Lack of association between gestational age adjusted TSH percentiles and neurodevelopmental outcomes among preterm infants.

BACKGROUND: Limited evidence exists on whether subclinical hypothyroidism suggested by mildly elevated TSH levels affect neurodevelopment and growth in preterm infants. The objective of this study was to determine the association between gestational age adjusted TSH percentiles and neurodevelopmental outcomes among preterm infants. METHODS: Univariate linear regression analysis was conducted to determine, in infants born less than thirty-two weeks gestational age, the correlation between the TSH percentile on the last newborn screen and neurodevelopmental assessment scores and growth outcomes at eighteen to twenty-two months of corrected age. RESULTS: Seventy-four patients were enrolled in the study with a mean gestational age of 28.8 weeks. There was no correlation between the last TSH percentile value and Bayley-III cognitive composite score or other neurodevelopmental or growth outcomes. CONCLUSION: In a cohort of preterm infants, higher TSH percentiles suggesting potential subclinical hypothyroidism did not predict any adverse effect on neurodevelopmental or growth outcomes.

Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray.

In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients.

Feedback analysis and design of RF power links for low-power bionic systems.

This paper presents a feedback-loop technique for analyzing and designing RF power links for transcutaneous bionic systems, i.e., between an external RF coil and an internal RF coil implanted inside the body. The feedback techniques shed geometric insight into link design and minimize algebraic manipulations. We demonstrate that when the loop transmission of the link's feedback loop is -1, the link is critically coupled, i.e., the magnitude of the voltage transfer function across the link is maximal. We also derive an optimal loading condition that maximizes the energy efficiency of the link and use it as a basis for our link design. We present an example of a bionic implant system designed for load power consumptions in the 1-10-mW range, a low-power regime not significantly explored in prior designs. Such low power levels add to the challenge of link efficiency, because the overhead associated with switching losses in power amplifiers at the link input and with rectifiers at the link output significantly degrade link efficiency. We describe a novel integrated Class-E power amplifier design that uses a simple control strategy to minimize such losses. At 10-mW load power consumption, we measure overall link efficiencies of 74% and 54% at 1- and 10-mm coil separations, respectively, in good agreement with our theoretical predictions of the link's efficiency. At 1-mW load power consumption, we measure link efficiencies of 67% and 51% at 1- and 10-mm coil separations, respectively, also in good accord with our theoretical predictions. In both cases, the link's rectified output dc voltage varied by less than 16% over link distances that ranged from 2 to 10 mm.

Possible role of the receptor protein tyrosine phosphatase HmLAR2 in interbranch repulsion in a leech embryonic cell.

Accumulating evidence indicates that receptor protein tyrosine phosphatases (rPTPs) play major roles in growth cone migration. We have previously shown that the growth cones of the multiple parallel processes of an identified leech embryonic cell, the Comb cell (CC), express high levels of a leukocyte antigen-related (LAR)-like rPTP, HmLAR2. Embryonic injection of a polyclonal antibody to the receptor's ectodomain resulted in reduced process outgrowth and in processes crossing over each other, a behavior that is seldom observed in normal or control animals. Here we present results of injecting a soluble Fc-HmLAR2 ectodomain fusion protein into embryos in order to bind the endogenous ligands of HmLAR2. Single injections of the Fc-chimeric protein into the developing embryo resulted, 12 to 24 h postinjection, in clear morphological abnormalities, ranging from abnormally directed CC processes and crossovers to apparent growth cone collapse. At later times, 2 to 5 days post injection, growth cones appeared to have recovered and processes had continued to extend, but effects of the earlier guidance errors remained, with the CCs displaying a relatively high incidence of proximal guidance errors. When injected into the germinal plate of developing embryos, the fusion protein was found to bind selectively to the processes of the CCs themselves, in contrast to control injections of Fc alone or closely related Fc-tagged proteins, which did not decorate the CCs. Double-labeling experiments revealed an early phase of Fc-HmLAR2 labeling (within 20 min after application), during which the growth cones and filopodia of the CC showed significant binding of the receptor ectodomain, and a later phase (1-2 h after injection), when most of the label was redistributed away from the growth cones and into the proximal processes of the CC. In culture, HmLAR2-transfected COS cells were found to selectively bind the Fc-recombinant protein, but not Fc-tagged proteins bearing other closely related receptor ectodomains, demonstrating that the HmLAR2 ectodomain is capable of interacting homophilically. Together, our observations demonstrate that the rPTP HmLAR2 is critically involved in CC process extension through its participation in the regulation of growth cone structure, migration, and navigation. Moreover, since our experiments also indicate that HmLAR2 can bind to itself, we hypothesize that HmLAR2 has a key role in the mechanism of mutual repulsion that maintains the parallel growth of adjacent CC projections.

