Normal expression of the Fanconi anemia proteins FAA and FAC and sensitivity to mitomycin C in two patients with Seckel syndrome

Seckel syndrome is a rare autosomal recessive disorder. The classical presentation includes pre- and postnatal growth deficiency, mental retardation, and characteristic facial appearance. There have been several reports of associated hematological abnormalities and chromosomal breakage, findings suggestive of Fanconi anemia (FA). We tested for these findings in two Arabic patients with this syndrome. We compared the growth profile of lymphoblastoid cells from our patients and their parents with the FA group A cell line HSC72 in the presence and absence of mitomycin C (MMC). By Western analysis, we also determined the expression of FAA and FAC, two FA disease gene products that together account for approximately 80% of FA. Unlike HSC72 cells, cells from the patients were resistant to MMC, and both FAA and FAC proteins were expressed at similar levels in all cell lines. There is an increasing recognition of clinical variability and perhaps genetic heterogeneity in Seckel syndrome. Our results demonstrate that cross-link sensitivity comparable to FA is not a uniform finding in patients with Seckel syndrome.     

The value of deletion analysis for carrier detection in Duchenne muscular dystrophy (DMD)

We performed genetic analysis for carrier detection for several at-risk females in a four-generation Duchenne muscular dystrophy (DMD) pedigree using deletion analysis. We demonstrated that dosage analysis is a suitable alternative method to determine the carrier status of female relatives of DMD patients shown to have a deletion within the DMD gene. Subsequently, we diagnosed an affected male fetus for an at-risk female shown to be a DMD carrier by deletion analysis. The usefulness of deletion and linkage analysis are compared. In this family, linkage analysis was complicated by the unavailability of key family members, two recombination events and by previously undisclosed nonpaternity. We found that dosage analysis was more efficient than linkage for carrier evaluation in this family.     

Functional mapping of the human globus pallidus: contrasting effect of stimulation in the internal and external pallidum in Parkinson's disease

Our objective was to elaborate a functional map of the globus pallidus by correlating the intrapallidal localization of quadripolar electrodes implanted in parkinsonian patients with the clinical effect of the stimulation of each contact. Five patients with L-DOPA-responsive Parkinson's disease presenting severe motor fluctuations and L-DOPA-induced dyskinesias were treated by continuous bilateral high-frequency stimulation of the globus pallidus. The effects of stimulation on parkinsonian disability were tested through each of the four stimulating contacts of each electrode. The anatomical localization of each of the stimulating contacts was determined by confronting the pre- and post-operative magnetic resonance imaging with the anatomical atlas of Schaltenbrand and Wharen.(34) The registration procedure comprised digitization of the atlas, the use of deformation tools to fit atlas sections with magnetic resonance imaging sections, and three-dimensional reconstruction of both the atlas and the magnetic resonance imaging sections. Analysis of the 32 stimulating contacts tested did not reveal a somatotopic organization in the pallidal region investigated but demonstrated that high-frequency stimulation had contrasting effects depending on whether it was applied to the external or the internal pallidum. Akinesia was improved by stimulation of the external pallidum but worsened by stimulation of the internal pallidum. In contrast, parkinsonian rigidity was improved by stimulation of either part of the pallidum. The areas in the internal pallidum where stimulation worsened akinesia were those in which stimulation reduced or suppressed L-DOPA-induced dyskinesias. Conversely, stimulation applied to the external pallidum induced dyskinesias. The fact that rigidity was improved by stimulation of the internal and external pallidum suggests that the neuronal bases of parkinsonian rigidity are different from those of akinesia and dyskinesias. The effect on akinesia and dyskinesias is in agreement with the current model of basal ganglia circuitry(10) if high-frequency stimulation activates rather than inhibits pallidal neurons, a possibility which is very likely since there are marked anatomical, biochemical and electrophysiological differences between the globus pallidus and the subthalamic nucleus.This study demonstrates that high-frequency stimulation of the globus pallidus in parkinsonian patients has contrasting effects depending on whether it is applied to the external or the internal part of this nucleus. The effect on akinesia and dyskinesias suggests that stimulation activates pallidal neurons, a result which challenges the generally accepted concept that high-frequency stimulation inactivates neurons in the region stimulated.     

