High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A.

Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.

Routine obstetrical interventions: research agenda for the next decade.

There are many interventions performed as a part of the active management of labor and birth that have remained unchanged over the years. Separating ritual from beneficial nursing care can guide the development of a research agenda. The agenda for the next 10 years can address some of the gaps remaining in the evidence-based foundation for routine interventions used during labor and birth. The gaps identify areas where unanswered questions prevent optimal care from occurring. These unanswered questions include optimal time for epidural administration; management of maternal movement during labor when routine interventions make this difficult; changing the practice of immediate, closed glottis coached pushing at 10 cm; continuous electronic fetal monitoring; routine administration of intravenous fluids; and finally, the use of oxytocin as augmentation or induction of labor.

An evidence-based consensus statement on the role and application of endosonography in clinical practice.

BACKGROUND: Endoscopic ultrasonography (EUS) has evolved over the past 20 years with the emergence of novel diagnostic and therapeutic indications. Our goal was to identify the best evidence supporting the use of EUS. MATERIALS AND METHODS: A six-step approach was employed to develop recommendations using accepted methodology. Twenty-two experienced endosonographers identified topics and reviewed studies using MeSH (medical subject headings) terminology and free text in PubMed. Medline and society abstracts were reviewed if necessary. The quality of evidence, the strength of recommendations, and level of consensus were graded and voted on. RESULTS: Consensus was reached for several clinical scenarios for which the impact of EUS findings was supported by a high level of evidence. These included diagnosis and staging of esophageal cancer, differential diagnosis of subepithelial lesions, thickened gastric folds, assessment of peritoneal involvement in patients with gastric cancer, mucosa-associated lymphoid tissue lymphoma, diagnosis of common bile duct/gallbladder stones, diagnosis of chronic pancreatitis, differential diagnosis of a solid mass in patients with chronic pancreatitis, differential diagnosis of pancreatic cyst, rectal cancer staging, and diagnosis and staging of non-small-cell lung cancer. The recommendations were adopted by the Brazilian Society of Gastrointestinal Endoscopy. Several indications continue to emerge and require additional validation.

The XLMR gene ACSL4 plays a role in dendritic spine architecture.

ACSL4 is a gene involved in non-syndromic X-linked mental retardation. It encodes for a ubiquitous protein that adds coenzyme A to long-chain fatty acids, with a high substrate preference for arachidonic acid. It presents also a brain-specific isoform deriving from an alternative splicing and containing 41 additional N-terminal amino acids. To start to unravelling the link between ACSL4 and mental retardation, we have performed molecular and cell biological studies. By retro-transcription polymerase chain reaction analyses we identified a new transcript with a shorter 5'-UTR region. By immunofluorescence microscopy in embryonic rat hippocampal neurons we report that ACSL4 is associated preferentially to endoplasmic reticulum tubules. ACSL4 knockdown by siRNAs in hippocampal neurons indicated that this protein is largely dispensable for these cells' gross architectural features (i.e. axonal and dendritic formation and final length) yet it is required for the presence of normal spines. In fact, reduced levels of ACSL4 led to a significant reduction in dendritic spine density and an alteration in spine/filopodia distribution. The possible mechanisms behind this phenotype are discussed.

Caring for the extremely obese woman during pregnancy and birth.

This article describes the special care needed by the pregnant woman who is extremely obese. Many pregnant women who are extremely obese have underlying medical conditions, and a multidisciplinary, coordinated approach to their care involving anesthesia providers, physicians, and the nursing staff is needed to develop a detailed plan for vaginal and cesarean births. Such an approach, begun preconceptionally or during pregnancy, can enable care to be delivered smoothly and safely and should include an evaluation of the unit's equipment and furniture to determine if they are appropriate for obese persons. Equipment that should be evaluated for size and weight limits include beds, operating room tables, commodes, wheelchairs, scales, walkers, blood pressure cuffs, transfer devices, and intermittent pneumatic compression devices.

Effects of oxytocin-induced uterine hyperstimulation during labor on fetal oxygen status and fetal heart rate patterns.

