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Margaret A Kenna

Publications and source records attributed to Margaret A Kenna.

15 recordsLinked to original sources

Intersection between the regulators of sister chromatid cohesion establishment and maintenance in budding yeast indicates a multi-step mechanism.

Sister chromatid cohesion is established during S phase and maintained until anaphase. The cohesin complex (Mcd1p/Scc1p, Smc1p, Smc3p Irr1p/Scc3p in budding yeast) serves a structural role as it is required at all times when cohesion exists. Pds5p colocalizes temporally and spatially with cohesin on chromosomes but is thought to serve as a regulator of cohesion maintenance during mitosis. In contrast, Ctf7p/Eco1p is required during S phase for establishment but is not required during mitosis. Here we provide genetic and biochemical evidence that the pathways of cohesion establishment and maintenance are intimately linked. Our results show that mutants in ctf7 and pds5 are synthetically lethal. Moreover, over-expression of either CTF7 or PDS5 exhibits reciprocal suppression of the other mutant's temperature sensitivity. The suppression by CTF7 is specific for pds5 mutants as CTF7 over-expression increases the temperature sensitivity of an mcd1 mutant but has no effect on smc1 or smc3 mutants. Three additional findings provide new insights into the process of cohesion establishment. First, over-expression of ctf7 alleles deficient in acetylase activity exhibit significantly reduced suppression of the pds5 mutant but exacerbated toxicity to the mcd1 mutant. Second, using chromosome spreads and chromatin immuno-precipitation, we find either cohesin complex or Pds5p chromosomal localization is altered in ctf7 mutants. Finally, biochemical analysis reveals that Ctf7p and Pds5p coimmunoprecipitate, which physically links these regulators of cohesion establishment and maintenance. We propose a model whereby Ctf7p and Pds5p cooperate to facilitate efficient establishment by mediating changes in cohesin complex on chromosomes after its deposition.

Alleles↗

GJB2 mutations and degree of hearing loss: a multicenter study.

Hearing impairment (HI) affects 1 in 650 newborns, which makes it the most common congenital sensory impairment. Despite extraordinary genetic heterogeneity, mutations in one gene, GJB2, which encodes the connexin 26 protein and is involved in inner ear homeostasis, are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss. Because of the high frequency of GJB2 mutations, mutation analysis of this gene is widely available as a diagnostic test. In this study, we assessed the association between genotype and degree of hearing loss in persons with HI and biallelic GJB2 mutations. We performed cross-sectional analyses of GJB2 genotype and audiometric data from 1,531 persons, from 16 different countries, with autosomal recessive, mild-to-profound nonsyndromic HI. The median age of all participants was 8 years; 90% of persons were within the age range of 0-26 years. Of the 83 different mutations identified, 47 were classified as nontruncating, and 36 as truncating. A total of 153 different genotypes were found, of which 56 were homozygous truncating (T/T), 30 were homozygous nontruncating (NT/NT), and 67 were compound heterozygous truncating/nontruncating (T/NT). The degree of HI associated with biallelic truncating mutations was significantly more severe than the HI associated with biallelic nontruncating mutations (P<.0001). The HI of 48 different genotypes was less severe than that of 35delG homozygotes. Several common mutations (M34T, V37I, and L90P) were associated with mild-to-moderate HI (median 25-40 dB). Two genotypes--35delG/R143W (median 105 dB) and 35delG/dela(GJB6-D13S1830) (median 108 dB)--had significantly more-severe HI than that of 35delG homozygotes.

Adolescent↗

Combined microtia and aural atresia: issues in cochlear implantation.

OBJECTIVES: This article presents the first report of cochlear implantation in a patient with congenital aural atresia, microtia, dysplastic cochlea and internal auditory canals, and bilateral profound sensorineural hearing loss (HL). This rare combination requires special management considerations. Preoperative issues include thorough evaluation of computed tomography and magnetic resonance imaging to determine favorable anatomy, cochlear implantation candidacy, and surgical planning. Intraoperative concerns include incision placement, surgical approach to the middle ear, and abnormal facial nerve anatomy. Postoperative use of a special headset combining a microphone and transmitter coil is required. STUDY DESIGN: Case report and literature review. METHODS: The patient's chart was reviewed for diagnostic studies, operative strategy, and postoperative auditory stimulation and testing. A literature review was performed. RESULTS: A 2-year-old male presented with bilateral aural atresia, microtia, and profound sensorineural HL. Imaging studies revealed multiple abnormalities of the cochlea, vestibule, and internal auditory canal, all of which were more favorable on the right side. An incision was designed to accommodate future microtia repair. The cochlear implant was placed without difficulty by way of a facial recess approach to the middle ear. Postoperative results include the detection of Ling sounds and voices in the environment as well as the ability to locate sounds. CONCLUSIONS: This is the first report of cochlear implantation in a patient with bilateral aural atresia, microtia, and profound sensorineural HL in conjunction with multiple inner ear abnormalities. Close collaboration among the otologist, neuroradiologist, and plastic surgeon is essential to coordinate surgical management and optimize cosmetic and functional outcomes in this unique population.

