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1.
N Engl J Med ; 382(4): 341-352, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31971679

RESUMO

BACKGROUND: Thyroid eye disease is a debilitating, disfiguring, and potentially blinding periocular condition for which no Food and Drug Administration-approved medical therapy is available. Strong evidence has implicated the insulin-like growth factor I receptor (IGF-IR) in the pathogenesis of this disease. METHODS: In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, we assigned patients with active thyroid eye disease in a 1:1 ratio to receive intravenous infusions of the IGF-IR inhibitor teprotumumab (10 mg per kilogram of body weight for the first infusion and 20 mg per kilogram for subsequent infusions) or placebo once every 3 weeks for 21 weeks; the last trial visit for this analysis was at week 24. The primary outcome was a proptosis response (a reduction in proptosis of ≥2 mm) at week 24. Prespecified secondary outcomes at week 24 were an overall response (a reduction of ≥2 points in the Clinical Activity Score plus a reduction in proptosis of ≥2 mm), a Clinical Activity Score of 0 or 1 (indicating no or minimal inflammation), the mean change in proptosis across trial visits (from baseline through week 24), a diplopia response (a reduction in diplopia of ≥1 grade), and the mean change in overall score on the Graves' ophthalmopathy-specific quality-of-life (GO-QOL) questionnaire across trial visits (from baseline through week 24; a mean change of ≥6 points is considered clinically meaningful). RESULTS: A total of 41 patients were assigned to the teprotumumab group and 42 to the placebo group. At week 24, the percentage of patients with a proptosis response was higher with teprotumumab than with placebo (83% [34 patients] vs. 10% [4 patients], P<0.001), with a number needed to treat of 1.36. All secondary outcomes were significantly better with teprotumumab than with placebo, including overall response (78% of patients [32] vs. 7% [3]), Clinical Activity Score of 0 or 1 (59% [24] vs. 21% [9]), the mean change in proptosis (-2.82 mm vs. -0.54 mm), diplopia response (68% [19 of 28] vs. 29% [8 of 28]), and the mean change in GO-QOL overall score (13.79 points vs. 4.43 points) (P≤0.001 for all). Reductions in extraocular muscle, orbital fat volume, or both were observed in 6 patients in the teprotumumab group who underwent orbital imaging. Most adverse events were mild or moderate in severity; two serious events occurred in the teprotumumab group, of which one (an infusion reaction) led to treatment discontinuation. CONCLUSIONS: Among patients with active thyroid eye disease, teprotumumab resulted in better outcomes with respect to proptosis, Clinical Activity Score, diplopia, and quality of life than placebo; serious adverse events were uncommon. (Funded by Horizon Therapeutics; OPTIC ClinicalTrials.gov number, NCT03298867, and EudraCT number, 2017-002763-18.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Oftalmopatia de Graves/tratamento farmacológico , Receptor IGF Tipo 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Diplopia/tratamento farmacológico , Método Duplo-Cego , Esquema de Medicação , Exoftalmia/tratamento farmacológico , Oftalmopatia de Graves/diagnóstico por imagem , Humanos , Análise de Intenção de Tratamento , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Órbita/diagnóstico por imagem , Receptor IGF Tipo 1/imunologia , Autorrelato
2.
J Hum Genet ; 65(2): 91-98, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31645654

RESUMO

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.

3.
Plast Reconstr Surg Glob Open ; 7(10): e2464, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31772892

RESUMO

The purpose of this article is to present a modified approach to the reconstruction of the upper and lower eyelids in floppy eyelid syndrome. A retrospective chart review was performed on all floppy eyelid patients who underwent simultaneous tightening of the upper and lower eyelid with a lateral tarsal strip, using a V-shaped incision in the lateral canthus, at University of Tennessee Hamilton Eye Institute from 2011 to 2012. Preoperative symptoms, surgical outcomes, complication rates, and postoperative symptoms were recorded. Nine eyes of 7 patients who underwent surgical correction for symptomatic floppy eyelids were included. All patients noted improvement in symptoms postoperatively, after reduction in the laxity of the upper and lower eyelid. Postoperative complications included buried lashes in the lateral canthus in 1 eye and a pyogenic granuloma in the lateral canthus of 1 eye. An excellent cosmetic outcome was noted in 78% (7/9) of eyes. No patients reported dissatisfaction nor required secondary surgical correction. The lateral canthal "V" incision provides an additional approach in the successful management of floppy eyelid syndrome involving the upper and lower eyelids. The design of the incision allows for excellent exposure of the lateral canthus for shortening of the eyelids with tarsal strip fixation, and it preserves the lateral canthal skin and canthus architecture. Further, the "V" incision is easily continued into the eyelid crease for blepharoplasty and ptosis repair when necessary.

