Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.

Membrane trafficking is a complex, essential process in eukaryotic cells responsible for protein transport and processing. Deficiencies in vacuolar protein sorting (VPS) proteins, key regulators of trafficking, cause abnormal intracellular segregation of macromolecules and organelles and are linked to human disease. VPS proteins function as part of complexes such as the homotypic fusion and vacuole protein sorting (HOPS) tethering complex, composed of VPS11, VPS16, VPS18, VPS33A, VPS39 and VPS41. The HOPS-specific subunit VPS41 has been reported to promote viability of dopaminergic neurons in Parkinson's disease but to date has not been linked to human disease. Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function. All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus. Zebrafish disease modelling supports the involvement of VPS41 dysfunction in the disorder, indicating lysosomal dysregulation throughout the brain and providing support for cerebellar and microglial abnormalities when vps41 was mutated. This provides the first example of human disease linked to the HOPS-specific subunit VPS41 and suggests the importance of HOPS complex activity for cerebellar function.

KCNA4 deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability.

BACKGROUND: Voltage-gated potassium channels are highly diverse proteins representing the most complex class of voltage-gated ion channels from structural and functional perspectives. Deficiency of these channels usually results in various human disorders. OBJECTIVES: To describe a novel autosomal recessive syndrome associated with KCNA4 deficiency leading to congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder. METHODS: We used SNP arrays, linkage analyses, autozygosity mapping, whole-exome sequencing, RT-PCR and two-electrode voltage-clamp recording. RESULTS: We identified a missense variant (p.Arg89Gln) in KCNA4 in four patients from a consanguineous family manifesting a novel syndrome of congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder. The variant was fully segregated with the disease and absent in 747 ethnically matched exomes. Xenopus oocytes were injected with human Kv1.4 wild-type mRNA, R89Q and WT/R89Q channels. The wild type had mean current amplitude that was significantly greater than those recorded from the cells expressing the same amount of mutant mRNA. Co-expression of the wild type and mutant mRNAs resulted in mean current amplitude that was significantly different from that of the wild type. RT-PCR indicated that KCNA4 is present in mouse brain, lens and retina. KCNA4 interacts with several molecules including synaptotagmin I, DLG1 and DLG2. The channel co-localises with cholinergic amacrine and rod bipolar cells in rats and is widely distributed in the central nervous system. Based on previous studies, the channel is highly expressed in outer retina, rod inner segments, hippocampus and concentrated in axonal membranes. CONCLUSION: KCNA4 (Kv1.4) is implicated in a novel syndrome characterised by striatal thinning, congenital cataract and attention deficit hyperactivity disorder. Our study highlights potassium channels' role in ocular and neuronal genetics.

Breastfeeding and Maternal Age-Related Cataract in the U.S. Population.

PURPOSE: An estimated 38 million and 50 million individuals will have cataract in the U.S. alone by 2030 and 2050, respectively. Breastfeeding is known to improve a number of health outcomes in both breastfed children and breastfeeding mothers. However, little is known about the relationship between breastfeeding and cataract, the leading cause of blindness worldwide, in breastfeeding mothers. This study was conducted to investigate the relationship between breastfeeding and maternal cataract extraction history in a nationally representative sample of the U.S. population. METHODS: A 10-year multistage, probability-sampling survey data was used to identify parous women aged ≥50 years who provided breastfeeding history and cataract extraction history (n = 4897). Breastfeeding history was considered positive if a participant reported breastfeeding at least one child for ≥1 month. The main outcome was cataract extraction history. Estimates are presented in odds ratios (OR) and 95% confidence intervals (95%CI). RESULTS: Approximately half of the studied women breastfed at least one child ≥1 month, and about 18% reported cataract extraction history. Participants with a positive breastfeeding history were less likely to have a positive cataract extraction history in both age-adjusted (OR = 0.814, 95%CI = 0.670-0.989) and multivariable logistic regression (OR = 0.794, 95%CI = 0.639-0.988). Higher number of breastfed children was also associated with a lower risk of cataract extraction history (OR = 0.934, 95%CI = 0.883-0.988). CONCLUSIONS: The findings suggest that breastfeeding may be associated with a decrease in the likelihood of age-related cataract extraction in parous women from the U.S. population.

Corneoscleral xanthogranuloma treated with chemotherapy: The room for nonsurgical management.

PURPOSE: To describe a clinical case of corneoscleral xanthogranuloma, a rare manifestation of juvenile xanthogranuloma, and xanthoma disseminatum, which responded well to chemotherapy. METHODS: Interventional case report and literature search. RESULTS: A 9-year-old female patient with a disseminated disease showed complete regression of her corneoscleral xanthogranuloma with methotrexate and azathioprine therapy. CONCLUSION: Since they are potentially blinding, corneoscleral xanthogranulomas are commonly surgically excised. While surgical resection has been widely advocated in the literature, immunosuppressive therapy alone may be a pertinent management line of corneoscleral xanthogranuloma, especially with systemic involvement.