OBJECTIVE: The objective of the study was to evaluate effects of oxytocin-induced hyperstimulation on fetal oxygen saturation and fetal heart rate patterns. STUDY DESIGN: Uterine activity of 56 women was evaluated retrospectively for hyperstimulation lasting 30 minutes using 2 definitions: group 1: 5 or more but less than 6 contractions in 10 minutes (n = 102, 30-minute periods); group 2: 6 or more contractions in 10 minutes (n = 56, 30-minute periods). Fetal oxygen saturation and heart rate patterns during each period and the preceding 30 minutes of less than 5 contractions in 10 minutes were compared. RESULTS: Hyperstimulation was associated with significant oxygen desaturation: (group 1 = 10.68 [20%] decrease from 52.14 to 41.46; P < .001); group 2 = 15.34 [29%] decrease from 52.02 to 36.68: P < .001) and significantly more nonreassuring fetal heart rate characteristics, compared with normal uterine activity. CONCLUSION: Hyperstimulation is associated with negative effects on fetal status. The more contractions in 30 minutes, the more pronounced the effect.

Spreading in narrow channels.

We study a lattice model for the spreading of fluid films, which are a few molecular layers thick, in narrow channels with inert lateral walls. We focus on systems connected to two particle reservoirs at different chemical potentials, considering an attractive substrate potential at the bottom, confining sidewalls, and hard-core repulsive fluid-fluid interactions. Using kinetic Monte Carlo simulations we find a diffusive behavior. The corresponding diffusion coefficient depends on the density and is bounded from below by the free one-dimensional diffusion coefficient, valid for an inert bottom wall. These numerical results are rationalized within the corresponding continuum limit.

[SOSIA classification of the frail elderly in nursing homes of region of Lombardy]. / La Classificazione SOSIA degli anziani ospiti delle residenze sanitario-assistenziali lombarde.

Since 2001, the region of Lombardy has accreditated nursing homes named R.S.A. "Residenza Sanitario-Assistenziale", which make up Italy's principal RSA network with the annual turnover of approximately 60,000 people. The most noteworthy element of the reform introduced is a concentration on resident's frailty rather than disability. This is assessed by using SOSIA, a form for intermediate observation of assistance. Residents are classified into eight classes of frailty, called isofrailty classes of SOSIA, which are differentiated by how compromised their motor and cognitive skills are, and by the presence of comorbidity. The study presents the methodology used to identify and estimate cut-offs of three indicators employed in SOSIA classification. It also discusses their characteristics versus other evaluation systems, such as Resource Utilization Group RUG-III and Autonomie Gerontologique--Groupes Iso-Resources AGGIR.

Nurse-physician communication during labor and birth: implications for patient safety.

OBJECTIVE: To describe communication between nurses and physicians during labor within the context of the nurse-managed labor model in community hospitals and its relationship to teamwork and patient safety. DESIGN: Multicenter qualitative study involving focus groups and in-depth interviews. SETTING: Labor and birth units in 4 Midwestern community hospitals. PARTICIPANTS: 54 labor nurses and 38 obstetricians. METHODS: Focus groups and in-depth interviews were conducted using open-ended questions. Data were analyzed using inductive coding methods to gain understanding from the perspective of those directly involved. MAIN OUTCOME MEASURES: Description of interdisciplinary interactions during labor. RESULTS: Nurses and physicians shared the common goal of a healthy mother and baby but did not always agree on methods to achieve that goal. Two clinical situations critical to patient safety (fetal assessment and oxytocin administration) were frequent areas of disagreement and sources of mutual frustration, often leading to less than optimal teamwork. Minimal communication occurred when the mother and fetus are doing well, and this seemed to be purposeful and considered normal. Physicians and nurses had distinct opinions concerning desirable traits of members of the other discipline. CONCLUSIONS: Interdisciplinary communication and teamwork could be improved to promote a safer care environment during labor and birth.

Disaster planning: are gerontological nurses prepared?