5.
Ophthalmic Plast Reconstr Surg ; 35(6): e131-e134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31593045

RESUMO

Two patients with previously diagnosed pheochromocytoma presented with facial pain and ptosis. Imaging revealed orbital lesions. Both patients were referred for surgical evaluation of the orbital mass. Surgical excision was performed for both. Pathology confirmed metastatic pheochromocytoma. Pheochromocytomas commonly metastasize to bone, liver, and other tissues. Five cases of metastasis to orbital bone have been previously described. These 2 cases are unique in that the metastases were not hormonally active, presented soon after initial diagnosis, and were treated palliatively with surgical excision. Previous treatment of orbital bony metastasis used radiotherapy. These cases demonstrate that surgical resection is a viable treatment option in these situations. Orbital metastasis of pheochromocytomas should be considered with the appropriate clinical presentation. These are the first documented cases of intraorbital metastasis, separate from the bony walls. Previously, orbital bony wall metastases were treated with radiation. Surgical excision is a viable option for treatment of such metastases.Orbital involvement should be considered in patients with systemic disease presenting with new ocular findings.


Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias Hepáticas/patologia , Neoplasias Orbitárias/secundário , Feocromocitoma/secundário , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Orbit ; : 1-5, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31106645

RESUMO

PURPOSE: To describe common risk factors in patients with Essential Skin Shrinkage (ESS) and identify corresponding histopathologic changes in lower eyelids. METHODS: A case-control study was performed after an Internal Review Board approval was obtained. Consecutive patients who underwent surgical repair for ectropion with ESS of the lower eyelid were enrolled along with 10 control patients. Informed consent was obtained on all patients. Fitzpatrick skin type, history of sun exposure and non-melanoma skin cancer was obtained along with relevant physical exam findings. Skin samples obtained during surgical repair were evaluated by light microscopy for the extent of dermal actinic change. Statistical analysis was performed. RESULTS: Sixteen study subjects and 10 control patients were enrolled. Subjects were found to be predominantly male, older than controls (p = 0.0011) and have Fitzpatrick skin type (FST) I or II while controls had type I, II or III (p = 0.0221). Hours of sun exposure reported by subjects ranged from 23,165 to greater than 125,000 h, versus 1,459 to 46,890 h in controls (p = 0.0002). Nine of 16 (56%) subjects had a history of skin cancer compared to only 3/10 controls (30%) (p = 0.2475). Histopathologic evaluation using the Fritschi scale for dermal actinic damage identified an average grade of 3.6 for subjects and 2.4 for controls (p = 0.0095). CONCLUSIONS: ESS is predominantly seen in male individuals with FST I or II and a history of extensive sun exposure. Histopathologic evaluation shows moderate to severe actinic damage. These individuals frequently have concomitant non-melanoma skin cancer.

7.
Orbit ; : 1-5, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31106646

RESUMO

PURPOSE: Traditional (tCDCR) and endoscopic conjunctivodacryocystorhinostomy (eCDCR) are challenging surgical techniques requiring general anesthesia, a facial incision, and a large osteotomy and mucosal flap. Minimally invasive CDCR (miCDCR) techniques eliminate the need for some of the steps in t/eCDCR. Introduced here is a variation of the miCDCR technique using a Naugle-Fleming knurled dilator (NKD) to create the osteotomy and instruments within a central line catheter kit to help easily place or replace a Jones' tube into position within a bony conduit. METHODS: This IRB-approved retrospective chart review examined all patients who underwent this miCDCR technique performed by two oculoplastic surgeons at Hamilton Eye Institute at the University of Tennessee Health Sciences Center from 2014 to 2016. INCLUSION CRITERIA: need for CDCR (either primary or repeat). EXCLUSION CRITERIA: loss to follow up prior to six months. Primary endpoints: operative time, incidence of tube migration and complications, and cessation of epiphora. RESULTS: Sixteen patients (nine men, seven women) were reviewed, with three undergoing bilateral procedure, totaling 19 cases. Age range: 47.0 to 84.0 years, average of 66.6 years (SD = 11.1). Ten patients had surgery under local/MAC augmented with IV sedation, and six had general anesthesia (38%). Average operative time was 17.4 min (SD = 10.9). One patient (5%) required revision in the six-month immediate post-operative period because of tube migration. All patients had cessation of epiphora. CONCLUSIONS: This procedure can be done safely and quickly without general anesthesia, resulting in a satisfactorily lower rate of tube migration and cessation of epiphora rates.