RNAi of the receptor tyrosine phosphatase HmLAR2 in a single cell of an intact leech embryo leads to growth-cone collapse.

Receptor protein tyrosine phosphatases (RPTPs) are important for growth-cone migration [1-5], but their specific roles have yet to be defined. Previously, we showed that the growth cones of the Comb cell, an embryonic cell in the leech, express high levels of an RPTP called HmLAR2 [6,7]. Here, we report the use of RNA interference (RNAi) to block expression of HmLAR2 in individual Comb cells in the developing embryo. HmLAR2 mRNA levels were reduced in the soma, processes and growth cones of Comb cells injected with double-stranded RNA (dsRNA) for HmLAR2, but no decrease was detected when control dsRNAs were injected. Consistent with this observation, the level of phosphotyrosine increased significantly in the growth cones of Comb cells injected with HmLAR2 dsRNA. Within 24 hours, the growth cones of treated cells showed a distinct collapsed phenotype, with sharp reductions in lamellipodial surface area and in numbers of filopodia. These experiments indicate a key role for LAR-like RPTPs in maintaining the integrity of the growth cone.

The role of a LAR-like receptor tyrosine phosphatase in growth cone collapse and mutual-avoidance by sibling processes.

Among the many cells or parts of cells that a growth cone may encounter during its embryonic migrations are other processes or parts of its parent cell. Such an event can be expected to be relatively frequent in the genesis of neuronal arbors, for instance, where the density of innervation of a target region can be quite high. Few experimental studies have addressed the very interesting question of whether a process "recognizes" siblings in some unique way, in a manner that can be distinguished from, say, how it interacts with unrelated cells. One example can be found in the leech, where sibling branches in the terminal fields of identified mechanosensory cells avoid each other strictly while permitting some significant continuing contact and overlap with homologues, a phenomenon that has been dubbed "self-avoidance." Another example has been reported in cultured Helisoma neurons, where severing a branch of a neuron allows sibling neurites to form electrical junctions with it, although normally sibling neurites do not do so. In both of these instances, coincidental activity was proposed as one means to achieve recognition of self and as possibly leading to the blocking of a continuing interaction among the parts, although alternative explanations were indeed considered possible.

Maintaining health in well older adults: initiatives for schools of nursing and The John A. Hartford Foundation for the 21st century.

In the past century, there has been a substantial increase in the number of older Americans and an increase in their life expectancy at birth. These trends will continue over the next century, marked by further increases in active life expectancy and marked changes in the racial and ethnic composition of the older population. While nursing has traditionally focused on the care of frail older individuals, most older adults--well older adults--enjoy a relatively high level of health and function. In this article, well older adults are defined as those with the physical, mental, social, and spiritual function or resources to meet the needs of everyday living. Recommendations for improving care of well older adults are provided, including reconceptualizing ways of thinking, expanding practice initiatives, building the science of nursing research in geriatrics and gerontology, developing education and training opportunities, and rethinking individual safety within the context of autonomy.

The leech receptor protein tyrosine phosphatase HmLAR2 is concentrated in growth cones and is involved in process outgrowth.

