Open Surgical Conversion of Popliteal Endograft Infection: Case Reports and Literature Review.

BACKGROUND: Endovascular treatment of popliteal aneurysms (PA) has increased in the last few years, quickly becoming the main treatment performed in many vascular centers, based on the acceptable and promising outcomes reported in the literature. However, endograft infections after endovascular popliteal aneurysm repair (EPAR) are the most dangerous complications to occur as they involve serious local compromise and usually require open surgical conversion and device explantation to preserve the affected extremity. CASE REPORT: We report two patients who were admitted to the emergency room of our hospital for pain and edema in the lower leg. Both patients had undergone exclusion of a ruptured PA a few years before by endovascular graft. CTA testing showed a significant volume of fluid-corpuscular collection related to perianeurysmal abscess collection in both cases. Blood cultures and drained material cultures were positive for Staphylococcus capitis in the first case and S. aureus in the second. Prophylactic antibiotics were administered for 10 days, then patients underwent an open surgical conversion with the complete explantation of endovascular material and a femoro-popliteal bypass using an autologous vein in the first case and a biological bovine pericardium prosthesis in the second case. The infective department of our hospital had defined a discharged specific antibiotic therapy for each patient, based on intraoperative microbiological samples. Furthermore, we have examined the literature and found six more cases described in case report articles that refer to popliteal graft infections by different microorganisms, mostly presenting acute limb ischemia as the first symptom and suggesting endograft explantation with open conversion and autologous vein bypass as the commonest therapeutic choice. CONCLUSIONS: The open surgical conversion of popliteal endograft infection is the best strategy to manage peripheral infection after an endovascular popliteal aneurysm repair procedure.

Successful Versus Failed Transition From Controlled Ventilation to Pressure Support Ventilation in COVID-19 Patients: A Retrospective Cohort Study.

OBJECTIVES: In patients with COVID-19 respiratory failure, controlled mechanical ventilation (CMV) is often necessary during the acute phases of the disease. Weaning from CMV to pressure support ventilation (PSV) is a key objective when the patient's respiratory functions improve. Limited evidence exists regarding the factors predicting a successful transition to PSV and its impact on patient outcomes. DESIGN: Retrospective observational cohort study. SETTING: Twenty-four Italian ICUs from February 2020 to May 2020. PATIENTS: Mechanically ventilated ICU patients with COVID-19-induced respiratory failure. INTERVENTION: The transition period from CMV to PSV was evaluated. We defined it as "failure of assisted breathing" if the patient returned to CMV within the first 72 hours. MEASUREMENTS AND MAIN RESULTS: Of 1260 ICU patients screened, 514 were included. Three hundred fifty-seven patients successfully made the transition to PSV, while 157 failed. Pao2/Fio2 ratio before the transition emerged as an independent predictor of a successful shift (odds ratio 1.00; 95% CI, 0.99-1.00; p = 0.003). Patients in the success group displayed a better trend in Pao2/Fio2, Paco2, plateau and peak pressure, and pH level. Subjects in the failure group exhibited higher ICU mortality (hazard ratio 2.08; 95% CI, 1.42-3.06; p < 0.001), an extended ICU length of stay (successful vs. failure 21 ± 14 vs. 27 ± 17 d; p < 0.001) and a longer duration of mechanical ventilation (19 ± 18 vs. 24 ± 17 d, p = 0.04). CONCLUSIONS: Our study emphasizes that the Pao2/Fio2 ratio was the sole independent factor associated with a failed transition from CMV to PSV. The unsuccessful transition was associated with worse outcomes.

Isolated Intramural Hematoma of Superior Mesenteric Artery: Case Reports and a Review of Literature.