Child, Preschool↗

Otitis media and the new guidelines.

Otitis media, including recurrent acute otitis media (AOM) and otitis media with effusion (OME), is one of the most common reasons for an illness-related visit to the primary care clinician. Until recently, antibacterial therapy was the standard treatment for most episodes of AOM and often for OME. However, in 1994, a clinical practice guideline on OME was developed by the Agency for Healthcare Policy and Research (now the Agency for Healthcare Research and Quality) and applied to normal children aged 1 to 3 years. The recommendations in the 1994 guideline were evidence based, widely discussed, and somewhat controversial but also acted as a starting point for some ideas about standardization of management of this very common disease. In 2004, revised clinical practice guidelines were published for OME that applied to children aged 2 months to 12 years and included children with developmental disabilities and underlying conditions that predispose them to OME. In addition, a new evidence-based clinical practice guideline for AOM was published in 2004. This guideline recognized that many episodes of AOM will resolve on their own without antimicrobial therapy, and on that basis, one of the recommendations for initial treatment of AOM in specified situations was watchful waiting without antibacterial therapy. This article briefly discusses the current knowledge about AOM and OME and then addresses the new AOM and OME guidelines point by point. It is important to remember that although important, these clinical practice guidelines are just guidelines and that actual management of the patient with otitis media depends on clinical judgement, the severity of the illness, other underlying medical conditions, ready access to adequate follow-up care, and other features, such as cultural differences. Surgical recommendations were not included in the AOM guidelines but were addressed in the OME guidelines. Further information about the efficacy and effectiveness of both sets of guidelines will likely include the results of prospective studies using the guidelines in both normal children and those with underlying medical conditions.

Acoustic Impedance Tests↗

The spindle pole body assembly component mps3p/nep98p functions in sister chromatid cohesion.

For successful chromosome segregation during mitosis, several processes must occur early in the cell cycle, including spindle pole duplication, DNA replication, and the establishment of cohesion between nascent sister chromatids. Spindle pole body duplication begins in G1 and continues during early S-phase as spindle pole bodies mature and start to separate. Key steps in spindle pole body duplication are the sequential recruitment of Cdc31p and Spc42p by the nuclear envelope transmembrane protein Msp3p/Nep98p (herein termed Mps3p). Concurrent with DNA replication, Ctf7p/Eco1p (herein termed Ctf7p) ensures that nascent sister chromatids are paired together, identifying the products of replication as sister chromatids. Here, we provide the first evidence that the nuclear envelope spindle pole body assembly component Mps3p performs a function critical to sister chromatid cohesion. Mps3p was identified as interacting with Ctf7p from a genome-wide two-hybrid screen, and the physical interaction was confirmed by both in vivo (co-immunoprecipitation) and in vitro (GST pull-down) assays. An in vivo cohesion assay on new mps3/nep98 alleles revealed that loss of Mps3p results in precocious sister chromatid separation and that Mps3p functions after G1, coincident with Ctf7p. Mps3p is not required for cohesion during mitosis, revealing that Mps3p functions in cohesion establishment and not maintenance. Mutated Mps3p that results in cohesion defects no longer binds to Ctf7p in vitro, demonstrating that the interaction between Mps3p and Ctf7p is physiologically relevant. In support of this model, mps3 ctf7 double mutant cells exhibit conditional synthetic lethality. These findings document a new role for Mps3p in sister chromatid cohesion and provide novel insights into the mechanism by which a spindle pole body component, when mutated, contributes to aneuploidy.

Acetyltransferases↗

Clinical practice guideline: Otitis media with effusion.

