Prevalence and Complications of Aberrant Subclavian Artery in Patients With Heritable and Nonheritable Arteriopathies.

BACKGROUND: An aberrant subclavian artery (ASA) (or lusoria) is the most common congenital anomaly of the aortic arch (0.5%-2.2%; female-to-male ratio 2:1 to 3:1). ASA can become aneurysmal and result in dissection, involving Kommerell's diverticulum when present and the aorta. Data of its significance in genetic arteriopathies are not available. OBJECTIVES: The purpose of this study was to assess the prevalence and complications of ASA in gene-positive and -negative nonatherosclerotic arteriopathies. MATERIALS: The series includes 1,418 consecutive patients with gene-positive (n = 854) and gene-negative arteriopathies (n = 564) diagnosed as part of institutional work-up for nonatherosclerotic syndromic and nonsyndromic arteriopathies. Comprehensive evaluation includes genetic counseling, next-generation sequencing multigene testing, cardiovascular and multidisciplinary assessment, and whole-body computed tomography angiography. RESULTS: ASA was found in 34 of 1,418 cases (2.4%), with a similar prevalence in gene-positive (n = 21 of 854, 2.5%) and gene-negative (n = 13 of 564, 2.3%) arteriopathies. Of the former 21 patients, 14 had Marfan syndrome, 5 had Loeys-Dietz syndrome, 1 had type-IV Ehlers-Danlos syndrome, and 1 had periventricular heterotopia type 1. ASA did not segregate with genetic defects. Dissection occurred in 5 of 21 patients with genetic arteriopathies (23.8%; 2 Marfan syndrome and 3 Loeys-Dietz syndrome), all with associated Kommerell's diverticulum. No dissections occurred in gene-negative patients. At baseline, none of the 5 patients with ASA dissection fulfilled criteria for elective repair according to guidelines. CONCLUSIONS: The risk of complications of ASA is higher in patients with genetic arteriopathies and is difficult to predict. In these diseases, imaging of the supra-aortic trunks should enter baseline investigations. Determination of precise indications for repair can prevent unexpected acute events such as those described.

The Management of Dry Eye Disease: Proceedings of Italian Dry Eye Consensus Group Using the Delphi Method.

Dry eye disease (DED) is a highly prevalent, chronic and progressive condition that affects 5-33% of the world's adult population [...].

Impediments to Heart Transplantation in Adults With MELASMT-TL1:m.3243A>G Cardiomyopathy.

BACKGROUND: The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results. OBJECTIVES: We analyzed factors preventing HTx in consecutive adult patients with MELASMT-TL1:m.3243A>G cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center. METHODS: The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives. RESULTS: The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis. CONCLUSIONS: High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELASMT-TL1:m.3243A>G patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.

Ocular Involvement in Hereditary Amyloidosis.

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

Pathologic substrate of gastropathy in Anderson-Fabry disease.

In both classic and late-onset AFD, mutations of the GLA gene cause deficient activity of the alpha-galactosidase enzyme resulting in intracellular accumulation of the undigested substrate. Gastrointestinal symptoms (GI) are common but non-specific and imputed to the AFD, irrespective of the demonstration of substrate accumulation in GI cells. We demonstrate substrate accumulation in gastric epithelial, vascular, and nerve cells of patients with classic AFD and, vice versa, absence of accumulation in late-onset AFD and controls.

An easy method for intraoperative confirmation of lacrimal sac patency in endoscopic dacryocystorhinostomy.

PURPOSE: Few studies have focused on the intranasal localization of the lacrimal sac during endoscopic dacryocystorhinostomy: landmarks in order to find the medial wall of the lacrimal sac have been described, but there is a lack of description of methods for the verification of the complete marsupialization of the lacrimal sac during surgery. In this report, we propose an easy and effective method for certain intraoperative identification of lacrimal sac. METHODS: A method in order to verify the effective marsupialization of the lacrimal sac is applied and described: to ensure that the opening of the sac in the nasal cavity is complete, the surgeon should identify the Rosenmuller valve, which is the end of the common canaliculus in the lacrimal sac. Continuous irrigation with saline solution through the inferior canaliculus can be useful to obtain a clean surgical area and to permit easy intraoperative identification of the valve. RESULTS: Between 2007 and 2015, 193 endoscopic dacryocystorhinostomies were performed in our institutions. Postoperative surgical success at last follow-up (minimum 12 months) was 93.8% (181 out of 193 of cases). No major complications were observed. CONCLUSIONS: Correct and complete exposure of the lacrimal sac during surgery is crucial for a good outcome: when the opening of the common canaliculus is identified, the surgeon is assured that the sac has been correctly and completely marsupialized inside the nasal cavity.

Genetic Screening of Anderson-Fabry Disease in Probands Referred From Multispecialty Clinics.

BACKGROUND: Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated.

Cataracts and Dupuytren disease: a case report and review of the literature.