Developing neurons extend long processes to specific distal targets using extracellular molecules as guidance cues to navigate through the embryo. Growth cones, specialized structures at the tip of the extending processes, are thought to accomplish this navigation through receptors that recognize guidance cues and modulate growth accordingly. In Drosophila, several receptor tyrosine phosphatases (rPTPs), including DLAR, have been shown to participate in directing neurite outgrowth. As yet, however, it is not known how rPTPs act to affect navigation. To gain insight into the mechanisms of rPTP-mediated outgrowth guidance, we have investigated the role of HmLAR2, a Hirudo medicinalis homologue of DLAR, in process outgrowth. HmLAR2 is expressed by, among other cells, a transient neuron-like template cell, the Comb cell. Here we present evidence that HmLAR2 protein becomes concentrated within their growth cones at a stage when C cell processes undergo rapid outgrowth. When antibodies raised against the extracellular domain of HmLAR2 were injected into intact embryos, they bound specifically to the C cell surface at growth cones and along processes and caused the partial internalization of HmLAR2 receptors. Moreover, the C cell processes were found to project aberrantly, to deviate from their normally highly regular trajectories and to extend shorter distances in the presence of the antibodies. We propose that HmLAR2 is required by the C cell for guidance and extension and suggest that it functions via its ectodomain to transduce extracellular guidance cues.

Two receptor tyrosine phosphatases of the LAR family are expressed in the developing leech by specific central neurons as well as select peripheral neurons, muscles, and other cells.

Receptor protein tyrosine phosphatases (rPTPs) are thought to play a crucial role in neuronal development, particularly in pathfinding by growing processes. We have cloned and sequenced two Hirudo medicinalis rPTPs that are homologous to the Drosophila and vertebrate rPTPs of the Leukocyte common antigen-related (LAR) subfamily. These Hirudo rPTPs, HmLAR1 and HmLAR2, are products of different, homologous genes, both containing two tandem intracellular phosphatase domains and ectodomains with three tandem Ig domains and different numbers of tandem fibronectin type III (FIII) domains. They are expressed in distinct patterns during embryogenesis. HmLAR1 mRNA is expressed by a subset of central and peripheral neurons and by several peripheral muscular structures, whereas HmLAR2 mRNA is expressed by a different subset of central neurons and by the peripheral, neuron-like Comb cells. HmLAR1 and HmLAR2 proteins are located on the neurites of central neurons. In addition, HmLAR2 is expressed on the cell body, processes, and growth cones of the Comb cells. Because of their CAM-like ectodomains and homology to proteins known to be involved in pathfinding and because they are expressed by different subsets of neurons, we hypothesize that HmLAR1 and HmLAR2 participate in navigational decisions that distinguish the sets of neurons that express them. Furthermore, we hypothesize that HmLAR2 is also involved in setting up the highly regular array of parallel processes established by the Comb cells. Lastly, we propose that the HmLAR1 ectodomain on peripheral muscle cells plays a role in target recognition via interactions with neuronal receptors, which might include HmLAR1 or HmLAR2.

Serotonin depletion after prolonged chlorpromazine treatment in a simpler model system.

1. Prolonged exposure of the pond snail Lymnaea stagnalis to micromolar concentrations of chlorpromazine (CPZ) results in marked changes in the serotonin (5-HT) content of the central nervous system. 2. High-performance liquid chromatography with electrochemical detection indicates that levels of 5-HT, but not those of dihydroxyphenyl-alanine (DOPA), dopamine or norepinephrine, were significantly decreased (e.g., to less than 40% of normal after 30 days of exposure to 1 microM CPZ in the bathing water). 3. Glyoxylate-induced fluorescence was depressed to undetectable levels in central, serotonergic neurons. 4. Performance of 5-HT-dependent motor behaviors was impaired. 5. The present results, in accord with earlier studies on the effects of chronic exposure to haloperidol, suggest that previously overlooked mechanisms of monoamine downregulation may contribute to long-term effects of antipsychotic drugs.