(1) Background: Spontaneous isolated intramural hematoma of the superior mesenteric artery (SIHSMA) is a rare entity often considered as a subset of spontaneous isolated dissection of the superior mesenteric artery (SIDSMA). It is characterized by a completely thrombosed false lumen with or without an ulcer-like projection with computed tomography (CT) imaging. The recent literature describes few reports with a relatively short-term follow-up. The natural course, prognosis, and treatment options for SIHSMA still lack consensus. We present two cases of acute abdominal pain in a young man due to IMH of the superior mesenteric artery with an extensive literature review. (2) Case report: A 46-year-old male patient was submitted to an urgent CTA for acute abdominal pain, showing the presence of an isolated dissection of the superior mesenteric artery, determining significant stenosis of the vessel with collateral vessel patency. The patient referred to a recent COVID-19 infection, whose course was paucisymptomatic. He was conservatively treated with antiplatelet therapy and corticosteroid treatments, and, after a few days, the symptomatology completely regressed; also, the 2-month-control CTA showed complete IMH regression and the absence of any signs of residual stenosis. The second patient was a 61-year-old male patient who was submitted to an urgent CTA for acute abdominal pain, showing the presence of an isolated dissection of the superior mesenteric artery, not determining significant vessel stenosis. He was conservatively treated with antiplatelet therapy and corticosteroid treatment, and after a few days, the symptomatology completely regressed and the radiological control showed complete dissection regression. (3) Conclusion: SISHSMA is a rare entity of vascular pathology, and conservative management represents the best medical strategy. We propose corticosteroid treatment as one of the most appropriate tools in the conservative treatment of SISHSMA.

Agreement Between Viscoelastic Coagulation Monitor (VCM), TEG 5000, and Coagulation Tests in Critically Ill Patients: A Multicenter Study.

The performance of viscoelastic coagulation monitor (VCM) compared with TEG 5000 (TEG) is unknown. In this multicenter study, the authors evaluated the agreement among VCM/TEG parameters and their relationship with standard coagulation tests in critically ill patients. Viscoelastic coagulation monitor, TEG, and laboratory samples were analyzed simultaneously. Viscoelastic coagulation monitor/TEG agreement was computed by Bland and Altman's plots, association with laboratory parameters was studied with Spearman's correlation coefficient and random-intercept linear models. One-hundred and twenty-seven patients enrolled, 320 paired observations: 210 (65.6%) under unfractioned heparin (UFH), 94 (29.4%) under low molecular weight heparin (LMWH), 16 (5.0%) no heparin. Under UFH prolonged clot formation times and reduced the amplitude of viscoelastic tracings on both devices, especially on TEG. The type of heparin affected the agreement between VCM/TEG homolog parameters. Reaction time (TEG-R) resulted 23.1 min longer than the homolog clotting time (VCM-CT) under UFH; maximum amplitude (TEG-MA) resulted 29.5 mm higher than maximum clot firmness (VCM-MCF) under LMWH. Weak correlation was observed between VCM-CT/TEG-R and activated partial thromboplastin time (aPTT)/anti-Xa; no correlation was found between VCM-alpha/TEG-angle and fibrinogen concentration. Viscoelastic coagulation monitor-MCF showed strong (LWMH) to moderate (UFH) correlation with platelet count, while TEG-MA only showed lower correlation. Viscoelastic coagulation monitor and TEG are differently affected by heparin. The platelet count is well represented by VCM-MCF even during UFH administration.

A comparative multicentric long-term study of un-augmented modified Nishida procedure vs augmentation in unilateral sixth nerve palsy.

PURPOSE: To compare the effectiveness of three procedures: modified Nishida procedure alone vs modified Nishida procedure combined with medial rectus recession (MRc) vs modified Nishida procedure combined with MRc and botulinum toxin (BT) for severe unilateral sixth nerve palsy. DESIGN: Consecutive, interventional case series. METHODS: The medical records of a consecutive series of patients with severe unilateral sixth nerve palsy who underwent modified Nishida procedure in multiple centres were reviewed. Surgical technique was decided preoperatively at the surgeon's discretion. The preoperative and postoperative findings were compared. RESULTS: Of the 43 patients with abducens palsy that received the procedure, 32 were included (mean age 38.6 ± 19.8 years). Mean preoperative deviation was 63.0 ± 27.3 prism dioptres (PD) and mean limitation of abduction -4.5 ± 1.2. Five patients underwent a modified Nishida procedure alone, 24 patients had an additional MRc and 3 patients were also injected with BT. Overall, the average correction of modified Nishida technique by itself was 29.4 ± 6.6 PD (range 20-36) and adding a MRc corrected 62.6 ± 23.8 PD (range 24-120). Modified Nishida procedure, MRc and BT altogether corrected 95.0 ± 18.0 PD (range 75-110). No postoperative complications were observed in any of the patients. CONCLUSIONS: Excellent outcomes with fewer complications are obtained with modified Nishida procedure alone. The need for additional procedures such as MRc and BT which increase the effect in primary position can be determined depending on passive duction and preoperative horizontal deviation.