Is Dietary Milk Intake Associated with Cataract Extraction History in Older Adults? An Analysis from the US Population.

BACKGROUND: Galactose accumulation in the lens tissue is known to be cataractogenic. Whether consistent dietary intake of lactose-which consists of glucose and galactose-predisposes to senile cataract remains unclear. This study was conducted to investigate the association between a number of dietary milk intake indicators and cataract extraction history in a representative sample of older adults from the US population. Methods and Materials. This is a cross-sectional, population-based study. Participants of the United States National Health and Nutrition Examination Survey 2001-2008 who were ≥50 years old and provided a complete history of their usual daily dietary intake were included. Exclusion criteria were special diets, extreme daily energy intake, and missing outcome (i.e., cataract extraction history). Indicators of milk intake used were early-life intake regularity, current daily milk/total dairy intake amounts, and estimated lifelong milk exposure. Odds ratios (OR) and 99% confidence intervals (99% CI) were calculated with fitting weights to better represent the population-based estimates. RESULTS: Among the 5930 studied participants, early-life milk intake regularity was not associated with cataract extraction history in age/sex/ethnicity-adjusted and multivariable-adjusted models (p trend = 0.064 and 0.094, respectively). Current daily milk intake was associated with a slight reduction in the likelihood of cataract extraction in the age/sex/ethnicity-adjusted model (OR = 0.885 per cup equivalents, 99% CI = 0.795-0.986) and in the multivariable model (OR = 0.871 per cup equivalents, 99% CI = 0.746-0.993). However, no such association was observed between quartiles of current dietary milk intake and cataract extraction history (p trend = 0.064 and 0.094, respectively). Current daily milk intake was associated with a slight reduction in the likelihood of cataract extraction in the age/sex/ethnicity-adjusted model (OR = 0.885 per cup equivalents, 99% CI = 0.795-0.986) and in the multivariable model (OR = 0.871 per cup equivalents, 99% CI = 0.746-0.993). However, no such association was observed between quartiles of current dietary milk intake and cataract extraction history (p trend = 0.064 and 0.094, respectively). Current daily milk intake was associated with a slight reduction in the likelihood of cataract extraction in the age/sex/ethnicity-adjusted model (OR = 0.885 per cup equivalents, 99% CI = 0.795-0.986) and in the multivariable model (OR = 0.871 per cup equivalents, 99% CI = 0.746-0.993). However, no such association was observed between quartiles of current dietary milk intake and cataract extraction history (. CONCLUSION: There appears to be no direct relationship between several indicators of dietary milk consumption and cataract extraction history in the general American population.

Visual and refractive outcomes and complications in femtosecond laser-assisted versus conventional phacoemulsification cataract surgery: findings from a randomised, controlled clinical trial.

BACKGROUND/AIM: To compare visual and refractive outcomes, changes in intraocular pressure (IOP), and complications of femtosecond laser-assisted cataract surgery (FLACS) to conventional phacoemulsification surgery (CPS) in paired eyes from the same patients. METHODS: This is a secondary analysis of an intraindividual, randomised, controlled clinical trial including 110 paired eyes from 55 patients that were randomised into either FLACS or CPS groups. Outcomes were recorded at baseline and postoperatively during a 3-month follow-up period. RESULTS: Uncorrected distance visual acuity and corrected distance visual acuity were similar between FLACS and CPS over the follow-up period (p>0.05). The mean absolute refractive error was not significantly different between the two groups at postoperative month 1 (POM1) (0.3±0.2 D in FLACS vs 0.4±0.3 D in CPS, p=0.18) and month 3 (POM3) (0.3±0.3 D in FLACS vs 0.3±0.3 D in CPS, p=0.71). IOP was statistically higher in the FLACS group on postoperative day 1 (20.6±5.7 mm Hg for FLACS and 18.0±4.9 mm Hg for CPS, p=0.01). However, it was similar between the two groups subsequently (p>0.05). Intraoperatively, one case of posterior capsular block syndrome was observed in the FLACS group. Postoperatively, one case of newly developed glaucoma was observed in the FLACS group and one case of retinal tears in the CPS group. CONCLUSION: The 3-month postoperative refractive and visual outcomes were comparable between FLACS and CPS in paired eyes from the same patients. Complication rate was low in the study population.

Outcomes and complications of iris-fixated intraocular lenses in cases with inadequate capsular support and complex ophthalmic history.

