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David Solomon

Publications and source records attributed to David Solomon.

At least 19 recordsLinked to original sources
PubMed2024

Towards genomic medicine: a tailored next-generation sequencing panel for hydroxyurea pharmacogenomics in Tanzania.

BACKGROUND: Pharmacogenomics of hydroxyurea is an important aspect in the management of sickle cell disease (SCD), especially in the era of genomic medicine. Genetic variations in loci associated with HbF induction and drug metabolism are prime targets for hydroxyurea (HU) pharmacogenomics, as these can significantly impact the therapeutic efficacy and safety of HU in SCD patients. METHODS: This study involved designing of a custom panel targeting BCL11A, ARG2, HBB, HBG1, WAC, HBG2, HAO2, MYB, SAR1A, KLF10, CYP2C9, CYP2E1 and NOS1 as potential HU pharmacogenomics targets. These genes were selected based on their known roles in HbF induction and HU metabolism. The panel was designed using the Illumina Design Studio (Illumina, San Diego, CA, USA) and achieved a total coverage of 96% of all genomic targets over a span of 51.6 kilobases (kb). This custom panel was then sequenced using the Illumina MiSeq platform to ensure high coverage and accuracy. RESULTS: We are reporting a successfully designed Illumina (MiSeq) HU pharmacogenomics custom panel encompassing 51.6 kilobases. The designed panel achieved greater than 1000x amplicon coverage which is sufficient for genomic analysis. CONCLUSIONS: This study provides a valuable tool for research in HU pharmacogenomics, especially in Africa where SCD is highly prevalent, and personalized medicine approaches are crucial for improving patient outcomes. The custom-designed Illumina (MiSeq) panel, with its extensive coverage and high sequencing depth, provides a robust platform for studying genetic variations associated with HU response. This panel can contribute to the development of tailored therapeutic strategies, ultimately enhancing the management of SCD through more effective and safer use of hydroxyurea.

Hydroxyurea↗
PubMed2006

WAVE1 is required for oligodendrocyte morphogenesis and normal CNS myelination.

Myelin formation involves the outgrowth of an oligodendrocyte cell process that can be regarded as a giant lamellipodium because it is an actively growing structure with extruded cytoplasm. The actin cytoskeleton is critical to morphogenesis, but little is known about regulation of actin dynamics in oligodendrocytes. Wiskott-Aldrich syndrome protein family verprolin homologous (WAVE) proteins mediate lamellipodia formation; thus, we asked whether these proteins function in oligodendrocyte process formation and myelination. Here, we show that WAVE1 is expressed by oligodendrocytes and localizes to the lamella leading edge where actin polymerization is actively regulated. CNS WAVE1 expression increases at the onset of myelination. Expression of dominant-negative WAVE1 impaired process outgrowth and lamellipodia formation in cultured oligodendrocytes. Similarly, oligodendrocytes isolated from mice lacking WAVE1 had fewer processes compared with controls, whereas neurons and astrocytes exhibited normal morphology. In white matter of WAVE1-/- mice, we found regional hypomyelination in the corpus callosum and to a lesser extent in the optic nerve. In optic nerve from WAVE1-/- mice, there were fewer nodes of Ranvier but nodal morphology was normal, implicating a defect in myelin formation. Our in vitro findings support a developmentally dynamic and cell-autonomous role for WAVE1 in regulating process formation in oligodendrocytes. Additionally, WAVE1 function during CNS myelination appears to be linked to regional cues. Although its loss can be compensated for in many CNS regions, WAVE1 is clearly required for normal amounts of myelin to form in corpus callosum and optic nerve. Together, these data demonstrate a role for WAVE1 in oligodendrocyte morphogenesis and myelination.

Animals↗
PubMed2006

Head control strategies during whole-body turns.

Recent reports have described the motion of individual body segments during turns toward visual targets. During a whole-body turn, the head's trajectory in space is determined by both body-in-space rotation and head-on-body rotation. To inform subsequent investigations of head control strategies during turns, we provide a kinematic description of head and pelvis rotation in 20 healthy human subjects as they performed step turns toward a visible target or in the direction of a previously seen target. At the time of peak head velocity in space, the head was moving faster than the pelvis by approximately 54 degrees s(-1) when turning toward a visible target, and approximately 25 degrees s(-1) when turning in a remembered direction. Peak head velocities were slower in the absence of a visual target, but pelvis velocities were not significantly different. The pattern of relative motion between the head and pelvis followed a temporal sequence. Early in the turn, the head rotated with respect to the pelvis in the same direction as the pelvis was rotating in space. During the mid portions of the turn, en bloc rotation of the head and pelvis predominated. Later in the turn, head-in-space velocity was lower than pelvis-in-space velocity, and was thus relatively stabilized. This pattern of head movement during turns is quite similar to eye-in-head movements during large eye-head gaze shifts. This suggests that in addition to saccadic and stabilization mechanisms, a specific control strategy to move segments together should be incorporated into models of gaze reorienting behavior.