9.
Ophthalmic Plast Reconstr Surg ; 35(5): 487-490, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30844914

RESUMO

PURPOSE: To analyze the spontaneous eyelid blink and sphincter closure activity of the orbicularis oculi by measuring the horizontal eyelid movement. METHODS: Individuals 18+ years of age, any ethnicity, and gender were recruited. Participants completed a questionnaire to determine eligibility. Exclusion criteria included the following: history of facial trauma, nerve palsy, surgery, use of periorbital neuromodulators or filler within the past year, thyroid eye disease, and eyelid or ocular surface disease. Data were collected from participants by decade. Eyelid blinks were recorded using the FPS 1000HD. The motions of 3 spontaneous blinks in primary gaze were recorded. All blinks were reviewed and one chosen for most accurate analysis. Horizontal palpebral fissure width and its changes of open and closed eye measurements were taken using National Institute of Health ImageJ software version 2.0. The data were subjected to SAS version 9.4 analysis using paired t test, t test, and linear models. RESULTS: One hundred thirty-six patients were recruited. Fourteen patients were excluded; 122 patients were used in analysis. Ages ranged from 22 to 90 years. Participants were divided into 6 groups according to age (20-29, 30-39, 40-49, 50-59, 60-69, and 70+ years of age). The average horizontal fissure length across all ages was 24.23 mm. Average change in horizontal fissure length decreased 1.42 mm among all ages. There was a statistically significant difference comparing age 20-29 decade to age 70+ decade. CONCLUSIONS: Horizontal fissure length changes with eyelid blink and defines 1 component of the eyelid sphincter.


Assuntos
Envelhecimento/fisiologia , Piscadela/fisiologia , Pálpebras/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1265-1272, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30682498

RESUMO

Human methylmalonyl-CoA epimerase (MCEE) catalyzes the interconversion of d-methylmalonyl-CoA and l-methylmalonyl-CoA in propionate catabolism. Autosomal recessive pathogenic variations in MCEE reportedly cause methylmalonic aciduria (MMAuria) in eleven patients. We investigated a cohort of 150 individuals suffering from MMAuria of unknown origin, identifying ten new patients with pathogenic variations in MCEE. Nine patients were homozygous for the known nonsense variation p.Arg47* (c.139C > T), and one for the novel missense variation p.Ile53Arg (c.158T > G). To understand better the molecular basis of MCEE deficiency, we mapped p.Ile53Arg, and two previously described pathogenic variations p.Lys60Gln and p.Arg143Cys, onto our 1.8 Šstructure of wild-type (wt) human MCEE. This revealed potential dimeric assembly disruption by p.Ile53Arg, but no clear defects from p.Lys60Gln or p.Arg143Cys. We solved the structure of MCEE-Arg143Cys to 1.9 Šand found significant disruption of two important loop structures, potentially impacting surface features as well as the active-site pocket. Functional analysis of MCEE-Ile53Arg expressed in a bacterial recombinant system as well as patient-derived fibroblasts revealed nearly undetectable soluble protein levels, defective globular protein behavior, and using a newly developed assay, lack of enzymatic activity - consistent with misfolded protein. By contrast, soluble protein levels, unfolding characteristics and activity of MCEE-Lys60Gln were comparable to wt, leaving unclear how this variation may cause disease. MCEE-Arg143Cys was detectable at comparable levels to wt MCEE, but had slightly altered unfolding kinetics and greatly reduced activity. These studies reveal ten new patients with MCEE deficiency and rationalize misfolding and loss of activity as molecular defects in MCEE-type MMAuria.