Bilateral vertebral artery occlusion following cervical spine trauma--case report

A 41-year-old female presented with a rare case of bilateral vertebral artery occlusion following C5-6 cervical spine subluxation after a fall of 30 feet. Digital subtraction angiography showed occlusion of the bilateral vertebral arteries. Unlocking of the facet joint, posterior wiring with iliac crest grafting, and anterior fusion were performed. The patient died on the 3rd day after the operation. This type of injury has a grim prognosis with less than a third of the patients achieving a good outcome.     

The dorsal motor nucleus of the vagus (DMNV) in sudden infant death syndrome (SIDS): Pathways leading to apoptosis

Sudden infant death syndrome (SIDS) remains the commonest cause of death in the post-neonatal period in the developed world. A leading hypothesis is that an abnormality in the brainstem of infants who succumb to SIDS, either causes or predisposes to failure to respond appropriately to an exogenous stressor. Neuronal apoptosis can lead to loss of cardiorespiratory reflexes, compromise of the infant's ability to respond to stressors such as hypoxia, and ultimately a sleep-related death. The dorsal motor nucleus of the vagus (DMNV) is a medullary autonomic nucleus where abnormalities have regularly been identified in SIDS research. This review collates neurochemical findings documented over the last 30 years, including data from our laboratory focusing on neuronal apoptosis and the DMNV, and provides potential therapeutic interventions targeting neurotransmitters, growth factors and/or genes.     

Epidemiology,etiology, and outcomes of in-hospital cardiac arrest in Lebanon

BACKGROUNDIn-hospital cardiac arrest (IHCA) constitutes a significant cause of morbidity and mortality. As data is scarce in the Middle East and Lebanon, we devised this study to shed some light on it to better inform both hospitals and policymakers about the magnitude and quality of IHCA care in Lebanon.METHODSWe analyzed retrospective data from 680 IHCA events at the American University of Beirut Medical Center between July 1, 2016 and May 2, 2019. Sociodemographic variables included age and sex, in addition to the comorbidities listed in the Charlson comorbidity index. IHCA event variables were day, event location, time from activation to arrival, initial cardiac rhythm, and the total number of IHCA events. We also looked at the months and years. We considered the return of spontaneous circulation (ROSC) and survival to discharge (StD) to be our outcomes of interest.RESULTSThe incidence of IHCA was 6.58 per 1,000 hospital admissions (95% CI: 6.09−7.08). Non-shockable rhythms were 90.7% of IHCAs. Most IHCA cases occurred in the closed units (87.9%) (intensive care unit, respiratory care unit, neurology care unit, and cardiology care unit) and on weekdays (76.5%). ROSC followed more than half the IHCA events (56%). However, only 5.4% of IHCA events achieved StD. Both ROSC and StD were higher in cases with a shockable rhythm. Survival outcomes were not significantly different between day, evening, and nightshifts. ROSC was not significantly different between weekdays and weekends; however, StD was higher in events that happened during weekdays than weekends (6.7%vs. 1.9%, P = 0.002). CONCLUSIONSThe incidence of IHCA was high, and its outcomes were lower compared to other developed countries. Survival outcomes were better for patients who had a shockable rhythm and were similar between the time of day and days of the week. These findings may help inform hospitals and policymakers about the magnitude and quality of IHCA care in Lebanon.

