. In addition, recent studies suggest an association between heavy tumor pigmentation, tumor size, cell type, and risk of metastasis. Although many variables will influence the final treatment option, pigmentation of the lesion should also be considered.

Effects of Genistein Isoflavone (4',5',7-Trihydroxyisoflavone) and Dexamethasone on Functional Characteristics of Spermatozoa.

Caudal epididymal spermatozoa were used to study the influence of genistein isoflavone and dexamethasone (dxm) on the functional characteristics of spermatozoa. The effects of genistein alone and in combination with dxm on sperm motility, sperm morphology, spontaneous acrosome reaction (AcR), and ionophore A23187-induced AcR were investigated. The FITC-PSA/Hoechst 33258 staining procedure was used to assess sperm cell viability and AcR status and thus to differentiate between true AcR and acrosome degeneration. The overall results indicated that (1) lower doses of genistein alone, or in combination with dxm, did not significantly influence sperm motility or sperm morphology; (2) ionophore A23187 induced AcR in rat spermatozoa; (3) there appeared to be no direct correlation between sperm motility and AcR, (4) higher doses of genistein, alone or in combination with dxm, significantly interfered with percentage sperm motility and caused significant detachment of sperm heads but did not cause morphological defects; and (5) higher doses of genistein caused significant decrease in sperm acrosome reactivity with long duration of exposure. In view of the fact that sperm capacitation and AcR are physiological prerequisites for successful fertilization of oocytes, the findings suggest that chronic exposure of spermatozoa to high doses of genistein could be associated with infertility problems through suppression/inhibition of AcR and sperm motility. Dexamethasone did not appear to influence the effect of genistein on the functionality of postspermatogenic spermatozoa.

Cost effectiveness scenario analysis for a proposed trial of hormone replacement therapy.

Whereas evaluation of resource implications and quality of life are often incorporated into assessments of health technology, the decision to undertake the assessment is still mostly driven by interests in the clinical outcomes alone. A systematic approach to evaluating expected returns to health technology assessment has not been readily taken up by research funders or assessors. This paper sets out a specific methodology for ex ante evaluation or triage and proposes a decision procedure, using alternative outcome scenarios and the associated policy changes and costs and benefits, against a background of likely clinical practice in the absence of the assessment. The methodology is used to consider implications of a proposed major clinical trial to assess the long term costs and benefits of hormone replacement therapy.

Low back pain of mechanical origin: randomized comparison of chiropractic and hospital outpatient treatment.

Reprinted with permission from the British Medical Journal 300:1431-1437.1990. Objective - To compare chiropractic and hospital outpatient treatment for managing low back pain of mechanical origin.Design - Randomized controlled trial. Allocation to chiropractic or hospital management by minimization to establish groups for analysis of results according to initial referral clinic, length of current episode, history, and severity of back pain. Patients were followed up for up to two years.Setting - Chiropractic and hospital outpatient clinics in 11 centers.Patients - 741 patients aged 18-65 who had no contraindications to manipulation and who had not been treated within the past month.Interventions - Treatment at the discretion of the chiropractors, who used chiropractic manipulation in most patients, or of the hospital staff, who most commonly used Maitland mobilization or manipulation, or both.Main outcome measures - Changes in the score on the Oswestry pain disability questionnaire and in the results of tests of straight leg raising and lumbar flexion.Results - Chiropractic treatment was more effective than hospital outpatient management, mainly for patients with chronic or severe back pain. A benefit of about 7 percent points on the Oswestry scale was seen at two years. The benefit of chiropractic treatment became more evident throughout the follow-up period. Secondary outcome measures also showed that chiropractic was more beneficial.Conclusions - For patients with low back pain in whom manipulation is not contraindicated, chiropractic almost certainly confers worthwhile, long-term benefit in comparison with hospital outpatient management. The benefit is seen mainly in those with chronic or severe pain. Introducing chiropractic into NHS practice should be considered.J Orthop Sports Phys Ther 1991;13(6):278-287.

Low back pain of mechanical origin: randomised comparison of chiropractic and hospital outpatient treatment.

OBJECTIVE: To compare chiropractic and hospital outpatient treatment for managing low back pain of mechanical origin. DESIGN: Randomised controlled trial. Allocation to chiropractic or hospital management by minimisation to establish groups for analysis of results according to initial referral clinic, length of current episode, history, and severity of back pain. Patients were followed up for up two years. SETTING: Chiropractic and hospital outpatient clinics in 11 centres. PATIENTS: 741 Patients aged 18-65 who had no contraindications to manipulation and who had not been treated within the past month. INTERVENTIONS: Treatment at the discretion of the chiropractors, who used chiropractic manipulation in most patients, or of the hospital staff, who most commonly used Maitland mobilisation or manipulation, or both. MAIN OUTCOME MEASURES: Changes in the score on the Oswestry pain disability questionnaire and in the results of tests of straight leg raising and lumbar flexion. RESULTS: Chiropractic treatment was more effective than hospital outpatient management, mainly for patients with chronic or severe back pain. A benefit of about 7% points on the Oswestry scale was seen at two years. The benefit of chiropractic treatment became more evident throughout the follow up period. Secondary outcome measures also showed that chiropractic was more beneficial. CONCLUSIONS: For patients with low back pain in whom manipulation is not contraindicated chiropractic almost certainly confers worthwhile, long term benefit in comparison with hospital outpatient management. The benefit is seen mainly in those with chronic or severe pain. Introducing chiropractic into NHS practice should be considered.