11.
J Inherit Metab Dis ; 42(4): 673-685, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30693532

RESUMO

Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl-CoA mutase and methionine synthase. Methylmalonyl-CoA mutase is required for the catabolism of certain (branched-chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl-Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl-Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S-adenosylmethionine, the most important cellular methyl-donor. Disruption of methionine synthase has wide-ranging implications for all methylation-dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5-methyltetrahydrofolate as a one-carbon donor. Folate-bound one-carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate-mediated one-carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.

12.
Am J Epidemiol ; 187(9): 2002-2010, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635277

RESUMO

We quantified measles transmissibility during a measles outbreak in Ohio in 2014 to evaluate the impact of public health responses. Case incidence and the serial interval (time between symptom onset in primary cases and secondary cases) were used to assess trends in the effective reproduction number R (the average number of secondary cases generated per case). A mathematical model was parameterized using early R values to determine the size and duration of the outbreak that would have occurred if containment measures had not been initiated, as well as the impact of vaccination. As containment started, we found a 4-fold decline in R (from approximately 4 to 1) over the course of 2 weeks and maintenance of R < 1 as control measures continued. Under a conservative scenario, the model estimated 8,472 cases (90% confidence interval (CI): 8,447, 8,489) over 195 days (90% CI: 179, 223) without control efforts and 715 cases (90% CI: 103, 1,338) over 128 days (90% CI: 117, 139) when vaccination was included; 7,757 fewer cases (90% CI: 7,130, 8,365) and 67 fewer outbreak days (90% CI: 48, 98) were attributed to vaccination. Vaccination may not account entirely for transmission reductions, suggesting that changes in community behavior (social distancing) and other control efforts (isolation, quarantining) are important. Our findings highlight the benefits of measles outbreak response and of understanding behavior change dynamics.


Assuntos
Sarampo/transmissão , Modelos Biológicos , Prática de Saúde Pública , Surtos de Doenças , Humanos , Sarampo/epidemiologia , Ohio/epidemiologia
13.
J Neurol Sci ; 383: 123-127, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-29246599

RESUMO

BACKGROUND: Methylenetetrahydrofolate-reductase (MTHFR) deficiency is a rare autosomal recessive disorder affecting intracellular folate metabolism with affection of different organ systems and clinical manifestation usually in childhood. OBJECTIVE: We report on four adult members of a family with MTHFR deficiency presenting with neurological and thromboembolic complications in adulthood. METHODS: Extensive diagnostic work-up including genetic testing was performed in four adult members. RESULTS: The male siblings aged 42 and 32years presented with various neurological symptoms, and a recent history of deep vein thrombosis. Extensive diagnostic work-up revealed total homocysteine (tHcy) plasma concentrations of 135µmol/L and 231µmol/L. and compound heterozygosity for two novel MTHFR gene mutations in exon 2 (c.202C>G, p.Arg68Gly) and intron 10 (c.1632+2T>G), and the known polymorphic variant MTHFR c.665C>T (p.Ala222Val, MTHFR 677C>T). Their mother was heterozygous for MTHFR c.1632+2T>G and c.665C>T, and a paternal relative was heterozygous for MTHFR c.202.C>G and MTHFR c.665C>T mutation. Both brothers showed partial response to therapy with betaine and multivitamins with clinical improvement. MTHFR activity was determined in fibroblast extracts and was around 4% of the mean control. Cell culture analysis indicated a re-methylation defect due to MTHFR deficiency. CONCLUSION: Severe hyperhomocysteinemia due to two mutations of the MTHFR gene resulted in severe neurological symptoms in adulthood. Vitamin and methionine supplementation stabilize tHcy plasma levels. Severity of clinical manifestation varied greatly between the siblings. Damages to the nervous system may be present for years before becoming clinically manifest.