Acoustic Stimulation↗
PubMed2005

Christian bioethics, secular bioethics, and the claim to cultural authority.

Though the papers in this volume for the most part address the question, "What is Christian about Christian Bioethics", this paper addresses instead a closely related question, "How would a Christian approach to bioethics differ from the kind of secular academic bioethics that has emerged as such an important field in the contemporary university?" While it is generally assumed that a secular bioethics rooted in moral philosophy will be more culturally authoritative than an approach to bioethics grounded in the contingent particularities of a religious tradition, I will give reasons for rejecting this assumption. By examining the history of the recent revival of academic bioethics as well as the state of the contemporary moral philosophy on which it is based I will suggest that secular bioethics suffers from many of the same liabilities as a carefully articulated Christian bioethics. At the end of the paper I will turn briefly to examine the question of how, in light of this discussion, a Christian bioethics might best be pursued.

Bioethics↗
PubMed2005

Niemann-Pick type C disease in two affected sisters: ocular motor recordings and brain-stem neuropathology.

Two sisters with Niemann-Pick disease type C were examined: the brain in one sister, who had died, was examined, and eye movements in the other, surviving sister were recorded. Ocular motor recordings showed marked slowing of vertical saccades with relative sparing of horizontal saccades, pursuit, and the vestibulo-ocular reflex. Neuropathological findings included glial fibrillary lesions in the area of the posterior commissure and neuronal loss in the rostral interstitial nucleus of the MLF with preservation of the interstitial nucleus of Cajal and ocular motor complex. These neuropathologic findings correlate well with our current understanding of the anatomy and physiology of the supranuclear control of vertical gaze.

Adult↗
PubMed2004

Acute Hearing Loss.

Acute hearing loss (AHL) is a medical urgency. The management of patients presenting with sudden deafness involves detecting the causal mechanism and administering emergency therapeutic drugs to restore hearing by minimizing the period of cellular ischemia to the inner ear. Acute management of AHL consists of administering a 10-day course of high-dose corticosteroids (prednisone 60 to 80 mg) until a cause can be established. Magnetic resonance imaging with gadolinium is indicated, with a study dedicated to the internal auditory canals. The natural history of idiopathic AHL is characterized by spontaneous improvement in two thirds of patients. Maximum improvement occurs within 2 weeks of onset of AHL. In the vast majority of patients (>90%), the AHL is idiopathic. For an identifiable etiology, the treatment is specific and may consist of stopping ototoxic medications, repair of perilymphatic fistulas, administering antimicrobial agents for viral or bacterial infections, correction of metabolic imbalances, management of stroke, and possible surgery for cerebellopontine angle tumors. Management of idiopathic AHL is controversial. Various therapeutic agents, such as vasodilators, diuretics, anticoagulants, plasma expanders, contrast agents, and carbogen inhalation, have been tried in single therapy or as a combination therapy. The empiric use of these drugs is mainly based on improving the blood circulation and restoring the oxygen tension to the inner ear. The use of interventional procedures, such as low-density lipoprotein apheresis as well as newer drug delivery systems for corticosteroids, and immunosuppressive agents have opened new options in the treatment of AHL secondary to immune-mediated diseases of the inner ear. Prognosis for AHL is best when patients are seen early, begin recovery within 2 weeks, and have a mild hearing loss (<90 dB) with upward-sloping audiograms. Greater than 90 dB of hearing loss along with flat or down sloping audiogram, advanced age, and presence of vertigo are adverse prognostic factors for recovery of hearing loss.

Journal Article↗
PubMed2003

The long-term course of rapid-cycling bipolar disorder.