BACKGROUND: To report the indications, visual outcomes, and intra-operative and post-operative complications of iris-sutured posterior chamber intraocular lens (IOL) in eyes with inadequate capsular support and complex ocular history. METHODS: A chart review and data analysis of eyes that underwent iris fixation of posterior chamber (PC) IOL for correction of aphakia, dislocated and subluxed IOLs, ectopia lentis, and IOL exchange. Data included clinical risk factors, associated eye conditions, previous surgeries, and concomitant procedures. The pre-operative and post-operative vision, manifest refraction, endothelial cell density, intraocular pressure (IOP), as well as intra-operative and post-operative complications were also recorded. RESULTS: One hundred and seventeen eyes from 114 patients were examined with a mean follow-up of 22.4 months. The most common identifiable predisposing risk factor was high myopia in 23 eyes. A significant improvement in uncorrected and best corrected visual acuity compared with baseline was observed. The most common post-operative complications included recurrent IOL subluxation in 16 (13.7%) eyes, IOP spike in 7 (5.9%) eyes, cystoid macular oedema in 5 (4.3%) eyes, and epiretinal membrane formation in 4 (3.4%) eyes. There was one (0.85%) case of sterile endophthalmitis. CONCLUSIONS: Iris suture fixation of PC IOLs is a good treatment option for eyes with inadequate capsular support and complex ocular history.

Publisher Correction: RNA-Seq transcriptome profiling in three liver regeneration models in rats: comparative analysis of partial hepatectomy, ALLPS, and PVL.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RNA-Seq transcriptome profiling in three liver regeneration models in rats: comparative analysis of partial hepatectomy, ALLPS, and PVL.

The liver is a unique organ that has a phenomenal capacity to regenerate after injury. Different surgical procedures, including partial hepatectomy (PH), intraoperative portal vein ligation (PVL), and associated liver partition and portal vein ligation for staged hepatectomy (ALPPS) show clinically distinct recovery patterns and regeneration. The observable clinical differences likely mirror some underlying variations in the patterns of gene activation and regeneration pathways. In this study, we provided a comprehensive comparative transcriptomic analysis of gene regulation in regenerating rat livers temporally spaced at 24 h and 96 h after PH, PVL, and ALPPS. The time-dependent factors appear to be the most important determinant of post-injury alterations of gene expression in liver regeneration. Gene expression profile after ALPPS showed more similar expression pattern to the PH than the PVL at the early phase of the regeneration. Early transcriptomic changes and predicted upstream regulators that were found in all three procedures included cell cycle associated genes (E2F1, CCND1, FOXM1, TP53, and RB1), transcription factors (Myc, E2F1, TBX2, FOXM1), DNA replication regulators (CDKN1A, EZH2, RRM2), G1/S-transition regulators (CCNB1, CCND1, RABL6), cytokines and growth factors (CSF2, IL-6, TNF, HGF, VEGF, and EGF), ATM and p53 signaling pathways. The functional pathway, upstream, and network analyses revealed both unique and overlapping molecular mechanisms and pathways for each surgical procedure. Identification of molecular signatures and regenerative signaling pathways for each surgical procedure further our understanding of key regulators of liver regeneration as well as patient populations that are likely to benefit from each procedure.

Refractive and Visual Outcomes and Rotational Stability of Toric Intraocular Lenses in Eyes With and Without Previous Ocular Surgeries: A Longitudinal Study.

PURPOSE: To evaluate visual and refractive outcomes and rotational stability of toric intraocular lens (IOL) implantation in eyes with previous ocular surgeries. METHODS: This controlled, longitudinal cohort study included a total of 133 eyes (59 study cases with a history of corneal, vitreoretinal, and/or glaucoma surgery and 74 randomly selected controls without a history of ocular surgery) that had cataract and corneal astigmatism treated with toric IOL implantation. Postoperative outcomes were recorded at postoperative 1 month and 3 to 12 months. RESULTS: Refractive prediction errors were within ±1.00 diopter (D) of target in 93.5% and 88.4% of the study cases at postoperative 1 month and 3 to 12 months, respectively. They were within ±0.50 D of target in 56.5% and 60.5% of the cases during the same follow-up intervals, respectively. Study cases showed statistically significantly inferior uncorrected distance visual acuity (UDVA) compared to controls at 1 month postoperatively (0.27 ± 0.24 and 0.17 ± 0.21 logMAR, respectively, P = .027) but not during the later follow-up (0.19 ± 0.19 and 0.16 ± 0.19 logMAR, respectively, P = .431). Corrected distance visual acuity (CDVA) was slightly lower in the study cases than in controls at 1 month postoperatively (0.13 ± 0.16 and 0.07 ± 0.14, respectively, P = .005) and subsequent follow-up months (0.10 ± 0.13 and 0.03 ± 0.10, respectively, P < .001). Of the examined study cases, 93.9% and 88.4% had IOL axes within 5° of intended axis at postoperative 1 month and 3 to 12 months, respectively. CONCLUSIONS: Toric IOLs provided significant and sustained improvement in visual acuity and refraction in eyes with a history of prior ophthalmic surgery. Refractive outcomes achieved postoperatively were comparable to those in eyes without a prior history of ophthalmic surgery, although the rate of visual recovery may be different. [J Refract Surg. 2019;35(12):781-788.].