Assuntos
Homocistinúria/complicações , Homocistinúria/fisiopatologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Espasticidade Muscular/complicações , Espasticidade Muscular/fisiopatologia , Tromboembolia/complicações , Tromboembolia/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Família , Feminino , Homocisteína/sangue , Homocistinúria/genética , Homocistinúria/terapia , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Espasticidade Muscular/genética , Espasticidade Muscular/terapia , Mutação , Transtornos Psicóticos/complicações , Transtornos Psicóticos/genética , Transtornos Psicóticos/fisiopatologia , Transtornos Psicóticos/terapia , Tromboembolia/genética , Tromboembolia/terapia
14.
Orbit ; 36(5): 322-324, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28742978

RESUMO

To compare post-operative results and complications in patients who undergo enucleation with or without suture closure of the conjunctiva. This was a retrospective chart review study. Review of 50 cases of enucleation surgery at the University of Arkansas for Medical Sciences and Arkansas Children's Hospital between July 2011 and December 2014. Criteria for inclusion in the study were all cases of enucleation that had extraocular muscles attached to a spherical orbital implant with or without conjunctival closure, and at least 2 months of postoperative follow up. Post-operative complications were evaluated. A total of 36 cases fulfilled the criteria for inclusion in the study; 12 cases with direct sutured layered direct closure of Tenon's and then conjunctiva and 24 cases with Tenon's capsule sutured closure but without direct conjunctival sutured closure. No implant complications were identified in either group (p = 1.0). Mean follow-up for all groups was 16.71 months (range 2 to 43 mo., SD 11.94). Mean follow up for the non-closure group was 14.42 months (range 2.25 to 36 mo., SD 10.35). Two cases in the conjunctival closure group developed a conjunctival cyst, affecting prosthesis fit, approximately 3 months postoperatively: no such cysts were identified in the non-conjunctival closure group. Fisher exact test for cyst formation between the two groups was not statistically significant (p = 0.1048). Direct conjunctival closure following enucleation surgery does not appear to increase the risk of extrusion, exposure, or infection. Foregoing direct closure decreases surgical time and reduces cost. It is unclear if this decreases conjunctival cyst formation.


Assuntos
Túnica Conjuntiva/cirurgia , Enucleação Ocular/métodos , Técnicas de Sutura , Cápsula de Tenon/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Oftalmopatias/cirurgia , Olho Artificial , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Músculos Oculomotores/cirurgia , Implantes Orbitários , Complicações Pós-Operatórias , Implantação de Prótese , Estudos Retrospectivos
15.
J Biol Chem ; 292(28): 11980-11991, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28572511

RESUMO

Vitamin B12 (cobalamin (Cbl)), in the cofactor forms methyl-Cbl and adenosyl-Cbl, is required for the function of the essential enzymes methionine synthase and methylmalonyl-CoA mutase, respectively. Cbl enters mammalian cells by receptor-mediated endocytosis of protein-bound Cbl followed by lysosomal export of free Cbl to the cytosol and further processing to these cofactor forms. The integral membrane proteins LMBD1 and ABCD4 are required for lysosomal release of Cbl, and mutations in the genes LMBRD1 and ABCD4 result in the cobalamin metabolism disorders cblF and cblJ. We report a new (fifth) patient with the cblJ disorder who presented at 7 days of age with poor feeding, hypotonia, methylmalonic aciduria, and elevated plasma homocysteine and harbored the mutations c.1667_1668delAG [p.Glu556Glyfs*27] and c.1295G>A [p.Arg432Gln] in the ABCD4 gene. Cbl cofactor forms are decreased in fibroblasts from this patient but could be rescued by overexpression of either ABCD4 or, unexpectedly, LMBD1. Using a sensitive live-cell FRET assay, we demonstrated selective interaction between ABCD4 and LMBD1 and decreased interaction when ABCD4 harbored the patient mutations p.Arg432Gln or p.Asn141Lys or when artificial mutations disrupted the ATPase domain. Finally, we showed that ABCD4 lysosomal targeting depends on co-expression of, and interaction with, LMBD1. These data broaden the patient and mutation spectrum of cblJ deficiency, establish a sensitive live-cell assay to detect the LMBD1-ABCD4 interaction, and confirm the importance of this interaction for proper intracellular targeting of ABCD4 and cobalamin cofactor synthesis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Lisossomos/metabolismo , Erros Inatos do Metabolismo/genética , Modelos Moleculares , Mutação , Proteínas de Transporte Nucleocitoplasmático/genética , Transportadores de Cassetes de Ligação de ATP/química , Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Substituição de Aminoácidos , Domínio Catalítico , Linhagem Celular Transformada , Células Cultivadas , Células HeLa , Humanos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Lisossomos/enzimologia , Lisossomos/patologia , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/patologia , Simulação de Acoplamento Molecular , Proteínas de Transporte Nucleocitoplasmático/química , Proteínas de Transporte Nucleocitoplasmático/deficiência , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Transporte Proteico , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Homologia Estrutural de Proteína , Vitamina B 12/metabolismo
16.
J Clin Diagn Res ; 11(3): NC05-NC08, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28511421