Modulation of in vivo neuronal sprouting by serotonin in the adult CNS of the snail.

1. During in situ recovery from a lesion to the cerebrobuccal connective (CBC) in the snail Achatina fulica, neurons of the buccal ganglia undergo extensive regeneration and sprouting as assessed by axonal dye-fillings of the CBC. 2. These changes are preceded by the distal degeneration of severed fibres from the serotonergic metacerebral giant neuron (MCG), which results in the depletion of serotonin (5-HT) in the ipsilateral buccal ganglion. We have investigated the potential role of this depletion in causing some of the ensuing neuroplastic events. 3. Pharmacological depletion of 5-HT using either 5,7-dihydroxtryptamine or p-chlorophenylalanine in normal, unlesioned animals was found to produce supernumerary neuronal labelling similar to that seen following a lesion. 4. Systemic daily injections of 5-HT were found to partly suppress the sprouting response following the CBC lesion. For example, the contralateral, uninjured MCG which is normally induced by the lesion to sprout novel projections into the denervated ganglion, is suppressed from doing so by the 5-HT treatment. 5. These growth inhibiting effects of 5-HT upon the contralateral MCG could be antagonized by the prior administration of the 5-HT receptor blocker cyproheptadine, suggesting a specific receptor mediated action. 6. We suggest that 5-HT may play a role in governing the state of neuronal outgrowth in vivo in the CNS of the adult snail, as has been suggested by early development and neuronal cultural studies.

Tyrosine hydroxylase-negative, dopaminergic neurons are targets for transmitter-depleting action of haloperidol in the snail brain.

1. The effects of long term administration of micromolar concentrations of the D2 antagonist haloperidol upon monoaminergic neurons in the snail Lymnaea stagnalis was investigated. 2. Treatment by bath application with 0.5-2.0 micromolar haloperidol, caused a significant, continuous depletion of dopamine levels in the nervous system as revealed by high performance liquid chromatography. 3. A transient depletion of serotonin was also observed, but DOPA and norepinephrine levels were unaffected. Similar depletion of dopamine was observed after the land snail, Achatina fulica, was injected with haloperidol on each of 4 consecutive days. 4. The depletion of dopamine as revealed with glyoxylate-induced fluorescence in Lymnaea appears to be restricted to a subpopulation of catecholaminergic neurons which are immuno-negative for tyrosine hydroxylase, the synthetic enzyme responsible for the conversion of tyrosine to DOPA. 5. The results thus demonstrate a depleting action of low micromolar doses of chronic haloperidol on specific subsets of dopaminergic neurons and a novel preparation for studying catecholaminergic mechanisms operating across the animal kingdom.

Mode of action of antipsychotic drugs: lessons from simpler models.

The monoaminergic system of the pond snail Lymnaea stagnalis changed markedly following prolonged exposure to chlorpromazine (CPZ). HPLC-ED indicated that levels of serotonin (5-HT), but not those of dopamine, were significantly decreased (e.g., to less than 40% after 30 days of treatment with 1 microM CPZ). Glyoxylate-induced fluorescence was depressed to undetectable levels in selected subpopulations of 5-HT neurons. Performance of 5-HT-dependent motor behaviors was impaired, and a considerably decreased firing activity was observed in affected 5-HT neurons. The present results, in accord with past ones with haloperidol, suggest that a previously overlooked mechanism of monoamine down-regulation may contribute to affects of antipsychotic drugs.

Morphological changes and functional recovery following axotomy of a serotonergic cerebrobuccal neurone in the land snail Achatina fulica.