Identification of novel genomic imbalances in Saudi patients with congenital heart disease.

BACKGROUND: Quick genetic diagnosis of a patient with congenital heart disease (CHD) is quite important for proper health care and management. Copy number variations (CNV), chromosomal imbalances and rearrangements have been frequently associated with CHD. Previously, due to limitations of microscope based standard karyotyping techniques copious CNVs and submicroscopic imbalances could not be detected in numerous CHD patients. The aim of our study is to identify cytogenetic abnormalities among the selected CHD cases (n = 17) of the cohort using high density oligo arrays. RESULTS: Our screening study indicated that six patients (~35%) have various cytogenetic abnormalities. Among the patients, only patient 2 had a duplication whereas the rest carried various deletions. The patients 1, 4 and 6 have only single large deletions throughout their genome; a 3.2 Mb deletion on chromosome 7, a 3.35 Mb deletion on chromosome 3, and a 2.78 Mb a deletion on chromosome 2, respectively. Patients 3 and 5 have two deletions on different chromosomes. Patient 3 has deletions on chromosome 2 (2q24.1; 249 kb) and 16 (16q22.2; 1.8 Mb). Patient 4 has a 3.35 Mb an interstitial deletion on chromosome 3 (3q13.2q13.31).Based on our search on the latest available literature, our study is the first inclusive array CGH evaluation on Saudi cohort of CHD patients. CONCLUSIONS: This study emphasizes the importance of the arrays in genetic diagnosis of CHD. Based on our results the high resolution arrays should be utilized as first-tier diagnostic tool in clinical care as suggested before by others. Moreover, previously evaluated negative CHD cases (based on standard karyotyping methods) should be re-examined by microarray based cytogenetic methods.

Serum testosterone levels and other determinants of sperm retrieval in microdissection testicular sperm extraction.

BACKGROUND: Microdissection testicular sperm extraction (microTESE) has become the standard of care for sperm retrieval in non-obstructive azoospermia (NOA) patients. Understanding the significant determinants of microTESE outcomes may result in improvements in sperm retrieval rates and provide better-informed clinical decisions. METHODS: This is a clinical retrospective study conducted through chart review of 421 NOA patients who underwent microTESE between August 2009 and July 2015 in a tertiary-care referral hospital. Clinical, biochemical and histopathological characteristics were collected. Normal serum testosterone level was defined as testosterone >9.9 nmol/L. Multiple logistic regression was used to identify determinants of microTESE in the studied population. A P<0.05 was considered significant. RESULTS: Sperms were successfully retrieved in 39.4% of cases. The average testosterone level was 11.51±7.40 and 11.67±6.42 in patients with successful and unsuccessful microTESE, respectively (P=0.820). No significant association was found between serum testosterone level and sperm motility and amount. Of all variables, histological subtype remained to be the most significant determinant of microTESE outcomes in the examined population, with hypospermatogenesis having over a 3-fold higher odd of successful microTESE than sertoli-cell only. CONCLUSIONS: Serum testosterone level appears to have no significant association with microTESE outcomes in NOA. The underlying histological pattern is a significant determinant of the procedure's success.

Immature mediastinal teratoma with unusual histopathology: A case report of multi-lineage, somatic-type malignant transformation and a review of the literature.

Germ cell tumors (GCTs) represent a well-recognized group of heterogeneous neoplasms with diverse clinical, histopathological, diagnostic, and prognostic characteristics. We present a rare case of a locally aggressive, chemotherapy-resistant immature mediastinal teratoma with a peculiar histological finding of a multilineage somatic-type malignant degeneration. A 21-year-old male patient presented with a 3-week history of persistent, blood-tinged productive cough and shortness of breath. A contrast-enhanced computed tomography (CT) scan of the chest showed a heterogeneous mass occupying the right hemithorax and abutting on adjacent structures. CT-guided biopsy was consistent with immature teratoma. Combination chemotherapy with bleomycin, etoposide, and cisplatin was initiated, albeit without success; the mass showed interval progression in size, and surgical resection through clamshell incision was performed. Histological assessment of the resected mass confirmed the diagnosis of immature teratoma and revealed an extensive multilineage malignant differentiation into sarcomatous, carcinomatous, and melanomatous components. The patient underwent an uneventful recovery but presented 2 months later with extensive liver and bone melanomatous metastases. In this report, relevant findings from the literature are also highlighted. Despite being exceptionally rare, such tumors carry poor prognosis. Understanding the clinicopathological characteristics and biological behavior of such tumors may provide an insight into interventions tailored to improve the otherwise dismal disease outlook.