RESUMO

INTRODUCTION: Blepharophimosis Syndrome (BPES) is a complex and rare disease characterized by epicanthus inversus, telecanthus, lateral ectropion, narrowed or shortened inter-palpebral fissure distance and ptosis. It is mostly bilateral and may or may not be symmetrical. It is typically inherited as an autosomal dominant trait. In sporadic cases, the disease may occur without a prior family history as a genetic mutation from a deletion or translocation of the FOXL2 gene, which maps to chromosome 3q23. Surgical treatment of this disease poses an oculoplastic challenge due to multiple complex eyelid deformities. AIM: To evaluate the functional and cosmetic outcome of telecanthus and epicanthus correction by a Mustarde's rectangular double Z-Plasty and trans-nasal fixation using 1-0 prolene suture in BPES. MATERIALS AND METHODS: This was prospective, interventional study of 16 patients over a period of three years. In this study, all patients had BPES with prominent epicanthus and telecanthus. Mustarde's double Z-plasty and trans-nasal fixation with 1-0 prolene suture was performed in the first of a two-stage operation. If ectropion was present, the lateral ectropion was corrected by a base-out flap transfer from the upper eyelid to the lower eyelid. After three months, a 2nd stage was undertaken, involving a lateral canthoplasty for horizontal widening of a short palpebral fissure and a tarso frontalis sling with silicone rod for correction of moderate to severe ptosis. Patients were followed up for six months to one year with postoperative ophthalmologic examinations and photographs. RESULTS: Out of 16 patients, 10 were females and six were males. All the patients had bilateral involvement. In this study preoperative Inner Intercanthal Distance (IICD) ranged from 38 mm to 42 mm and the mean IICD was 41.2±0.57 mm. Postoperative IICD ranged from 31 mm to 34 mm. Horizontal Palpebral Fissure Length (HPFL) ranged from 20 mm to 23 mm and the mean value of HPFL was 21.50 mm preoperatively. Postoperative HPFL ranged from 26 mm to 29 mm and had a mean value of 28.50 mm, which was much improved after a combined correction of telecanthus and lateral canthoplasty. The mean preoperative IICD and HPFL ratio was 1.77 and was reduced to a postoperative value of 1.2. The Marginal Reflex Distance1 (MRD-1) test value improved from +1.25 mm to +3.50 mm postoperatively after placement of a tarsofrontalis sling with silicone rod using the Fox's Pentagon technique. In this study, two eyes had minimal unequal correction but were cosmetically and functionally acceptable. Correction of IICD is possible up to 6 mm. No major complication e.g., CSF rhinorrhea was noted in this series and preoperative prominent epicanthal folds were abolished. CONCLUSION: Here we propose a two-staged procedure involving a combined Mustarde's double Z-plasty with transnasal fixation using a 1-0 prolene suture with a flap transfer from the upper lid to the lower lid in the first stage and a lateral canthoplasty with a tarsofrontalis sling and silicone rod in the second stage. This technique is effective to correct epicanthus, telecanthus, ptosis and lateral ectropion in BPES with good cosmetic and functional outcome.

17.
J Vasc Surg Venous Lymphat Disord ; 5(3): 358-362, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28411703

RESUMO

OBJECTIVE: Although duplex ultrasound (DUS) imaging is the current gold standard in the diagnosis of femoropopliteal deep venous thrombosis, it is not an optimal diagnostic modality to diagnose iliocaval occlusion. Screening for iliocaval occlusion thus remains a challenge for clinicians because of the lack of a reliable noninvasive technique. This challenge results in most patients undergoing computed tomography venography or magnetic resonance venography or invasive venography and intravascular ultrasound imaging. This study reports a novel, yet simple, reproducible and intuitive, surface DUS finding of physiologic flow reversal within the superficial epigastric vein (SEV) as a sign of proximal iliocaval occlusion (ICO). METHODS: This was a retrospective study of 15 patients who were diagnosed with ICO based on the finding of SEV flow reversal on DUS imaging. Patient demographics, presenting CEAP C scores, ICO characteristics, correlation with advanced imaging, and short-term follow-up findings are reported. RESULTS: Physiologic reversal of the SEV resulted in confirmation of ICO in all patients who underwent advanced imaging, including computed tomography venography or traditional venogram along with intravascular ultrasound imaging. All patients who underwent follow-up DUS scans demonstrated normalization of the SEV flow after ICO recanalization. CONCLUSIONS: ICO can result in deep venous thrombosis, post-thrombotic syndrome, and chronic venous insufficiency. Physiologic flow reversal in SEV is diagnostic of ICO. To the best of our knowledge, this is the first report of this novel DUS finding.


