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PRCIS: In the largest clinic-based study to date, our review of 588 patients presenting with glaucoma in Northern Ghana revealed 36% of these had primary angle closure glaucoma (PACG). OBJECTIVE: Glaucoma is the second leading cause of blindness worldwide. In Africa, glaucoma is an established public health problem, and PACG is not commonly discussed. Recognizing it is important because of its negative impact on visual morbidity, and also because its treatment is different from primary open angle glaucoma. In response to the observation of many PACG cases at the Northern Community Eye Hospital in Tamale, Ghana, we investigated the proportion of those attending with a first diagnosis of glaucoma who had PACG. PATIENTS AND METHODS: Using the electronic records, we identified 976 patients who attended with a first diagnosis of glaucoma between January 2021 and October 2022. Of these, 588 met the inclusion criterion of a clear glaucoma subtype diagnosis. RESULTS: Of these 316 (53.7%) had primary open angle glaucoma, 210 (35.7%) PACG, and 62 (10.5%) secondary glaucoma. Thus, over a third of presenting glaucomas had PACG. CONCLUSION: This study highlights that PACG is present in about a third of patients presenting to our clinic in North Ghana. Our study demonstrates the importance of a clear diagnostic pathway including gonioscopy in the assessment of glaucoma patients and the consideration of wider training on angle closure glaucoma diagnosis and management.

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This is the case of a 51-year-old woman with chronic progressive external ophthalmoplegia (CPEO) alongside some comorbidities in a low-resource setting. This report seeks to sensitise clinicians about this rare condition in order to increase their index of suspicion and avoid misdiagnosis.

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BACKGROUND: There is increasing interest in lifestyle modification and integrative medicine approaches to treat and/or prevent mild cognitive impairment (MCI) and Alzheimer's disease and related dementias (ADRD). OBJECTIVE: To address the need for a quantifiable measure of brain health, we created the Resilience Index (RI). METHODS: This cross-sectional study analyzed 241 participants undergoing a comprehensive evaluation including the Clinical Dementia Rating and neuropsychological testing. Six lifestyle factors including physical activity, cognitive activity, social engagements, dietary patterns, mindfulness, and cognitive reserve were combined to derive the RI (possible range of scores: 1-378). Psychometric properties were determined. RESULTS: The participants (39 controls, 75 MCI, 127 ADRD) had a mean age of 74.6±9.5 years and a mean education of 15.8±2.6 years. The mean RI score was 138.2±35.6. The RI provided estimates of resilience across participant characteristics, cognitive staging, and ADRD etiologies. The RI showed moderate-to-strong correlations with clinical and cognitive measures and very good discrimination (AUC: 0.836; 95% CI: 0.774-0.897) between individuals with and without cognitive impairment (diagnostic odds ratio = 8.9). Individuals with high RI scores (> 143) had better cognitive, functional, and behavioral ratings than individuals with low RI scores. Within group analyses supported that controls, MCI, and mild ADRD cases with high RI had better cognitive, functional, and global outcomes than those with low RI. CONCLUSION: The RI is a brief, easy to administer, score and interpret assessment of brain health that incorporates six modifiable protective factors. Results from the RI could provide clinicians and researchers with a guide to develop personalized prevention plans to support brain health.

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Maternal embryonic leucine zipper kinase (MELK) is frequently overexpressed in cancer, but the role of MELK in cancer is still poorly understood. MELK was shown to have roles in many cancer-associated processes including tumor growth, chemotherapy resistance, and tumor recurrence. To determine whether the frequent overexpression of MELK can be exploited in therapy, we performed a high-throughput screen using a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential when MELK is overexpressed. We identified two such genes: LAG2 and HDA3. LAG2 encodes an inhibitor of the Skp, Cullin, F-box containing (SCF) ubiquitin-ligase complex, while HDA3 encodes a subunit of the HDA1 histone deacetylase complex. We find that one of these synthetic lethal interactions is conserved in mammalian cells, as inhibition of a human homolog of HDA3 (Histone Deacetylase 4, HDAC4) is synthetically toxic in MELK overexpression cells. Altogether, our work identified a novel potential drug target for tumors that overexpress MELK.

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Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype. We find that aneuploid cells are much more sensitive to the energy metabolism regulating drug ZLN005 than their euploid counterparts. Furthermore, cells with an ongoing CIN phenotype, induced by spindle assembly checkpoint (SAC) alleviation, are significantly more sensitive to the Src kinase inhibitor SKI606. We show that inhibiting Src kinase increases microtubule polymerization rates and, more generally, that deregulating microtubule polymerization rates is particularly toxic to cells with a defective SAC. Our findings, therefore, suggest that tumors with a dysfunctional SAC are particularly sensitive to microtubule poisons and, vice versa, that compounds alleviating the SAC provide a powerful means to treat tumors with deregulated microtubule dynamics.