Graduate primary care training: a collaborative alternative for family practice, internal medicine, and pediatrics.

The Residency Program in Social Medicine at Montefiore Medical Center is a collaborative, integrated training program for primary care pediatricians, internists, and family physicians within one interdisciplinary organization. Since 1970 we have trained more than 200 physicians, prepared them for board certification in their specialty, emphasized the psychosocial aspects and social determinants of health and illness, and shared a faculty, curriculum, and commitment to provide medical care for inner-city, underserved populations. We discuss the program's history and curriculum, administrative and academic structure, shared "cross-track" faculty units (psychosocial; social medicine; and research, education, and evaluation), and graduates' practice outcomes. The interdisciplinary character of the Residency Program in Social Medicine helps physicians successfully serve the underserved and exemplifies that interdisciplinary medical education succeeds when interdisciplinary health care teams are organized for optimal patient care. Only the federal government has the perspective and power to foster more interdisciplinary collaboration and strengthen primary care education in a period of shrinking resources.

Inhibition of gene expression in transformed plants by antisense RNA.

We report the successful suppression of nopaline synthase (EC 1.5.1.19) enzymatic activity in the leaves of tobacco plants via the overproduction of RNAs complementary to the nopaline synthase (nos) mRNA. Several different regions of the nos gene were fused, in antisense orientation, to the promoter from a strongly expressed petunia chlorophyll a/b-binding protein gene. These constructions were directly introduced into a tobacco line which contained a single copy of the wild-type nos gene and transgenic plants were regenerated. The degree of nopaline synthase suppression in the leaves of the double transformants ranged up to 85% and was dependent on the particular region of the nos gene present in the antisense RNA. The most effective nos antisense sequences were derived from the 3' half of the nos gene transcript. In addition, we report a new sensitive method for the detection and quantitation of nopaline synthase activity in crude plant extracts.

Relative hypoplasia of the optic nerve.

Meticulous comparison of optic nervehead size has revealed detectable differences in as many as 10% of patients. In many cases the larger nervehead has a larger cup. This may result in the false impression of glaucoma and may be the most common cause of asymmetric cupping in the absence of active, progressive disease. Two cases demonstrating this finding are reviewed with a discussion of its detection and diagnosis.

Trypanosoma theileri: antibody-dependent killing by purified populations of bovine leucocytes.

Bovine leucocytes were assayed for their cytotoxic activity against Trypanosoma theileri, a large haemoflagellate parasite of cattle. Cytotoxicity was assessed by 3H-uridine release from pre-labelled parasites and also by light microscopy. Cytotoxicity proved to be totally dependent upon the presence of specific antibody. Serum and the immunoglobulin fraction of colostrum from normal adult cattle and serum from normal colostrum fed calves mediated cytotoxicity; serum from SPF colostrum deprived calves possessed no cytotoxic activity. Neutrophils, eosinophils, monocytes and macrophages obtained from both the peripheral blood and mammary gland of heifers were cytotoxic to T. theileri epimastigotes. Lymphocytes failed to mediate cytotoxicity either in the presence or absence of specific antibody. Despite the large size of this trypanosome all effector cells phagocytosed T. theileri. Phagocytosis by macrophages and eosinophils preceded specific isotope release, however neutrophils mediated 50% specific isotope release during the phagocytic period, suggesting extracellular cell-mediated lysis.

Nutrition and cognitive development among rural Guatemalan children.

Women and children from four Guatemalan villages participated in a voluntary food supplementation program for seven years. In two of the villages, they received a vitamin and mineral fortified, high-protein calorie supplement. In the other two villages, the vitamin-mineral fortified supplement contained no protein and a relatively small number of calories. Cognitive tests were administered regularly to children ages three to seven, and anthropometric measures obtained. In addition, measures of families' social milieu were collected at several points in time. Using multiple regression analysis, we find that both nutritional and social environmental measures are related to various dimensions of cognitive competence. The results suggest that nutritional intake, independent of social factors, affects cognitive development. There is also some evidence that the children who receive the high-protein calorie supplement (and whose mothers received it during pregnancy and lactation) are more likely to score high in cognitive performance. Our results, while not diminishing social environmental explanations of differences in cognitive function, suggest benefits from nutrition intervention programs in rural areas of lesser-developed countries.