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121.
NA Hanchard DR Murdock PL Magoulas M Bainbridge D Muzny YQ Wu M Wang AL McGuire JR Lupski RA Gibbs CW Brown 《Clinical genetics》2013,83(5):457-461
The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future. 相似文献
122.
123.
Shu Yang Jennifer A. Fifita Kelly L. Williams Sadaf T. Warraich Roger Pamphlett Garth A. Nicholson Ian P. Blair 《Neurobiology of aging》2013
Mutations in PFN1, a gene encoding the actin monomer-binding protein profilin 1, were recently reported in 1% to 2% of familial amyotrophic lateral sclerosis (ALS) patients. In vitro functional studies suggested that PFN1 mutations lead to ubiquitin-positive inclusions and impairment of cytoskeletal pathways. In the present study, mutation analysis of PFN1 was performed in an Australian cohort of 110 ALS families and 715 sporadic ALS patients. No PFN1 mutations were identified in familial ALS patients. Two rare non-synonymous variants (E117D and E117G) were found in sporadic ALS patients at similar incidences to that reported in public SNP databases. Immunostaining of PFN1 in sporadic ALS and familial ALS patients, including those with mutations in SOD1, FUS, UBQLN2 and C9ORF72, found no PFN1-positive inclusions in spinal motor neurons. Our data suggest that PFN1 mutations and pathology are not common in an Australian ALS cohort of predominantly European ancestry. 相似文献
124.
Ruzieh Mohammed Sacks Cody D. Grewal Simran S. Aboujamous Nader M. Grubb Blair P. Fedorowski Artur 《Clinical autonomic research》2021,31(2):231-237
Clinical Autonomic Research - Orthostatic intolerance (OI) is a group of disorders characterized by symptoms that occur upon standing and resolve with recumbence. Although well established but not... 相似文献
125.
126.
Traumatic Brain Injury and Suicidal Ideation Among U.S. Operation Enduring Freedom and Operation Iraqi Freedom Veterans 下载免费PDF全文
Jaimie L. Gradus Blair E. Wisco Matthew T. Luciano Katherine M. Iverson Brian P. Marx Amy E. Street 《Journal of traumatic stress》2015,28(4):361-365
Traumatic brain injury (TBI) is associated with suicidal behavior among veterans, and gender differences in the strength of associations may exist. Almost all research has been limited to Veterans Health Administration (VHA) patients, and it is unclear if findings generalize to veterans who do not use VHA services. We examined gender‐ and VHA‐user‐specific associations between TBI related to deployment and postdeployment suicidal ideation in a U.S. national sample of 1,041 female and 880 male Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) veterans. Path analysis was used to estimate TBI and suicidal ideation association, and examine PTSD and depression symptomatology in these associations. TBI was associated with suicidal ideation among male VHA users, OR = 3.64, 95% CI [2.21, 6.01]; and male and female nonusers, OR = 2.24, 95% CI [1.14, 4.44] and OR = 2.65, 95% CI [1.26, 5.58], respectively, in unadjusted analyses. This association was explained by depression symptoms among male and female nonusers. Among male VHA users an association between TBI and suicidal ideation remained when accounting for depression symptoms, OR = 2.50, 95% CI [1.33, 4.71]. Our findings offered evidence of an association between TBI and suicidal ideation among male OEF/OIF VHA users. 相似文献
127.
128.
Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults 总被引:5,自引:0,他引:5
STUDY OBJECTIVE: To determine the steady-state, extracellular, and intracellular pulmonary disposition of moxifloxacin (MXF), levofloxacin (LEVO), and azithromycin (AZI) relative to that of the plasma over a 24-h dosing interval. DESIGN: Randomized, multicenter, open-label investigation. PATIENTS: Forty-seven older adults (mean [+/- SD] age, 62 +/- 13 years) undergoing diagnostic bronchoscopy. INTERVENTIONS: Oral administration of MXF, 400 mg, LEVO, 500 mg daily for five doses, or AZI, 500 mg for one dose, then 250 mg daily for four doses. BAL and venipuncture were completed at 4, 8, 12, or 24 h following the administration of the last dose. MEASUREMENTS AND RESULTS: Steady-state MXF, LEVO, and AZI concentrations were determined in the plasma, epithelial lining fluid (ELF), and alveolar macrophages (AMs). The concentrations of all three agents were greatest in the AMs followed by the ELF compared to the plasma. Plasma concentrations were similar to those previously reported with these agents. The mean ELF concentrations at 4, 8, 12, and 24 h were as follows: MXF, 11.7 +/- 11.9, 7.8 +/- 5.1, 10.5 +/- 3.7, and 5.7 +/- 6.3 micro g/mL, respectively; LEVO, 15.2 +/- 4.5, 10.2 +/- 6.7, 6.9 +/- 4.4, and 2.9 +/- 1.7 micro g/mL, respectively; and AZI, 0.6 +/- 0.4, 0.7 +/- 0.4, 0.9 +/- 0.5, and 0.9 +/- 0.7 micro g/mL, respectively. The AM concentrations at 4, 8, 12, and 24 h were as follows: MXF, 47.7 +/- 47.6, 123.3 +/- 126.4, 26.2 +/- 19.4, and 32.8 +/- 16.5 micro g/mL, respectively; LEVO, 28.5 +/- 30.2, 26.1 +/- 15.7, 28.3 +/- 12.6, and 8.2 +/- 6.1 micro g/mL, respectively; and AZI, 71.8 +/- 50.1, 73.8 +/- 75.3, 155.9 +/- 81.3, and 205.2 +/- 256.3 micro g/mL, respectively. CONCLUSIONS: The intrapulmonary concentrations of MXF, LEV, and AZI were superior to those obtained in the plasma. The AM concentrations of all agents studied were more than adequate relative to the minimum concentration required to inhibit 90% of the organism population (MIC(90)) of the common intracellular pathogens (< 1 micro g/mL). These data indicate that attainable extracellular concentrations of AZI are insufficient to reliably eradicate Streptococcus pneumoniae, based on the agent's current minimum inhibitory concentration profile, whereas the mean concentrations of MXF and LEVO in the ELF exceed the MIC(90) of the S pneumoniae population. Moreover, MXF concentrations exceeded the S pneumoniae susceptibility breakpoint (1.0 micro g/mL) at all time points, while 2 of 15 concentrations (13%) failed to maintain LEVO concentrations above the breakpoint (2.0 micro g/mL) throughout the dosing interval. 相似文献
129.
Healing of mat mutations and control of mating type interconversion by the mating type locus in Saccharomyces cerevisiae 总被引:1,自引:0,他引:1 下载免费PDF全文
Strathern JN Blair LC Herskowitz I 《Proceedings of the National Academy of Sciences of the United States of America》1979,76(7):3425-3429
Homothallic yeasts switch cell types (mating types a and α) at high frequency by changing the alleles of the mating type locus, MATa and MATα. We have proposed in the cassette model that yeast cells contain silent MATa and MATα blocs (“cassettes”), copies of which can be substituted at the mating type locus for the resident information. The existence of silent cassettes was originally proposed to explain efficient switching of a defective MATα locus (matα) to a functional MATα locus. We report here that this “healing” of mat mutations is a general property of the mating type interconversion system and is not specific to the class of matα mutations studied earlier: a defective MATa (mata1) switches readily to MATa and various matα loci switch readily to MATα. These observations satisfy the prediction of the cassette model that all mutations within MATa and MATα be healed. These studies also identify MAT functions that control the switching process: the same functions known to promote sporulation and prevent mating in a/α cells also inhibit the switching system in a/α cells. Finally, we present additional characterization of a natural variant of MATα, MATα-inc [Takano, I., Kusumi, T. & Oshima, Y. (1973) Mol. Gen. Genet. 126, 19-28] that is insensitive to switching. Our observation that MATα-inc acts in cis suggests that it may be altered in a site concerned with excision of MATα-inc or its replacement by another cassette. 相似文献
130.
We studied the actions of the octapeptide hormone angiotensin II (AII) on isolated cardiac Purkinje fibers. AII (1 to 75 nm) increased the height and duration of the plateau phase of the action potential and increased the strength of contraction in these preparations. These effects were not blocked by propranolol (10?6m). A two-microelectrode voltage clamp technique combined with simultaneous tension measurements was used to study the AII-induced changes in membrane current and contractile activation. AII enhanced peak tension and promoted an inward shift in the net membrane current-voltage relation at test voltages between ?40 and 0 mV. The inward shift in current was maintained for the duration of the 500 ms test voltage step. The AII-induced current shift was reduced or abolished when external calcium concentration was decreased from 5.4 mm to 1.8 mm, and was inhibited by the calcium antagonist D600. 相似文献