This article is a review of basic, but important information about disaster planning considerations for older populations. The recent hurricane experiences in the South confirmed how critical this planning is, and the importance of early evacuation in saving lives. This is highlighted when comparing the official responses during Hurricane Katrina and Hurricane Rita. Advance preparations result in more control and safety in a dangerous situation. In New Orleans, the delay in evacuation of older adults resulted in panic and confusion, without an easy solution. Those who could not be easily evacuated remained, sometimes at great cost. Gerontological nurses need to advocate for the planning and resources that would assist older adults in a safe and early evacuation if indicated. Adequate support personnel, transportation, and pre-positioned supplies should all be in place for use following a disaster event. Rescue is more costly than evacuation, in both resources and human suffering, and places both rescuers and victims at risk. Each individual, facility, and community needs disaster and evacuation plans that are widely disseminated in advance of any disaster. These plans must address the unique needs of older adults. Hurricane Katrina demonstrated the importance of evacuation before the impact of disaster. When individuals have advance notice of an impending disaster, evacuation can be conducted in a more orderly, planned way to get older adults to safety. Hurricane Rita proved that even advance evacuation is not problem-free, but is well worth the effort. Each facility needs to be prepared to be self-sustaining, to "shelter in place" for at least 72 hours. This requires having the resources and supplies to support at least minimal safe function. However, facilities in locations that could be isolated for longer periods of time should consider having even more supplies in reserve. Recent events may prompt gerontological nurses to ask themselves, their facilities, and communities--Are we prepared?

Terrorism and the pregnant woman.

Pregnant women and their infants are vulnerable, during and following a terrorist event. The threat poses a dual challenge: assessment and treatment of the trauma patient, and assessment and treatment of the pregnant woman. Some injuries in the pregnant woman are obvious; some injuries may not be easily observable. Obtaining an obstetric history coupled with careful nursing assessments ensure prompt and appropriate emergency treatment. Obstetricians, certified nurse midwives, nurse practitioners, and perinatal nurses are uniquely qualified to perform these assessments because of their understanding of the changes in maternal physiology and anatomy during pregnancy. The pregnant woman can sustain injuries owing to trauma or exposure to biological, chemical, or radiological agents. Following trauma, assessment of the gravid uterus is needed, as well as the use of traditional diagnostic, pharmacologic, or resuscitative procedures. The perinatal care provider must be familiar with the hematological changes that normally suppress any immune response to the fetus and how these protective changes increase the risk from biological agents, such as anthrax and smallpox.

Efficacy of intrauterine resuscitation techniques in improving fetal oxygen status during labor.

OBJECTIVE: To evaluate the efficacy of 3 common intrauterine resuscitation techniques used during labor. METHODS: Intrauterine resuscitation techniques were prospectively evaluated in healthy women during labor. Forty-two women were randomized to either a 500-mL or 1,000-mL intravenous (IV) fluid bolus over 20 minutes. Fifty-one women were randomized to 1 of 6 position sequences including supine with the head elevated 30 degrees , left lateral and right lateral for 15 minutes each in succession. Forty-nine women received 10 L/min of oxygen (O(2)) via nonrebreather face mask for 15 minutes. Differences in fetal oxygen saturation (FSpO(2)) were evaluated before, during, and after each intervention. RESULTS: An IV fluid bolus of 1,000 mL had a greater effect on FSpO(2) than an IV fluid bolus of 500 mL (500 mL: mean increase 3.7; 1,000 mL: mean increase 5.2; P = .05). Fetal oxygen saturation was higher in a lateral position (left mean 48.3%, right mean 47.7%) than in a supine position (mean supine 37.5%, P = .03). Oxygen administration increased FSpO(2) (mean increase 8.7, P = .03). The effect persisted for more than 30 minutes after the O(2) was discontinued (P = .03). For fetuses with FSpO(2) less than 40% before maternal O(2) administration, the increase was greater (mean increase 11.4) than for those with FSpO(2) of 40% or greater (mean increase 7.6, P = .03). CONCLUSION: An intravenous fluid bolus of 1,000 mL, lateral positioning, and O(2) administration at 10 L/min via nonrebreather face mask are effective in increasing FSpO(2) during labor.

Effects of immediate versus delayed pushing during second-stage labor on fetal well-being: a randomized clinical trial.