The clinical practice guideline on otitis media with effusion (OME) provides evidence-based recommendations on diagnosing and managing OME in children. This is an update of the 1994 clinical practice guideline "Otitis Media With Effusion in Young Children," which was developed by the Agency for Healthcare Policy and Research (now the Agency for Healthcare Research and Quality). In contrast to the earlier guideline, which was limited to children aged 1 to 3 years with no craniofacial or neurologic abnormalities or sensory deficits, the updated guideline applies to children aged 2 months through 12 years with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae. The American Academy of Pediatrics, American Academy of Family Physicians, and American Academy of Otolaryngology-Head and Neck Surgery selected a subcommittee composed of experts in the fields of primary care, otolaryngology, infectious diseases, epidemiology, hearing, speech and language, and advanced practice nursing to revise the OME guideline. The subcommittee made a strong recommendation that clinicians use pneumatic otoscopy as the primary diagnostic method and distinguish OME from acute otitis media (AOM). The subcommittee made recommendations that clinicians should (1) document the laterality, duration of effusion, and presence and severity of associated symptoms at each assessment of the child with OME; (2) distinguish the child with OME who is at risk for speech, language, or learning problems from other children with OME and more promptly evaluate hearing, speech, language, and need for intervention in children at risk; and (3) manage the child with OME who is not at risk with watchful waiting for 3 months from the date of effusion onset (if known), or from the date of diagnosis (if onset is unknown). The subcommittee also made recommendations that (4) hearing testing be conducted when OME persists for 3 months or longer, or at any time that language delay, learning problems, or a significant hearing loss is suspected in a child with OME; (5) children with persistent OME who are not at risk should be reexamined at 3- to 6-month intervals until the effusion is no longer present, significant hearing loss is identified, or structural abnormalities of the eardrum or middle ear are suspected; and (6) when a child becomes a surgical candidate, tympanostomy tube insertion is the preferred initial procedure. Adenoidectomy should not be performed unless a distinct indication exists (nasal obstruction, chronic adenoiditis); repeat surgery consists of adenoidectomy plus myringotomy, with or without tube insertion. Tonsillectomy alone or myringotomy alone should not be used to treat OME. The subcommittee made negative recommendations that (1) population-based screening programs for OME not be performed in healthy, asymptomatic children and (2) antihistamines and decongestants are ineffective for OME and should not be used for treatment; antimicrobials and corticosteroids do not have long-term efficacy and should not be used for routine management. The subcommittee gave as options that (1) tympanometry can be used to confirm the diagnosis of OME and (2) when children with OME are referred by the primary clinician for evaluation by an otolaryngologist, audiologist, or speech-language pathologist, the referring clinician should document the effusion duration and specific reason for referral (evaluation, surgery), and provide additional relevant information such as history of AOM and developmental status of the child. The subcommittee made no recommendations for (1) complementary and alternative medicine as a treatment for OME based on a lack of scientific evidence documenting efficacy and (2) allergy management as a treatment for OME based on insufficient evidence of therapeutic efficacy or a causal relationship between allergy and OME. Last, the panel compiled a list of research needs based on limitations of the evidence reviewed. The purpose of this guideline is to inform clinicians of evidence-based methods to identify methods to identify, monitor, and manage OME in children aged 2 months through 12 years. The guideline may not apply to children older than 12 years because OME is uncommon and the natural history is likely to differ from younger children who experience rapid developmental change. The target population includes children with or without developmental disabilities or underlying conditions that predispose to OME and its sequelae. The guideline is intended for use by providers of health care to children, including primary care and specialist physicians, nurses and nurse practitioners, physician assistants, audiologists, speech-language pathologists, and child development specialists. The guideline is applicable to any setting in which children with OME would be identified, monitored, or managed. This guideline is not intended as a sole source of guidance in evaluating children with OME. Rather, it is designed to assist primary care and other clinicians by providing an evidence-based framework for decision-making strategies. It is not intended to replace clinical judgment or establish a protocol for all children with this condition, and may not provide the only appropriate approach to diagnosing and managing this problem.

Acoustic Impedance Tests↗

Medical management of childhood hearing loss.

Hearing loss in children is common. Advances in the identification of infectious diseases at birth or in utero, genetic testing, and diagnostic imaging now permit many infants and children to be identified and treated sooner. Treatment and rehabilitation should be instituted early so that the effects of hearing loss on communication are minimized and the child's social and academic skills maximized. CHL can usually be managed medically or surgically with subsequent return to normal or near normal hearing. Children with SNHL, and their future hearing will benefit from new antiviral agents, less antibiotics, ototoxic more focused chemotherapy, and possibly genetic therapy. Digital and programmable hearing aids, more accessible FM systems, cochlear implants, and bone-anchored hearing aids provide significant rehabilitation potential for children with even very significant hearing losses. Early identification and prevention, however, remain the best strategies to combat hearing loss in children.

Child↗

Human EFO1p exhibits acetyltransferase activity and is a unique combination of linker histone and Ctf7p/Eco1p chromatid cohesion establishment domains.