BACKGROUND: Rapid cycling among patients with bipolar affective disorders is important because of its implications for long-term prognosis and for the use of antidepressants. To our knowledge, no prospective study has, as yet, described the course of this phenomenon beyond 5 years. METHODS: From 345 patients with bipolar I or bipolar II disorder followed up for a mean (SD) of 13.7 (6.1) years as part of the National Institute of Mental Health Collaborative Depression Study, 89 (25.8%) were identified who, during 1 or more years of follow-up, manifested a pattern that met DSM-IV criteria for rapid cycling. These patients were compared with the remaining bipolar patients by demographics, overall affective morbidity, morbidity during specific treatment conditions, and the likelihood of suicidal behavior. Analyses assessed whether the use of tricyclic antidepressants for depressive symptoms was associated with the persistence of rapid cycling or with tendencies to switch from depressive to manic or hypomanic phases. RESULTS: The 89 patients who showed a rapid cycling pattern were significantly more likely to have had an illness onset before 17 years of age and were more likely to make serious suicide attempts. In 4 of 5 cases, rapid cycling ended within 2 years of its onset. Resolutions were not associated with decreases in tricyclic antidepressant use. Throughout follow-up, patients prone to rapid cycling experienced more depressive morbidity than other bipolar patients, particularly when lithium carbonate was being used without tricyclic antidepressants. The use of these antidepressants was not more likely in the weeks preceding shifts from depression to mania or hypomania. CONCLUSIONS: These results indicate that bipolar patients who develop a rapid cycling pattern suffer substantial depressive morbidity and are at high risk for serious suicide attempts. These findings do not implicate tricyclic antidepressants or, by inference, serotonin reuptake inhibitors in the promotion of affective instability.

Adult↗
PubMed2003

Long-term symptomatic status of bipolar I vs. bipolar II disorders.

Weekly affective symptom severity and polarity were compared in 135 bipolar I (BP I) and 71 bipolar II (BP II) patients during up to 20 yr of prospective symptomatic follow-up. The course of BP I and BP II was chronic; patients were symptomatic approximately half of all follow-up weeks (BP I 46.6% and BP II 55.8% of weeks). Most bipolar disorder research has concentrated on episodes of MDD and mania and yet minor and subsyndromal symptoms are three times more common during the long-term course. Weeks with depressive symptoms predominated over manichypomanic symptoms in both disorders (31) in BP I and BP II at 371 in a largely depressive course (depressive symptoms=59.1% of weeks vs. hypomanic=1.9% of weeks). BP I patients had more weeks of cyclingmixed polarity, hypomanic and subsyndromal hypomanic symptoms. Weekly symptom severity and polarity fluctuated frequently within the same bipolar patient, in which the longitudinal symptomatic expression of BP I and BP II is dimensional in nature involving all levels of affective symptom severity of mania and depression. Although BP I is more severe, BP II with its intensely chronic depressive features is not simply the lesser of the bipolar disorders; it is also a serious illness, more so than previously thought (for instance, as described in DSM-IV and ICP-10). It is likely that this conventional view is the reason why BP II patients were prescribed pharmacological treatments significantly less often when acutely symptomatic and during intervals between episodes. Taken together with previous research by us on the long-term structure of unipolar depression, we submit that the thrust of our work during the past decade supports classic notions of a broader affective disorder spectrum, bringing bipolarity and recurrent unipolarity closer together. However the genetic variation underlying such a putative spectrum remains to be clarified.

Adolescent↗
PubMed2003

Ocular and perceptual responses to linear acceleration in microgravity: alterations in otolith function on the COSMOS and Neurolab flights.

In this paper we review space flight experiments performed by our laboratory. Rhesus monkeys were tested before and after 12 days in orbit on COSMOS flights 2044 (1989) and 2229 (1992-1993). There was a long-lasting decrease in post-flight ocular counter-rolling (70%) and vergence (50%) during off-vertical axis rotation. In one animal, the orientation of optokinetic after-nystagmus shifted by 28 degrees from the spatial vertical towards the body vertical early post-flight. Otolith-ocular and perceptual responses were also studied in four astronauts on the 17-day Neurolab shuttle mission (STS-90) in 1998. Ocular counter-rolling was unchanged in response to 1-g and 0.5-g Gy centrifugation during and after flight and to post-flight static roll tilts relative to pre-flight values. Orientation of the optokinetic nystagmus eye velocity axis to gravito-inertial acceleration (GIA) during centrifugation was also unaltered by exposure to microgravity. Perceptual orientation to the GIA was maintained in-flight, and subjects did not report sensation of translation during constant velocity centrifugation. These studies suggest that percepts and ocular responses to tilt are determined by sensing the body vertical relative to the GIA. The findings also raise the possibility that 'artificial gravity' during the Neurolab flight counteracted adaptation of these otolith-ocular responses.