Modified Nishida's procedure in a case of medial rectus hypoplasia.

Introduction: We report a case of large angle exotropia in a child with limitation of adduction in the left eye with a radiological finding of hypoplastic medial rectus. Methods: A 3- year- old male child presented with left eye large angle exotropia, left face turn, -4 adduction limitation and severe amblyopia. Orbital imaging revealed hypoplasia of the medial rectus and intraoperatively a thin medial rectus was noted. The surgical procedure planned was lateral rectus recession combined with Modified Nishida's technique in the left eye. In this technique the superior and inferior recti were transposed medially by inserting non-absorbable sutures in the sclera posteriorly, closer to the upper and lower borders of the medial rectus muscle. Result: There was improvement in adduction of left eye and reduction of original deviation following maximal lateral rectus recession and a modified Nishida's approach. The early and optimal correction of exotropia also improved the compliance to patching with subsequent gain in visual acuity of the amblyopic eye. Conclusion: Modified Nishida's technique has the advantage of no muscle splitting and no tenotomy, remains a less invasive surgical procedure to correct large deviations. The modification of placing the bellies closer to medial rectus augments the effect and further improves adduction in cases with severe limitation of adduction. This technique can thus be considered as a possible surgical approach in young children with large angle exotropia due to hypoplastic medial rectus.

Latent Dirichlet allocation model for world trade analysis.

International trade is one of the classic areas of study in economics. Its empirical analysis is a complex problem, given the amount of products, countries and years. Nowadays, given the availability of data, the tools used for the analysis can be complemented and enriched with new methodologies and techniques that go beyond the traditional approach. This new possibility opens a research gap, as new, data-driven, ways of understanding international trade, can help our understanding of the underlying phenomena. The present paper shows the application of the Latent Dirichlet allocation model, a well known technique in the area of Natural Language Processing, to search for latent dimensions in the product space of international trade, and their distribution across countries over time. We apply this technique to a dataset of countries' exports of goods from 1962 to 2016. The results show that this technique can encode the main specialisation patterns of international trade. On the country-level analysis, the findings show the changes in the specialisation patterns of countries over time. As traditional international trade analysis demands expert knowledge on a multiplicity of indicators, the possibility of encoding multiple known phenomena under a unique indicator is a powerful complement for traditional tools, as it allows top-down data-driven studies.

Quiste congénito del conducto nasolacrimal/dacrio-cistocele: causa de dacriocistitis no diagnosticada / Congenital cyst of nasolacrimal duct/dacriocistocele: cause of non-diagnosed dacriocistitis

RESUMEN Se presenta dos casos de pacientes menores de 5 meses los cuales durante las primeras semanas de vida presentan descarga ocular muco-purulenta de manera recurrente. Posteriormente en la endoscopia se encuentra en los dos casos masas quísticas intranasales dando un diagnóstico de dacriocistocele más quiste congénito del conducto nasolagrimal. El dacriocistocele es una causa muy rara de obstrucción del conducto nasal y más raro cuando viene acompañado de un quiste congénito del conducto nasolagrimal. Debido a su rareza y a su sintomatología muchas veces atípica resulta en un diagnóstico complicado para el otorrinolaringólogo y para el oftalmólogo.

ABSTRACT Two cases of patients younger than 5 months are presented, who during the first weeks of life have recurrent muco-purulent ocular dis-charge. Subsequently, in endoscopy, in both cases, intranasal cystic masses were found, resulting in a diagnosis of dacryocystocele plus congenital cyst of the lacrimal duct. Dacryocystocele is an uncommon cause of nasal duct obstruction, but it becomes less common when accompanied by a congenital tear duct cyst. Due to its uncommonness and its often-atypical symptoms, it results in a complicated diagnosis for the ENT and the ophthalmologist.