BACKGROUND: Although there are two methods of caring for women with epidural anesthesia during second-stage labor (coached closed-glottis pushing immediately at 10-cm cervical dilation or delayed pushing until the woman feels the urge to push, passive fetal descent, and encouragement of open-glottis pushing when the woman has the urge to push), there are limited data concerning which method is most optimal for fetal well-being. OBJECTIVE: To evaluate effects on fetal well-being, as measured by fetal oxygen saturation, of two different methods of second-stage labor nursing care for women with epidural anesthesia. METHODS: Forty-five nulliparous women who had progressed to the second stage were randomized to 1 of 2 groups (immediate or delayed pushing). Fetal oxygen saturation was continuously monitored and values at 10 cm, initiation of pushing and immediately prior to birth, as well as the amount of time that fetal oxygen saturation values were abnormal (< or =30%) were compared between groups. Also evaluated were additional measures of fetal well-being such as fetal heart rate patterns, Apgar scores, and umbilical cord blood gases and maternal outcomes including length of labor, method of birth, and perineal status. RESULTS: There was a significant difference between groups in fetal oxygen desaturation during the second stage (immediate: M = 12.5; delayed: M = 4.6) F(1, 43) = 12.24, p = .001, and in the number of > or =2-min epochs of fetal oxygen saturation <30% (immediate: M = 7.9; delayed: M = 2.7), F(1, 43) = 6.23, p = .02. There were more variable decelerations of the fetal heart rate in the immediate pushing group (immediate: M = 22.4; delayed: M = 15.6) F(1, 43) = 5.92, p = .02. There were no differences in length of labor, method of birth, Apgar scores, or umbilical cord blood gases. Women who pushed immediately had more perineal lacerations (immediate: n = 13; delayed: n = 5) chi(1, N = 45) = 6.54, p = .01. DISCUSSION: Delayed pushing results in less fetal oxygen desaturation and less > or =2-min epochs of fetal oxygen saturation <30% during second-stage labor than the immediate pushing method; thus, delayed pushing is more favorable for fetal well-being as measured by fetal oxygen saturation.

Role of the HLA-DP Glu 69 and the TNF-alpha TNF-alpha 2 gene markers in susceptibility to beryllium hypersensitivity.

Berylliosis is an environmental chronic inflammatory disorder of the lung caused by inhalation of beryllium dusts, characterized by the accumulation of CD4+ T cells and macrophages in the lower respiratory tract. Beryllium presentation to CD4+ T cells from patients with berylliosis results in T cell activation and these Be-specific CD4+ T cells undergo clonal proliferation and Th1-type cytokine production such as interleukin-2, interferon-gamma and tumor necrosis factor-alpha. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with major histocompatibility gene and the TNF-alpha gene. The HLA-DP glutamic 69 residue was shown to be the MHC genetic marker associated with disease susceptibility; furthermore the TNF-alpha TNFA-308*2 allele was found to be independently associated with HLA-DP Glu69 in the determination of berylliosis risk.

How do expert labor nurses view their role?

OBJECTIVE: To examine how expert perinatal nurses in a nurse-managed labor model view their role in caring for mothers during labor and birth. DESIGN: Focus group methodology. Data were analyzed using inductive coding methods to gain understanding from the perspective of those providing the care. SETTING: Labor and birth units in four large Midwestern medical centers. PARTICIPANTS: Fifty-four expert labor nurses. INCLUSION CRITERIA: 5 years experience in nursing care during labor and birth in institutions where nurse-managed labor was the predominant practice model. RESULTS: Four common themes related to nursing roles were identified. These included knowing the labor process and the intuitive nature of nursing care provided by expert labor nurses based on years of experience, knowing the woman and letting her body guide labor, advocacy for laboring woman, and the autonomous nature of the nurse-managed labor model. CONCLUSIONS: Expert labor nurses developed a keen sense of intuitive knowledge based on their years of experience. They reported using hands-on high-touch supportive care techniques with the potential to affect labor and birth outcomes. Autonomy is perceived as a key component of practice within the nurse-managed labor model.

Enoxaparina como alternativa antitrombótica para la cirugía en pacientes de alto riesgo tromboembólico crónicamente anticoagulados con dicumarínicos / Enoxaparinas an alternative to antocoagulant therapy in hight risk patients under chronic treatment with vitamin K antagonists