Acceleration↗
PubMed2002

Serotonin reuptake inhibitors for dizziness with psychiatric symptoms.

OBJECTIVE: To investigate the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) for the treatment of patients with dizziness and major or minor psychiatric symptoms, with or without neurotologic illnesses. DESIGN: Review of 60 consecutive cases of patients with dizziness who were treated with an SSRI for at least 20 weeks during the 30-month period from July 1998 to December 2000. SETTING: Tertiary care, multidisciplinary referral center. PATIENTS: Sixty men and women, aged 13 to 81 years, with (1) psychogenic dizziness, (2) dizziness due to a neurotologic condition, as well as significant psychiatric symptoms, or (3) idiopathic dizziness. INTERVENTIONS: Open-label treatment with an SSRI titrated to 1 of 3 end points: optimal clinical benefit, intolerable adverse effects, or no therapeutic response. MAIN OUTCOME MEASURE: Change in dizziness and psychiatric symptoms measured by the 7-point, clinician-rated, Clinical Global Impressions-Improvement Scale. RESULTS: Thirty-eight (63%) of 60 patients in the intent-to-treat sample and 32 (84%) of 38 patients who completed treatment improved substantially. The response rates did not differ between patients with major psychiatric disorders and those with lesser psychiatric symptoms. Patients whose only diagnosis was a psychiatric disorder and those with coexisting peripheral vestibular conditions or migraine headaches fared better than patients with central nervous system deficits. Before being treated with an SSRI, two thirds of the study patients took meclizine hydrochloride and/or benzodiazepines, with minimal benefit. CONCLUSIONS: Treatment with SSRIs relieved dizziness in patients with major or minor psychiatric symptoms, including those with peripheral vestibular conditions and migraine headaches. Patients fared far better with SSRI treatment than with treatment with vestibular suppressants or benzodiazepines.

Adolescent↗
PubMed2002

Chronic Dizziness.

The mainstay of treatment is a specialized form of physical therapy that intentionally induces symptoms of dizziness with head movements, moving visual targets, and changes in position. Patients must be motivated to experience discomfort during the early stages of rehabilitation, doing the types of activities that they likely have been avoiding. Time must be spent convincing the patient of the necessity to deliberately provoke dizziness in order for the exercises to work. It is important to not overmedicate with vestibular suppressants, and to treat any co-existing mood or anxiety disorder, as these interfere with the adaptive plasticity that is the basis of successful rehabilitation.

Journal Article↗
PubMed2002

The prospectively observed course of illness among depressed patients who commit suicide.

OBJECTIVE: These analyses were conducted to describe the course of illness among patients with major affective disorders who commit suicide. METHOD: Twenty-nine patients who entered a long-term, high-intensity follow-up study of major affective disorders and who later committed suicide within 1 year of their last follow-up interview were individually matched to other patients by age, sex, the presence or absence of lifetime drug or alcohol abuse, time to last interview and polarity. Those who suicided were compared with their controls by depressive and substance abuse morbidity during follow-up, treatment resistance, treatment compliance, suicidal behavior and psychosocial adjustment. RESULTS: Among the various measures used to characterize the course of illness during a mean follow-up of 4.3 years, only those pertaining to suicidal behavior robustly separated the suicide group from their controls. Suicidal behavior in the remote past seemed as predictively important as suicidal behavior during follow-up. CONCLUSION: Of the various features monitored over time in patients with major affective disorder, suicidal behavior itself was the clearest correlate of risk for completed suicide.

Adult↗
PubMed2002

Exertional dizziness and autonomic dysregulation.

OBJECTIVES: To define the clinical characteristics and treatment of dizziness induced by physical exertion and to investigate autonomic nervous system function in exertional dizziness. STUDY DESIGN: Retrospective case series from a review of 1400 patients evaluated for dizziness at a neurotology referral center, identifying those with predominantly exertional symptoms. METHODS: Records of patients with exertional dizziness were screened to eliminate those with known vestibular deficits, cardiopulmonary illnesses, and psychiatric disorders. The clinical characteristics, evaluation results, and treatment of nine patients with purely exertional dizziness were described. RESULTS: The cohort included 4 male and 5 female patients (age range, 13-53 y) with symptoms for 1 to 8 years. Only one patient had a history of autonomic symptoms: phlebotomy-induced syncope in childhood. No patient was taking medications that caused dizziness or orthostasis. All patients experienced "spacey" or "foggy" head sensations without vertigo during exertion. Provocative activities ranged from standing upright for extended periods to running and swimming. On examination, voluntary hyperventilation provoked moderate symptoms in all patients (without nystagmus or anxiety), although no patient had spontaneously occurring, hyperventilation-related complaints. Seven patients underwent autonomic testing. Tilt table tests (n = 5) produced severe symptoms in one patient and mild symptoms in two patients. Sodium lactate infusions (n = 6) provoked marked symptoms in four patients and moderate symptoms in one patient. All were treated for autonomic dysregulation. Seven patients improved substantially and resumed all of their premorbid activities. Two improved slightly. CONCLUSIONS: In nine patients with exertional dizziness, autonomic challenges were provocative, and medications for autonomic dysregulation were effective. Exertional dizziness may be a clinical manifestation of autonomic nervous system dysregulation.