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy.

Importance: Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU). Objective: To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy. Design, Setting, and Participants: This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020. Exposures: Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission. Main Outcomes and Measures: Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression. Results: Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29). Conclusions and Relevance: In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.

Challenging Surgical Approach to a Lost Inferior Rectus Muscle Following Penetrating Orbital Trauma.

A 37-year-old man suffered a penetrating left orbital injury with rupture of the inferior rectus muscle and avulsion of the optic nerve. The orbit was explored and the inferior rectus muscle stump was identified 25 mm from the limbus. Despite this, the muscle was successfully reattached and the patient achieved satisfactory postoperative alignment. [J Pediatr Ophthalmol Strabismus. 2019;56:e49-e52.].

Bilateral Symmetric and Asymmetric Superior Rectus Recession for Patients with Dissociated Vertical Deviation.

PURPOSE: To evaluate the outcome of bilateral symmetric and asymmetric superior rectus (SR) recessions in patients with bilateral dissociated vertical deviation (DVD) without oblique dysfunction and determine factors that might influence the surgical outcome. DESIGN: Retrospective study. METHODS: All patients who underwent bilateral SR recession for bilateral DVD from January 2012 to December 2016 at an eye hospital in New Delhi, India were included. Indication for surgery was decompensated DVD in 1 or both eyes. Symmetric SR recession was performed for symmetric DVD and asymmetric SR recession was performed for asymmetric DVD of 10 prism diopters (PD) or more. Patients with a minimum follow-up of 6 months were included. Success was defined as absence of manifest DVD in both eyes at the final postoperative visit. RESULTS: Medical records of 27 patients were analyzed. Their median age at surgery was 8 years [interquartile range (IQR), 6-10 years] and mean follow-up was 16.3 months (range, 6-48 months). Symmetric and asymmetric surgeries were performed in 19 and 8 patients, respectively. The amount of SR recession performed ranged from 5 to 10 mm. The median DVD reduced from 9 PD (IQR, 6-14 PD) to 5 PD (IQR, 3-8 PD) in the right eye (P = 0.015) and 9 PD (IQR, 7-12 PD) to 6 PD (IQR, 3-10 PD) in the left eye (P = 0.016) after surgery. Successful outcome was seen in 63% of patients. There was no difference in successful outcome with respect to age, sex, preoperative horizontal deviation, preoperative vertical deviation, postoperative residual horizontal deviation, surgical technique, asymmetry of SR recession, and magnitude of preoperative DVD. Patients with a preference for fixation were more likely to have a successful outcome. CONCLUSIONS: Bilateral SR recession resulted in a success rate of 63% after single operation for bilateral DVD without oblique dysfunction. We found that the probability of a successful outcome did not depend on age at surgery, sex, preoperative horizontal or vertical deviation, magnitude of preoperative DVD, symmetry of SR recession, or surgical technique.

Pediatric Frontalis Suspension With Braided Polyester: A Comparison of Two Techniques.

PURPOSE: To demonstrate the benefits of using braided polyester in the management of severe or recurrent ptosis in children and young adults and to compare the efficacy of two surgical techniques. METHODS: Retrospective, non-randomized record review of 30 patients (43 eyelid procedures) affected by congenital or acquired severe ptosis who underwent frontalis suspension with braided polyester from 2008 to 2016. Two surgical techniques were compared: the base-down triangle and the Fox pentagon, both of which were performed using a closed technique. Functional success was defined as clearing of the visual axis. Complications and results were examined. RESULTS: Functional success was obtained in 39 eyes of 43 procedures. Marginal reflex distance increased an average of 2.51 mm with the base-down triangle technique and 1.70 mm with the Fox pentagon technique (P = .05). The vertical palpebral fissure height increased an average of 4.60 mm with the base-down triangle technique and 2.45 mm with the Fox pentagon technique (P < .001). Mean follow-up duration was 38.6 months. Complications included untied suture (n = 2), suture dehiscence (n = 1), cellulitis (n = 2), and granuloma (n = 1). CONCLUSIONS: Braided polyester was found to be a safe, effective, easy-to-handle, and low-cost sling material for frontalis suspension and should be considered for clinical use, especially in developing countries where the cost and availability of other materials represents a significant barrier to treatment. In the authors' experience, the base-down triangle technique appeared superior to the Fox pentagon technique. [J Pediatr Ophthalmol Strabismus. 2018;55(4):229-233.].