We have examined an identified serotonergic neurone in Achatina fulica and described the normal morphological and physiological characteristics of this cell. Injury-induced changes in this neurone following in vivo recovery are described and compared with in vitro gastropod models of regeneration. Nickel-lysine and biocytin dye-fills of the metacerebral giant (MCG) neurone, together with serotonin-like immunoreactivity, revealed an extensive innervation of the ipsilateral buccal ganglion, much greater than that previously reported. Labelled MCG fibres were seen to ramify throughout the ganglion, providing extensive neuropilar innervation. Serotonin-immunoreactive fibres were seen not only within the neuropile but also within the cell body layer of the buccal ganglia, surrounding many of the cell bodies with varicose fibres. Dye-fills also revealed a minor contralateral buccal innervation not previously described. This view of a predominantly ipsilateral innervation of the buccal ganglia by the MCG was supported by electrophysiological measurements. The ipsilateral buccal follower cell B1 displayed an increase in depolarization in response to repeated trains of action potentials to the MCG, whereas the contralateral B1 showed only a weak depolarization in response to the identical stimuli. Following a crush to the cerebral-buccal connective (CBC), the MCG rapidly regenerated its injured projections, displaying both morphological and physiological recovery within 5-10 days. The original, severed fibres of the MCG were, however, replaced by a multitude of smaller neurites, which persisted for up to 3 months (the longest recovery period examined). Despite this morphological difference between normal and regenerated fibres, the MCG re-established functionally equivalent connections upon B1. In contrast with previous in vitro studies using gastropods, serotonin-like immunoreactivity revealed that severed distal fibres from the MCG rapidly degenerated (2-6 days), resulting in a transient unilateral depletion of serotonin in the buccal ganglia. We suggest that this loss of serotonin in the lesioned ganglion may play a functional role in regeneration, as has been suggested in vitro.

Serotonin depletors, 5,7-dihydroxytryptamine and p-chlorophenylalanine, cause sprouting in the CNS of the adult snail.

The effects of 5,7-dihydroxytryptamine (5,7-DHT) and p-chlorophenylalanine (PCPA) on neuronal morphology were investigated in Achatina fulica by backfilling the cerebrobuccal connective with nickel-lysine. Backfilling 21 days following injections of either 5,7-DHT or PCPA revealed supernumerary staining of fibers in different pathways of the cerebral and buccal ganglia and novel staining of somata in the cerebral ganglia. HPLC measurements confirm that drug treatments led to a 30-46% depletion of serotonin (5-HT) in the buccal ganglia. These results support the role suggested for 5-HT as a neuritogenic modulator and additionally advise caution in the use of pharmacological depletors in studies examining serotonergic function.

The state of quality management in HMOs.

Interest in total quality management (TQM) in health care is increasing rapidly as leaders search for positive strategies to deal with both costs and quality. We conducted a national telephone survey of 200 HMO medical directors, 451 physicians affiliated with managed care organizations, and 550 corporate health benefits officers to obtain their reports of the potential contributions, the current interest in, and the degree of implementation of TQM activities in their own managed care systems. A large majority of all respondents felt that TQM could help greatly in health care, as it has in other industries. Among HMO medical directors, 81% claimed that their organizations placed "a great deal of emphasis" on TQM, while only 34% of physicians and 35% of benefits officers agreed. Areas of implementation claimed by the HMOs tended to involve abstract matters such as mission statements and leadership commitment, while technical components of TQM, including data systems, training, and supplier management, appeared much less well-developed. The managed care organizations surveyed seem to be in the early phases of commitment to TQM. To achieve the results seen in other industries, these organizations will need much deeper levels of investment, understanding, and deployment of TQM than this survey reveals.

The neglected medical history and therapeutic choices for abdominal pain. A nationwide study of 799 physicians and nurses.

A random national sample of 501 physicians and 298 nurse practitioners was presented a case vignette describing a patient with epigastric pain and endoscopy showing diffuse gastritis. Respondents were encouraged to request further information and then were asked for recommendations. History available if requested included substantial use of aspirin, coffee, cigarettes, and alcohol, and severe psychosocial stress. More than one third of the physicians chose to initiate therapy without seeking a relevant history. Nearly half of all physicians indicated that a prescription would be the single most effective therapy; 65% recommended a histamine antagonist. By contrast, only 19% of nurse practitioners opted to treat without taking further history; the nurse sample asked an average of 2.6 questions vs 1.6 for physicians; only 20% of the nurses recommended a prescription medication. These findings raise concerns about the adequacy of basic history taking in this setting and the underuse of nonpharmacologic approaches in favor of excessive reliance on prescription drugs, even when not indicated by clinical circumstances.