Adolescent↗
PubMed2002

Can temperament identify affectively ill patients who engage in lethal or near-lethal suicidal behavior? A 14-year prospective study.

Among affectively ill patients followed naturalistically for up to 14 years, 36 committed suicide, 120 attempted suicide, and 373 had no recorded suicide attempt. Comparing these three groups on clinical and intake personality revealed that suicide completed within 12 months was predicted by clinical but not personality variables, and suicide beyond 12 months was predicted by newly derived temperament factors, not clinical variables. Attempters and completers shared core characteristics: previous attempts, impulsivity, substance abuse, and psychic turmoil within a cycling/mixed bipolar disorder. Such temperament attributes as impulsivity and assertiveness were the best prospective predictors of completed suicides beyond 12 months with a sensitivity level of 74% and specificity level of 82%.

Adolescent↗
PubMedDate not supplied

Quality indicators for the management of medical conditions in nursing home residents.

PURPOSE: The purpose of this study was to develop a set of specific care processes associated with better outcomes for general medical conditions identified as quality improvement targets for institutionalized vulnerable elders. METHODS: A national panel of nursing home experts used a modified-Delphi process to rate the validity (process linked to improved outcomes) and feasibility (of implementation and measurement) of candidate measures for depression, diabetes, hearing impairment, heart failure, hypertension, ischemic heart disease, osteoarthritis, osteoporosis, pneumonia, stroke, and vision impairment. Each quality indicator was written as an "if" statement, describing persons to whom the quality indicator applied followed by a "then" statement identifying the care process to be provided. A separate clinical committee reviewed the resulting set of indicators. RESULTS: One hundred fourteen quality indicators were identified across the 11 medical conditions. The quality indicators capture a broad range of medical care addressing assessment, management, and follow up. Fifty-five indicators (48%) were identical to quality measures for community-dwelling vulnerable elders. A limited number were rated as questionably feasible to implement or measure (6 and 2, respectively). Thirty-eight (33%) would not be applied to measures of care quality for persons with advanced dementia or poor prognosis. CONCLUSIONS: Explicit care processes linked to improved nursing home outcomes for general medical conditions can be identified. Most of these care processes can be measured by medical records or interview. Nursing home quality measures for medical conditions must account for exclusions related to poor prognosis and advanced dementia.

Aged↗
PubMedDate not supplied

Feasibility of quality indicators for the management of geriatric syndromes in nursing home residents.

PURPOSE: The assessment and management of dementia, falls and mobility disorders, malnutrition, end-of-life issues, pressure ulcers, and urinary incontinence have been identified as important quality improvement targets for vulnerable elders residing in nursing homes. This study aimed to identify valid and feasible measures of specific care processes associated with improved outcomes for these conditions. METHODS: Nine experts in nursing home (NH) care participated in a modified Delphi process to evaluate potential quality indicators (QIs) for care in NHs. Panelists met and discussed potential indicators before completing confidential ballots rating validity (process associated with improved outcomes), feasibility of measurement (with charts or interviews), feasibility of implementation (given staffing resources in average community NHs), and importance (expected benefit and prevalence in NHs). The NH panel's median votes were used to identify a final set of QIs that were subsequently reviewed by a clinical oversight committee. RESULTS: Sixty-eight geriatric syndrome QIs were identified as valid and important in NH populations. Panelists assessed 12 (18%) of these QIs as having questionable feasibility to implement in average community nursing homes trying to provide quality care. Nine (13%) would not be included in systems assessing quality of care for persons with advanced dementia or poor prognosis. CONCLUSIONS: Steps of care critical to the assessment and management of geriatric syndromes in NHs were identified. Feasibility is an important issue for a significant number of these, indicating that much remains to be done to design systems that efficiently and reliably implement these care processes.

Accidental Falls↗