En la actualidad no existe un criterio uniforme para el manejo anticoagulante perioperatorio de los pacientes con alto riesgo tromboembólico y crónicamente anticoagulados con dicumarínicos. Se ha propuesto el uso de las HBPM en reemplazo de la heparina no fraccionada pero la experiencia publicada es escasa y no hay un consenso sobre la dosis y el momento adecuado para reiniciar la anticoagulación en el período post quirúrgico, especialmente en cirugía mayor. Nuestro objetivo fue evaluar la efectividad y seguridad de la enoxaparina 1 mg/kg SC cada 12 horas en el manejo perioperatorio de pacientes con alto riesgo tromboembólico. Resultados: 48 pacientes (edad promedio: 70 años, 32 hombres) anticoagulados por RVM 64,5 porciento y FA con antecedente de embolia o trombo auricular en 35,5 porciento. El 45 porciento requirió suspender los AO por una cirugía programada, 33 porciento por cirugía odontológica, 16 porciento cateterismo cardíaco y 6 porciento por una biopsia. Los pacientes suspendían la AO 3 a 5 días previos al procedimiento y lo reemplazaban por enoxaparina. la dosis promedio de enoxaparina fue de 80 mg cada 12 horas. El 92 porciento de los pacientes reinició AO en las primeras 24 horas de la cirugía. No se detectaron eventos trombóticos hasta 1 mes de la cirugía. Cuatro pacientes presentaron hemorragias, 3 sangrados menores y 1 sangrado mayor que requirió múltiples transfusiones. Conclusión: La enoxaparina puede ser una alternativa antitrombótica eficaz en pacientes con alto riesgo tromboembólico y permitirá mediante 1 o 2 dosis diarias (ajustadas al peso) el manejo ambulatorio con un bajo índice de sangrado

HLA-DP-unrestricted TNF-alpha release in beryllium-stimulated peripheral blood mononuclear cells.

Berylliosis is a granulomatous disorder of the lung caused by inhalation of beryllium (Be) and dominated by the accumulation of CD4+ T-helper (Th)1 memory T-cells proliferating in response to Be in the lower respiratory tract. Two gene markers have been associated with susceptibility to berylliosis: 1) the human leucocyte antigen (HLA)-DP gene whose allelic variants, carrying glutamate in position 69 of the beta-chain (HLA-DPGlu69), can bind Be directly and present it to interferon (IFN)-gamma releasing Th1 T-cell clones from patients with berylliosis; and 2) the cytokine gene tumour necrosis factor (TNF)-alpha which has been shown to increase berylliosis risk independent of HLA-DPGlu69. In order to determine whether TNF-alpha release was triggered by Th1 T-cell activation by Be stimulation in the context of HLA-DPGlu69 molecules, the proliferation of BeSO4-stimulated blood mononuclear cells and the release of IFN-gamma, TNF-alpha, RANTES (regulated on activation normal T-cell expressed and secreted), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4, IL-6, IL-8, IL-10 and IL-12 by BeSO4-stimulated blood mononuclear cells was quantified in 11 individuals with berylliosis using an anti-HLA-DP antibody as a probe for HLA-DP restricted T-cell activation. While proliferation and IFN-gamma release were completely abrogated by HLA-DP inhibition (inhibition with anti-HLA-DP monoclonal antibody (mAb): 88+/-16 and 77+/-16%, respectively; anti-HLA-DR: 29+/-38 and 14+/-10%, respectively), the release of TNF-alpha was not (inhibition with anti-HLA-DP mAb: 8.9+/-7.8%). No other cytokine was detected at significant levels. Moreover, Be was able to induce TNF-alpha production in healthy control subjects not exposed to Be in the absence of T-cell proliferation and IFN-gamma production. In conclusion, these data suggest that the tumour necrosis factor-alpha response of mononuclear cells is independent of the activation of beryllium-specific human leucocyte anitgen-DP restricted T-cells, which is consistent with the finding that the tumour necrosis factorA2 and the human leucocyte anitgen-DPGlu69 genetic markers are independently interacting in increasing berylliosis risk.

Plasma membrane ganglioside sialidase regulates axonal growth and regeneration in hippocampal neurons in culture.

It has been long recognized that the ganglioside GM1 plays a role in axonal growth and neuronal differentiation. However, the involvement of plasma membrane GM1 has been difficult to elucidate. This is possible now thanks to the recent cloning of plasma membrane ganglioside sialidase (PMGS), the enzyme responsible for the localized hydrolysis of oligosialogangliosides into GM1. In this work we show that PMGS mRNA and protein levels are high at early developmental stages of the hippocampus and low in adulthood both in vivo and in vitro. We also demonstrate that inhibition of PMGS activity blocks axonal elongation, whereas the increase in PMGS activity dramatically enhances axon growth and accelerates the polarization of cytoskeletal proteins. Finally, we show that axotomy close to the cell body in PMGS overexpressing neurons results in the regrowth of the original axon instead of randomly, as is the case in control neurons. In all, these results imply that PMGS activity through the modulation of GM1 surface levels is an important component of the machinery controlling axonal growth. We hypothesize that increasing PMGS activity in the adult nervous system may be useful to improve regeneration after nerve damage.