In-hospital cardiac arrest (IHCA) constitutes a significant cause of morbidity and mortality.^[1] Based on the American Heart Association’s Get With The Guidelines-Resuscitation (GWTG-R) registry data from 2003 to 2007, the approximated incidence of IHCAs in the United States was 211,000 annually or roughly 6 to 7 cardiac arrests per 1,000 hospital admissions.^[2,3] Data from 2008 to 2017 showed the incidence of IHCA increased to 292,000 annually or 9 to 10 IHCAs per 1,000 hospital admissions.^[1,4] In contrast, data from the United Kingdom National Cardiac Arrest Audit showed an incidence of 1.6 IHCAs per 1,000 hospital admissions in the United Kingdom from 2011 to 2013.^[1] Despite progress in resuscitation technology and care, survival outcomes following IHCA remain low at 15%−25% and vary radically between 0% and 42% worldwide.^[5,6] Sandroni, et al.^[5] showed that various patient and healthcare-related factors are associated with the survival outcomes of IHCA. The main patient-related factors are age, sex, initial cardiac rhythm, underlying medical condition, comorbidities, and the time of the IHCA event. In contrast, major healthcare-related factors are the protocols for IHCA care, duration and method of resuscitation, skills of healthcare professionals, time from code activation and the arrival of the code response team, and the location of the IHCA event.^[5,7] The study by Chen, et al.^[8] suggests that improving the quality of resuscitation care and minimizing other healthcare-related risk factors can markedly increase survival outcomes from IHCAs.^[6,9]Consistent and updated estimates of the magnitude and outcomes of IHCA are fundamental for monitoring and improving the delivery and quality of IHCA care in any healthcare setting. In Lebanon, studies have shown low survival rates (5.5%) from out-of-hospital cardiac arrest.^[10]The reported incidence of IHCA in the United Arab Emirates was 11.7 per 1,000 hospital admissions,^[6] and in Saudi Arabia was 7.76 per 1,000 hospital admissions.^[11] The reported survival to hospital discharge in the United States was only 10.4%,^[12] and it was only 7.9% in the United Kingdom.^[13] However, unlike European countries and the United States, the epidemiology of IHCA is unknown in Lebanon, suggesting the need for research in this area. Therefore, this study aimed to produce the first estimates of the incidence, characteristics, and outcomes of IHCA at a tertiary-care hospital in Lebanon.     

Axial parkinsonian symptoms can be improved: the role of levodopa and bilateral subthalamic stimulation

OBJECTIVE: To assess the effects of high frequency stimulation of the subthalamic nucleus (STN) on axial symptoms occurring in advanced stages of Parkinson's disease (PD). METHODS: The efficacy of STN stimulation on total motor disability score (unified Parkinson's disease rating scale (UPDRS) part III) were evaluated in 10 patients with severe Parkinson's disease. The subscores were then studied separately for limb akinesia, rigidity, and tremor, which are known to respond to levodopa, and axial signs, including speech, neck rigidity, rising from a chair, posture, gait, and postural stability, which are known to respond less well to levodopa. Patients were clinically assessed in the "off" and "on" drug condition during a levodopa challenge test performed before surgical implantation of stimulation electrodes and repeated 6 months after surgery under continuous STN stimulation. A complementary score for axial symptoms from the "activities of daily living" (ADL)-that is, speech, swallowing, turning in bed, falling, walking, and freezing-was obtained from each patient's questionnaire (UPDRS, part II). RESULTS: Improvements in total motor disability score (62%), limb signs (62%), and axial signs (72%) obtained with STN stimulation were statistically comparable with those obtained with levodopa during the preoperative challenge (68%, 69%, and 59%, respectively). When levodopa and STN stimulation were combined there was a further improvement in total motor disability (80%) compared with preoperative levodopa administration. This consisted largely of an additional improvement in axial signs (84%) mainly for posture and postural stability, no further improvement in levodopa responsive signs being found. Axial symptoms from the ADL showed similar additional improvement when levodopa and STN stimulation were combined. CONCLUSION: These findings suggest that bilateral STN stimulation improves most axial features of Parkinson's disease and that a synergistic effect can be obtained when stimulation is used in conjunction with levodopa treatment.