Axonal regeneration and sprouting following injury to the cerebral-buccal connective in the snail Achatina fulica.

Axonal sprouting and regeneration were studied in the land snail Achatina fulica following a unilateral crush to the cerebral-buccal connective. Both normal projection patterns and changes induced by injury were examined with axonal filling techniques. As expected, most staining was lost shortly after the crush when filling across the lesion site. Much of this decrease is attributable to the direct disruption of fiber pathways, but evidence also indicates that a limited amount of retraction of some neurites occurred during the first week. A subsequent, gradual increase in the numbers of stained elements culminated in supernumerary counts of fibers in many pathways and in some novel labeling of cell bodies. Maximum numbers of supernumerary fibers usually occurred 21-28 days after the lesion. Most of these extra neurites and cell bodies subsequently disappeared, and by day 35 the appearance of projections generally returned to within the ranges observed in normal, unlesioned animals. Together the results demonstrate the extent of neuritic regeneration, sprouting, and retraction that occurs in vivo within the gastropod nervous system following injury. The study also indicates the usefulness of such in vivo approaches to understand the long-term processes that contribute to the restoration of morphological and functional integrity.

Clinical decision-making in the evaluation and treatment of insomnia.

We interviewed a representative random sample of 501 office-based general physicians and 298 nurse practitioners to evaluate their approach to the symptoms of insomnia. Clinicians were presented with a standard case of a patient complaining of difficulty sleeping, with the age of the patient depicted as either 37 years or 77 years. Historical information was provided in response to practitioners' questions. In evaluating the history, physicians asked an average of 2.5 questions and were most likely to ask about psychologic problems. Only 47% of the physicians who were presented with the elderly case vignette elicited a sleep history. By contrast, nurse practitioners asked an average of 3.2 questions, and 60% of them took a sleep history. Despite many possible non-pharmacologic therapies for the patients presented, 46% of physicians identified a prescription medication as the single most effective therapy for the older patient, compared with 17% of nurse practitioners. These findings suggest that physicians place inadequate emphasis on history-taking in the evaluation of insomnia and resort to the use of psychoactive drugs even when non-pharmacologic approaches might be more effective.

The use of epidural morphine in patients undergoing total knee arthroplasty.

Sixty-six patients undergoing total knee arthroplasty were offered epidural morphine as a method of postoperative analgesia. Of the 66 patients, 50 completed the minimum protocol of 3 days in a special epidural monitoring unit and were thus available for study. In this study group, 86% stated that they obtained 75-100% relief of pain with each epidural injection. Greater than 90% of the patients rated the overall experience with epidural analgesia as excellent or good. Ninety percent stated that they would choose epidural morphine analgesia again if given the choice. Nausea and vomiting were the most common adverse effects, occurring in 34%. One patient experienced respiratory depression, which was reversed with Narcan. The most frequent complaint related to the procedure itself was the use of an apnea monitor; 18% of the patients considered this monitoring device intolerable. The progress of total knee arthroplasties in the epidural unit was monitored by range of motion achieved. At 72 hours the average motion was 10 degrees-87 degrees and at the end of the hospital stay was 6 degrees-98 degrees. The total hospital bill for epidural morphine analgesic patients was $469 more than for a conventional arthroplasty patient, though the mean duration of hospital stay was 1.7 days less for the epidural morphine patients. Epidural morphine provided excellent but inconsistent postoperative pain relief. When relief was present, aggressive in-house rehabilitation could be instituted, and a shorter overall hospital stay was achieved when compared with conventional analgesia. Nonetheless, the related adverse effects and inconsistent pain relief on many patients may preclude the use of epidural morphine as a single postoperative analgesic agent.