Italian COnsensus in Neuroradiological Anesthesia (ICONA).

Anesthetic management of patients undergoing endovascular procedures for treating intracranial aneurysms or cerebrovascular malformations must consider a number of specific challenges, in addition to those associated with anesthesia for other specialties. In addition to maintenance of physiological stability, manipulation of systemic and cerebral hemodynamic parameters may be required to treat any sudden unexpected catastrophic neurological events. A multidisciplinary group including neuro- and pediatric anesthesiologists, interventional neuroradiologists, neurosurgeons, and a clinical methodologist contributed to this document. This consensus working group from 21 Italian institutions identified open questions regarding the best practices for management of anesthesia during endovascular neuroradiological procedures for intracranial aneurysms and cerebrovascular malformations, and addressed these by formulating practical consensus statements. At the first meeting in November 2015, nine key areas were identified regarding choice of anesthetic, patient monitoring, hemodynamic targets, postoperative care, and the management of neuromuscular blockade, anticoagulant and/or antiplatelet therapy, and special considerations for pediatric patients. Nine subgroups were established and a medical librarian performed literature searches in the Cochrane and MEDLINE/PubMed databases for each group. Groups drafted literature summaries and provisional responses in the form of candidate consensus statements based on evidence, when possible, and clinical experience, when this was lacking. Final wording was agreed at a meeting in April 2016 and where possible evidence was graded using United States Preventive Services Task Force criteria. Consensus (defined as >90% agreement) was based on evidence, clinical experience, clinician preference, feasibility in the Italian healthcare system, and cost/benefit considerations.

Variants in SKP1, PROB1, and IL17B genes at keratoconus 5q31.1-q35.3 susceptibility locus identified by whole-exome sequencing.

Keratoconus (KTCN) is a protrusion and thinning of the cornea, resulting in impairment of visual function. The extreme genetic heterogeneity makes it difficult to discover factors unambiguously influencing the KTCN phenotype. In this study, we used whole-exome sequencing (WES) and Sanger sequencing to reduce the number of candidate genes at the 5q31.1-q35.3 locus and to prioritize other potentially relevant variants in an Ecuadorian family with KTCN. We applied WES in two affected KTCN individuals from the Ecuadorian family that showed a suggestive linkage between the KTCN phenotype and the 5q31.1-q35.3 locus. Putative variants identified by WES were further evaluated in this family using Sanger sequencing. Exome capture discovered a total of 173 rare (minor allele frequency <0.001 in control population) nonsynonymous variants in both affected individuals. Among them, 16 SNVs were selected for further evaluation. Segregation analysis revealed that variants c.475T>G in SKP1, c.671G>A in PROB1, and c.527G>A in IL17B in the 5q31.1-q35.3 linkage region, and c.850G>A in HKDC1 in the 10q22 locus completely segregated with the phenotype in the studied KTCN family. We demonstrate that a combination of various techniques significantly narrowed the studied genomic region and reduced the list of the putative exonic variants. Moreover, since this locus overlapped two other chromosomal regions previously recognized in distinct KTCN studies, our findings suggest that this 5q31.1-q35.3 locus might be linked with KTCN.

Pharmacological Modulation of Ischemic-Reperfusion Injury during Pringle Maneuver in Hepatic Surgery. A Prospective Randomized Pilot Study.