Proper segregation of chromosomes during mitosis requires that the products of chromosome replication are paired together-termed sister chromatid cohesion. In budding yeast, Ctf7p/Eco1p is an essential protein that establishes cohesion between sister chromatids during S phase. In fission yeast, Eso1p also functions in cohesion establishment, but is comprised of a Ctf7p/Eco1p domain fused to a Rad30p domain (a DNA polymerase) both of which are independently expressed in budding yeast. In this report, we identify and characterize the first candidate human ortholog of Ctf7p/Eco1p, which we term hEFO1p (human Establishment Factor Ortholog). As in fission yeast Eso1p, the hEFO1p open reading frame extends well upstream of the C-terminal Ctf7p/Eco1p domain. However, this N-terminal extension in hEFO1p is unlike Rad30p, but instead exhibits significant homology to linker histone proteins. Thus, hEFO1p is a unique fusion of linker histone and cohesion establishment domains. hEFO1p is widely expressed among the tissues tested. Consistent with a role in chromosome segregation, hEFO1p localizes exclusively to the nucleus when expressed in HeLa tissue culture cells. Moreover, biochemical analyses reveal that hEFO1p exhibits acetyltransferase activity. These findings document the first characterization of a novel human acetyltransferase, hEFO1p, that is comprised of both linker histone and Ctf7p/Eco1p domains.

Acetyltransferases↗

Extraesophageal reflux in pediatric patients with upper respiratory symptoms.

OBJECTIVE: To systematically review published literature describing the association between reflux and upper airway symptoms in children. DESIGN: Structured MEDLINE search of English-language articles published since 1966. SUBJECTS: We selected articles examining reflux in conjunction with stridor, apnea, sudden infant death syndrome, life-threatening events, and laryngomalacia. Studies that focused on lower airway symptoms or adults were excluded. OUTCOME MEASURES: Articles were abstracted for patient factors, elements of study design, methods of reflux diagnosis, and definition of pathologic reflux. RESULTS: Ninety-nine articles were identified, 56 of which specifically examined reflux and upper respiratory symptoms in children. Of these, 10 compared reflux incidence in symptomatic patients and a set of predetermined control patients, while the remainder reported prevalence data only. Overall, symptomatic patients were diagnosed with reflux frequently, with a range from 27% to 100%. In studies that attempted to compare patients with controls, only 2 provided statistical comparisons of the patient groups, and none adjusted for confounding owing to study design. There was marked heterogeneity in methods used to diagnose reflux in the studies reviewed, with only 34% using dual-channel pH testing; definitions of pathologic reflux were also variable. CONCLUSIONS: Evidence seems to support the hypothesis that reflux is associated with upper airway symptoms in children. However, the strength of this correlation and the risk of upper airway symptoms attributable to reflux are difficult to determine given the limitations of available literature. Future research studies should seek standard reflux testing methods, clear comparison groups, and more rigorous statistical methods.

Causality↗

The presentation and management of nasal dermoid: a 30-year experience.

OBJECTIVE: To review the presentation of nasal dermoid in children and present guidelines for its management. DESIGN: Retrospective study (January 1, 1970, through December 31, 2000). SETTING: Tertiary-care pediatric medical center. PATIENTS: Number of patients: 42 (28 boys and 14 girls). Intervention Extensive review of the initial presentation, significant family and medical history, workup, surgical approach, complication, and rate of recurrence. RESULTS: Mean age of presentation was 32 months. The most common presentation was a nasoglabellar mass, in 13 patients (31%). Five patients presented with an associated craniofacial abnormality. Thirty-nine patients (93%) underwent a preoperative imaging workup. Thirty-one (74%) did not show any clinical and/or radiographic indication of intracranial extension. Thirty-four (81%) underwent extracranial excision, and 8 (19%) underwent combined intracranial-extracranial excision. Five patients (12%) presented with recurrence, extracranially in 4 and intracranially in 1. No other complication was noted, with a mean follow-up of 7 years. CONCLUSIONS: Nasal dermoid is a rare congenital anomaly. Preoperative evaluation is essential to rule out intracranial extension. Surgical strategy depends on the location and extent of the lesion, ranging from local excision to a combined intracranial-extracranial approach. Recurrence is uncommon and often easily managed.

Adolescent↗

Utility of tonsillectomy in 2 patients with the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis.