Assuntos
Veia Ilíaca , Doenças Vasculares/diagnóstico por imagem , Veia Cava Inferior , Adulto , Idoso , Idoso de 80 Anos ou mais , Circulação Sanguínea/fisiologia , Constrição Patológica/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estômago/irrigação sanguínea , Ultrassonografia Doppler/métodos , Trombose Venosa/complicações , Adulto Jovem
19.
J Inherit Metab Dis ; 40(2): 297-306, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27743313

RESUMO

5,10-Methylenetetrahydrofolate reductase (MTHFR) catalyzes the NADPH-dependent reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate using FAD as the cofactor. Severe MTHFR deficiency is the most common inborn error of folate metabolism, resulting in hyperhomocysteinemia and homocystinuria. Approximately 70 missense mutations have been described that cause severe MTHFR deficiency, however, in most cases their mechanism of dysfunction remains unclear. Few studies have investigated mutational specific defects; most of these assessing only activity levels from a handful of mutations using heterologous expression. Here, we report the in vitro expression of 22 severe MTHFR missense mutations and two known single nucleotide polymorphisms (p.Ala222Val, p.Thr653Met) in human fibroblasts. Significant reduction of MTHFR activity (<20 % of wild-type) was observed for five mutant proteins that also had highly reduced protein levels on Western blot analysis. The remaining mutations produced a spectrum of enzyme activity levels ranging from 22-122 % of wild-type, while the SNPs retained wild-type-like activity levels. We found increased thermolability for p.Ala222Val and seven disease-causing mutations all located in the catalytic domain, three of which also showed FAD responsiveness in vitro. By contrast, six regulatory domain mutations and two mutations clustering around the linker region showed increased thermostability compared to wild-type protein. Finally, we confirmed decreased affinity for NADPH in individual mutant enzymes, a result previously described in primary patient fibroblasts. Our expression study allows determination of significance of missense mutations in causing deleterious loss of MTHFR protein and activity, and is valuable in detection of aberrant kinetic parameters, but should not replace investigations in native material.


Assuntos
Homocistinúria/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Espasticidade Muscular/genética , Mutação de Sentido Incorreto/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Domínio Catalítico/genética , Fibroblastos/metabolismo , Genótipo , Humanos , Hiper-Homocisteinemia/genética , Cinética , Proteínas Mutantes/genética , NADP/genética , Polimorfismo de Nucleotídeo Único/genética , Transtornos Psicóticos/genética , Tetra-Hidrofolatos/genética
20.
Artigo em Inglês | MEDLINE | ID: mdl-27709111

RESUMO

The study of single cells has evolved over the past several years to include expression and genomic analysis of an increasing number of single cells. Several studies have demonstrated wide spread variation and heterogeneity within cell populations of similar phenotype. While the characterization of these populations will likely set the foundation for our understanding of genomic- and expression-based diversity, it will not be able to link the functional differences of a single cell to its underlying genomic structure and activity. Currently, it is difficult to perturb single cells in a controlled environment, monitor and measure the response due to perturbation, and link these response measurements to downstream genomic and transcriptomic analysis. In order to address this challenge, we developed a platform to integrate and miniaturize many of the experimental steps required to study single-cell function. The heart of this platform is an elastomer-based integrated fluidic circuit that uses fluidic logic to select and sequester specific single cells based on a phenotypic trait for downstream experimentation. Experiments with sequestered cells that have been performed include on-chip culture, exposure to various stimulants, and post-exposure image-based response analysis, followed by preparation of the mRNA transcriptome for massively parallel sequencing analysis. The flexible system embodies experimental design and execution that enable routine functional studies of single cells.

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