BACKGROUND: The Pringle maneuver, which is performed during liver surgery to reduce blood loss, may result in liver ischemia/reperfusion injury resulting in metabolic, immunological, and microvascular changes, which may lead to hepatocellular damage. The aim of this study was the investigation of the effects of N-acetylcysteine (NAC) and methylprednisolone (MET) in the modulation of liver warm ischemia during hepatic resection. METHODS: Forty-eight patients were enrolled in a pilot double-blind, randomized clinical trial. The patients received either NAC, MET, or placebo. The primary endpoint was the reduction in postoperative alanine aminotransferase and bilirubin. The secondary endpoint was the difference in morbidity and mortality. RESULTS: All the 48 patients had liver resection with no mortality. Morbidity was observed in 8 (16 %) patients equally distributed among the groups. There was a significant favorable recovery of liver function tests in patients treated with NAC or MET compared with the placebo when the Pringle maneuver exceeded 70 min. CONCLUSIONS: The administration of NAC or MET prior to the Pringle maneuver during hepatic resection is associated with lower postoperative aberration in liver function tests compared with placebo when the Pringle maneuver exceeded 70 min. Larger studies are required to validate our findings and to investigate the specific role of NAC and MET in liver surgery.

Variant c.2262A>C in DOCK9 Leads to Exon Skipping in Keratoconus Family.

PURPOSE: Keratoconus (KTCN) is a degenerative disorder of the eye that is characterized by a conical shape and thinning of the cornea, resulting in impaired visual function. Previously, we identified heterozygous single base-pair substitutions in DOCK9, IPO5, and STK24, showing concurrent 100% segregation with the affected phenotype in an Ecuadorian family. As the pathogenic consequences of these variants were not obvious, we performed in vitro splicing analyses to determine their functional significance. METHODS: We generated expression constructs using patient DNA as a template corresponding to the wild-type and mutant alleles of DOCK9, IPO5, and STK24. After transfecting HeLa cells with each construct, total RNA samples were extracted, reverse transcribed, and amplified using specific primers. RESULTS: In vitro splicing analysis revealed that only c.2262A>C in exon 20 of DOCK9 led to aberrant splicing, resulting in the changed ratio between two protein isoforms: a normal transcript and a transcript with exon skipping. The exon skipping causes a premature stop codon, disrupting the functional domains of DOCK9 protein, which may alter the biological role of DOCK9 as a Cdc42 activator. CONCLUSIONS: Based on in vitro results, we demonstrated that c.2262A>C substitution in DOCK9, previously identified in KTCN-affected members of an Ecuadorian family, leads to a splicing aberration. However, because the mutation effect was observed in vitro, a definitive relationship between DOCK9 and KTCN phenotype could not be established. Our results indicate that further elucidation of the causes of KTCN is needed.

Substitution at IL1RN and deletion at SLC4A11 segregating with phenotype in familial keratoconus.

PURPOSE: Keratoconus (KTCN) is a thinning and anterior protrusion of the cornea that results in altered refractive powers and loss of visual acuity. Despite numerous studies, the reasons for development and progression of KTCN remain unknown. Genetic studies have led to identification of several loci linked with KTCN, including a locus in one multigenerational Ecuadorian family. The purpose of this study was to identify sequence variants in candidate genes segregating with the KTCN phenotype in another Ecuadorian family. METHODS: Nonparametric linkage analysis was performed in Ecuadorian family KTCN-019. Candidate genes IL1A, IL1B, IL1RN, and SLC4A11 were selected and examined in this family by direct sequencing of all exons, promoters, and intron-exon junctions. RESULTS: Two novel suggestive loci were identified in 2q13-q14.3 and 20p13-p12.2. Screening of the candidate genes revealed 66 sequence variants, including five novel variants, in both coding and noncoding regions. The substitution c.214+242C > T in the IL1RN gene was observed in all affected individuals and three apparently unaffected family members. The novel deletion of 54 nucleotides in position c.2558+149_2558+203 in SLC4A11 was observed in all patients but one, as well as two healthy individuals and one person with an unknown phenotype. CONCLUSIONS: The analyses of selected genes have led to identification of numerous sequence variants in the examined Ecuadorian family. Both substitution c.214+242C > T in IL1RN and novel deletion c.2558+149_2558+203del54 in SLC4A11 were observed significantly more frequently in family members with KTCN (P = 0.004525 and P = 0.00761, respectively), suggesting involvement of these two genes in KTCN etiology in the studied family.