OBJECTIVES: To review the various causes of period fever in childhood, including the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA), and to examine the value of tonsillectomy in the treatment of PFAPA syndrome. DESIGN: Retrospective case series. SETTING: Urban and tertiary care referral children's hospital. PATIENTS: Two patients who underwent tonsillectomy for presumed recurrent adenotonsillitis were later diagnosed as having PFAPA syndrome. Intervention Tonsillectomy. MAIN OUTCOME MEASURE: Frequency of PFAPA symptoms before and after tonsillectomy. RESULTS: No difference was found in the frequency of PFAPA symptoms after tonsillectomy. CONCLUSION: Although a larger series of patients is required, our initial experience suggests that tonsillectomy is not always beneficial for patients with PFAPA syndrome.

Adolescent↗

Neonatal hearing screening.

Neonatal hearing screening can be performed using reliable and reproducible methods. Intervention before the age of 6 months with hearing aids and appropriate educational support services will give the infant the best possible opportunity to develop language. Potential barriers to efficient implementation of a neonatal hearing screening program include access to appropriate and timely diagnostic and support services and insurance to cover the services. Without universal neonatal hearing screening, many children with hearing loss will be missed, which will have a direct negative impact on their speech, language, educational, and social development.

Hearing Disorders↗

Mechanical link between cohesion establishment and DNA replication: Ctf7p/Eco1p, a cohesion establishment factor, associates with three different replication factor C complexes.

CTF7/ECO1 is an essential yeast gene required for the establishment of sister chromatid cohesion. The findings that CTF7/ECO1, POL30 (PCNA), and CHL12/CTF18 (a replication factor C [RFC] homolog) genetically interact provided the first evidence that the processes of cohesion establishment and DNA replication are intimately coupled-a link now confirmed by other studies. To date, however, it is unknown how Ctf7p/Eco1p function is coupled to DNA replication or whether Ctf7p/Eco1p physically associates with any components of the DNA replication machinery. Here, we report that Ctf7p/Eco1p associates with proteins that perform partially redundant functions in DNA replication. Chl12p/Ctf18p combines with Rfc2p to Rfc5p to form one of three independent RFC complexes. By chromatographic methods, Ctf7p/Eco1p was found to associate with Chl12/Ctf18p and with Rfc2p, Rfc3p, Rfc4p, and Rfc5p. The association between Ctf7p/Eco1p and this RFC complex is biologically relevant in that (i) Ctf7p/Eco1p cosediments with Chl12p/Ctf18p in vivo and (ii) rfc5-1 mutant cells exhibit precocious sister separation. Previous studies revealed that Rfc1p or Rad24p associates with Rfc2p to Rfc5p to form two other RFC complexes independent of Ctf18p-RFC complexes. These Rfc1p-RFC and Rad24p-RFC complexes function in DNA replication or repair and DNA damage checkpoint pathways. Importantly, Ctf7p/Eco1p also associates with Rfc1p and Rad24p, suggesting that these RFC complexes also play critical roles in cohesion establishment. The associations between Ctf7p/Eco1p and RFC subunits provide novel evidence regarding the physical linkage between cohesion establishment and DNA replication. Furthermore, the association of Ctf7p/Eco1p with each of three RFC complexes supplies new insights into the functional redundancy of RFC complexes in cohesion establishment.

Acetyltransferases↗

The role of mitomycin in the prevention and treatment of scar formation in the pediatric aerodigestive tract: friend or foe?

OBJECTIVE: To evaluate the role of mitomycin in the prevention and treatment of scar formation in the pediatric aerodigestive tract. DESIGN: Prospective study; institutional review board-approved clinical trial. SETTING: Tertiary care pediatric medical center. PATIENTS: Fifteen patients; choanal atresia in 5 patients, airway stenosis in 8 patients, hypopharyngeal stenosis in 1 patient, and esophageal stenosis in 1 patient. OUTCOME: The efficacy and safety of mitomycin in the prevention of scar formation. INTERVENTION: All patients underwent surgical repair of the stenotic area, followed by topical application of mitomycin (1 mL of 0.4 mg/mL) for 4 minutes. RESULTS: Ten patients (67%) showed major improvement, 4 patients (27%) showed minor improvement, and 1 patient (7%) showed no improvement. CONCLUSION: Topical application of mitomycin can play an effective role in the prevention and treatment of scar formation in the aerodigestive tract.

Administration, Topical↗

Congenital absence of the incus bilaterally without other otologic anomalies: a new case report.

We describe only the third reported case of congenital, bilaterally absent includes that were not accompanied by another otologic abnormality. This condition was detected in a 3-year-old boy who was being evaluated for a hearing impairment and speech and language delay. The patient was treated with partial ossicular replacement prostheses, which resulted in an improvement in his hearing.

Acoustic Impedance Tests↗