Purpose. Dupuytren disease is an inherited proliferative and progressive connective disease. Ectopic disease may, however, be located distant from the palmar fascia. 
Methods. Case report and review of the literature. 
Results. We describe a case of symmetric bilateral posterior subcapsular cataracts associated with symmetric bilateral Dupuytren disease and symmetric bilateral Ledderhose disease in a 56-year-old Caucasian man. His medical history was negative for glucocorticoids intake, diabetes, and exposure to radiation. Serum transforming growth factor ß (TGF-ß)1 concentration has been evaluated and was found to be almost double compared to the controls. 
Conclusions. We speculate that the TGF-ß plays an important role for ocular and connective tissue disorders.

Pentacam sensitivity and specificity in detecting occludable angles.

PURPOSE: To assess the sensitivity and specificity of Pentacam measurements in detection of occludable angles and to provide cutoff values. METHODS: Observational, single-center, cross-sectional study on 64 Caucasian eyes: 28 (43.7%) primary narrow angles or primary angle-closure glaucoma, and 36 (56.2%) controls: all subjects were evaluated and classified by gonioscopy (Shaffer classification). The following measurements have been considered: superior and inferior anterior chamber angle (ACA), temporal and nasal ACA, anterior chamber depth (ACD) using 5 value representation (central, superior, inferior, nasal, temporal), and anterior chamber volume (ACV). Validity of Pentacam parameters to detect patients in Shaffer 0 or I class was assessed by receiver operating characteristic (ROC) curves analysis; cutoffs were chosen as to maximize sensitivity and specificity. RESULTS: All the considered Pentacam measures were statistically different between the 2 groups (p<0.0001). All Shaffer grade groups differed in all parameters (p<0.001), except for grade 0 and I, which did not differ in any. Area under the curve ROC analysis revealed high discriminant power of all Pentacam measures: ACA = 0.94; ACD = 0.91; ACD central = 0.89; and ACV = 0.89. Chosen cutoff values (ACA = 22.4°; ACD = 1.12 mm; ACD central = 1.93 mm; ACV = 84 mm3) allowed correct classification of narrow angles. CONCLUSIONS: The study pointed out a high power of Pentacam AVA, ACV, and ACD in detecting occludable angles. Pentacam is simple to use, reliable, and noncontact, provides parameters in a short period, and represents a possible screening tool.

Risk of dissection in thoracic aneurysms associated with mutations of smooth muscle alpha-actin 2 (ACTA2).

OBJECTIVE: To evaluate the prevalence and phenotype of smooth muscle alpha-actin (ACTA2) mutations in non-syndromic thoracic aortic aneurysms and dissections (TAAD). DESIGN: Observational study of ACTA2 mutations in TAAD. SETTING: Centre for Inherited Cardiovascular Diseases. PATIENTS: A consecutive series of 100 patients with TAAD. Exclusion criteria included genetically confirmed Marfan syndrome, Loeys-Dietz type 2, familial bicuspid aortic valve and Ehlers-Danlos type IV syndromes. INTERVENTIONS: Multidisciplinary clinical and imaging evaluation, genetic counselling and testing of ACTA2, and family screening. MAIN OUTCOME MEASURES: Prevalence of ACTA2 mutations and corresponding phenotypes. RESULTS: TAAD was familial in 43 cases and sporadic in 57 cases. Five mutations in the familial TAAD group (12%) were identified that were absent in controls. The known p.Arg149Cys and the novel p.Asp82Glu, p.Glu243Lys and p.Val45Leu mutations affected evolutionarily conserved residues. The IVS4+1G>A mutation was novel. Of 14 affected relatives, 13 were carriers of the mutation identified in the corresponding proband while one deceased relative had no genetic test. Type A dissection was the first manifestation of aortic aneurysm in four probands and occurred unexpectedly in five relatives. The aortic aneurysm was age dependent and absent in mutated children. Of nine patients who had acute dissection, five died following surgery. At dissection, the size of the aortic aneurysm ranged from 40 mm to 95 mm. Extravascular, ocular, skeletal, nervous and pulmonary traits were variably associated with TAAD, with iris flocculi being most common. CONCLUSIONS: Timely diagnosis of TAAD in the probands, genetic counselling and family screening identify predisposed relatives and prevent catastrophic aortic dissections.

Anterior chamber measurements taken with Pentacam: an objective tool in laser iridotomy.

PURPOSE: Laser iridotomy is the standard first-line intervention in both acute and chronic forms of angle closure because it prevents the recurrence of acute attacks and virtually eliminates the risk of an acute attack in the fellow eye. Pentacam is a new imaging modality which does not require probe contact or an immersion bath. The instrument will allow anterior segment morphology before and after laser peripheral iridotomy (LPI) to be quantified. The aim of the study is to evaluate the objective difference in changes of anterior chamber morphology after LPI with Pentacam. METHODS: Twenty eyes with a high risk of angle closure were evaluated with Pentacam rotating Scheimpflug camera before and after LPI. We measured anterior chamber volume, anterior chamber depth, and chamber angle before and after laser treatment. RESULTS: Statistically significant difference before and after LPI was noted in all anterior chamber measurements except central anterior chamber depth. CONCLUSIONS: This study confirms previous reports of increased anterior chamber volume and angle after LPI and Pentacam is a good objective instrument to demonstrate the efficacy of LPI.

Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies.

Marfan Syndrome (MFS) is an autosomal dominant disorder of the connective tissue due to mutations of Fibrillin-1 gene (FBN1) in more than 90% of cases and Transforming Growth Factor-Beta-Receptor2 gene (TGFB2R) in a minority of cases. Genotyping is relevant for diagnosis and genotype-phenotype correlations. We describe the FBN1 genotypes and related phenotypes of 81 patients who were referred to our attention for MFS or Marfan-like phenotypes. Patients underwent multidisciplinary pertinent evaluation in the adult or paediatric setting, according to their age. The diagnosis relied on Ghent criteria. To optimise DHPLC analysis of the FBN1 gene, all coding regions of the gene were directly sequenced in 19 cases and 10 controls: heterozygous amplicons were used as true positives. DHPLC sensitivity was 100%. Then, DHPLC was used to screen 62 other cases. We identified 74 FBN1 mutations in 81 patients: 64 were novel and 17 known. Of the 81 mutations, 41 were missense (50.6%), 27, either nonsense or frameshift mutations and predicted a premature termination codon (PTC) (33%), 11 affected splice sites (13.6%), and two predicted in-frame deletions (2.5%). Most mutations (67.9%) occurred in cbEGF-like modules. Genotype was clinically relevant for early diagnosis and conclusion of the diagnostic work-up in patients with incomplete or atypical phenotypes.

A comparison of methods for detecting adenovirus type 8 keratoconjunctivitis during a nosocomial outbreak in a Neonatal Intensive Care Unit.

BACKGROUND: An outbreak of epidemic keratoconjunctivitis (EKC) due to adenovirus (Ad) type 8 and involving 14 members of the hospital staff and 33 neonates admitted to the Neonatal Intensive Care Unit of the local University Hospital occurred between September and December 2000 in Pavia, Italy. The outbreak was preceded by an outbreak of EKC within the community. OBJECTIVE: To compare the performance of conventional virus isolation on cell cultures, direct detection of Ad antigens in conjunctival cells by a direct fluorescent assay (DFA) and Ad DNA detection in conjunctival swabs by polymerase chain reaction (PCR) for diagnosis of adenoviral conjunctivitis. STUDY DESIGN: Of conjunctival swabs collected from 47 patients, all were tested by virus isolation, 43 by direct Ad antigen detection, and 37 by Ad DNA detection. Direct Ad antigen detection was carried out by DFA using a group-specific monoclonal antibody. Detection and subgrouping of Ad DNA by nested PCR was performed using two sets of primers complementary to hexon and fiber genes, respectively. RESULTS: Ad was detected in 24/47 (51.1%), 21/43 (48.8%), and 23/37 (62.1%) samples by virus isolation, direct antigen detection and PCR, respectively. Overall, 30/47 (63.8%) samples were Ad-positive. Of 37 specimens tested in parallel by all three methods, Ad was detected by at least one of the three techniques in 26/37 (70.3%). All Ad isolates were identified as serotype 8 by neutralization, while all PCR-positive samples were identified as belonging to subgroup D. No other virus was isolated from any conjunctival swab. Time required for test completion was 9.6 (4-20) days for virus isolation, 1-2 h for DFA and 24 h for PCR. CONCLUSIONS: DFA was a sensitive and rapid assay but results depend on the quality of sample and the expertise of the observer. PCR was the most sensitive assay, although it takes longer to perform and requires dedicated facilities; thus, it could be restricted to DFA-negative samples. Virus isolation is still useful from an epidemiological point of view.

In vitro activity of sagamicin against ocular bacterial isolates.

The in vitro antibacterial activity of sagamicin, gentamicin, tobramycin and norfloxacin was evaluated against 180 recent clinical isolates obtained from patients with ocular infections. Good activity was demonstrated for the 3 aminoglycosides against methicillin-sensitive Staphylococcus aureus and Staphylococcus epidermidis. All 4 compounds showed a lower activity against methicillin-resistant staphylococci. Sagamicin was highly effective against enterobacteriaceae with a MIC(90) of 2 mg/l and presented good antipseudomonal activity similar to that of gentamicin. Intraocular lenses impregnated with a sagamicin solution showed a good antistaphylococcal activity immediately after preparation. In our strain collection, the ability to produce slime was more frequent among methicillin-resistant S. epidermidis strains than methicillin-sensitive S. epidermidis (85 versus 70%). The attachment of 2 S. epidermidis strains to plastic surfaces was partially prevented by sagamicin subinhibitory concentrations. On the contrary, sub-MIC levels of norfloxacin increased the adhesion of S. epidermidis.