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PURPOSE: Data on childhood blindness in Ghana are limited. The objectives of this study were to determine the major causes of childhood blindness and severe visual impairment (SVI) at Wa Methodist School for the Blind in Northern Ghana, and to compare our results to those published from other studies conducted in Ghana. METHODS: In this retrospective study, data from an eye screening at Wa Methodist School in November 2014 were coded according to the World Health Organization/Prevention of Blindness standardized reporting methodology. Causes of blindness/SVI were categorized anatomically and etiologically, and were compared to previously published studies. RESULTS: Of 190 students screened, the major anatomical causes of blindness/SVI were corneal scar/phthisis bulbi (CS/PB) (n = 28, 15%) and optic atrophy (n = 23, 12%). The major etiological causes of blindness/SVI were unknown (n = 114, 60%). Eighty-three (44%) students became blind before age one year. Of four published blind school surveys conducted in Ghana, CS/PB was the most common anatomical cause of childhood blindness. Over time, the prevalence of CS/PB within blind schools decreased in the north and increased in the south. Measles-associated visual loss decreased from 52% in 1987 to 10% in 2014 at Wa Methodist School. CONCLUSIONS: In a blind school in northern Ghana, CS/PB was the major anatomical cause of childhood blindness/SVI. While CS/PB has been the most common anatomical cause of childhood blindness reported in Ghana, there may be regional changes in its prevalence over time. Being able to identify regional differences may guide future public health strategies to target specific causes.

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The purpose of this work is to establish a reference scale of optic nerve pathway measurements in pediatric patients according to age using MRI. Optic nerve pathway measurements were retrospectively analyzed using an orbits equivalent sequence on brain MRI scans of 137 pediatric patients (72 male, 65 female, average age = 7.7 years, standard deviation  = 5.3). The examinations were performed on a 1.5-T or 3-T Siemens MR system using routine imaging protocols. Measurements include diameters of the orbital optic nerves (OON), prechiasmatic optic nerves (PON), optic tracts (OT), and optic chiasm (OC). Measurements were performed manually by 2 neuroradiologists, using post-processing software. Patients were stratified into five age groups for measurement analyses: (I) 0-1.49 years, (II) 1.5-2.99 years, (III) 3-5.99 years, (IV) 6-11.99 years, and (V) 12-18 years. The observed value range of OON mean diameter was 2.7 mm (Interquartile range (IQR) = 2.4-2.9), PON was 3.2 mm (IQR  =  3.05-3.5), OT 2.6 mm (IQR = 2-2.9). A strong positive correlation was established between age and mean diameter of OON (r = 0.73, p < .001), PON (r = 0.59, p < .001), and OT (r = 0.72, p < .001). A significant difference in mean OON diameters was found between age groups I-II (d = 0.3, p = .01), II-III (d = 0.5, p < .001), III-IV (d = 0.5, p < .001) followed by a plateau between IV-V (d = 0.l0, p = .19). OON/OT ratio maintained a steady mean value 1 (IQR = 0.93-1.1) regardless of age (p = .7). The diameter of optic pathways was found to increase as a function of age with consistent positive correlation between nerve and tract for all ages.

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Stem cells hold enormous promise for regenerative medicine as well as for engineering of model systems to study diseases and develop new drugs. The discovery of protocols that allow for generating induced pluripotent stem cells (IPSCs) from somatic cells has brought this promise steps closer to reality. However, as somatic cells might have accumulated various chromosomal abnormalities, including aneuploidies throughout their lives, the resulting IPSCs might no longer carry the perfect blueprint for the tissue to be generated, or worse, become at risk of adopting a malignant fate. In this review, we discuss the contribution of aneuploidy to healthy tissues and how aneuploidy can lead to disease. Furthermore, we review the differences between how somatic cells and stem cells respond to aneuploidy.

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Chromosomal instability (CIN) is a process leading to errors in chromosome segregation and results in aneuploidy, a state in which cells have an abnormal number of chromosomes. CIN is a hallmark of cancer, and furthermore linked to ageing and age-related diseases such as Alzheimer's. Various mouse models have been developed to explore the role of CIN in ageing and cancer. While these models reveal only a modest contribution of CIN to the initiation of cancer, they also clearly show that CIN is a powerful accelerator of cancer in a predisposed background. Other than cancer, CIN also appears to provoke premature ageing in some of the CIN models. In this review, we discuss the phenotypes of the various available mouse models, what we have learnt so far, and importantly, also which questions still need to be addressed.

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Microtubules execute diverse mitotic events that are spatially and temporally separated; the underlying regulation is poorly understood. By combining drug treatments, large-scale immunoprecipitation and mass spectrometry, we report the first comprehensive map of mitotic phase-specific protein interactions of the microtubule-end binding protein, EB1. EB1 interacts with some, but not all, of its partners throughout mitosis. We show that the interaction of EB1 with Astrin-SKAP complex, a key regulator of chromosome segregation, is enhanced during prometaphase, compared to anaphase. We find that EB1 and EB3, another EB family member, can interact directly with SKAP, in an SXIP-motif dependent manner. Using an SXIP defective mutant that cannot interact with EB, we uncover two distinct pools of SKAP at spindle microtubules and kinetochores. We demonstrate the importance of SKAP's SXIP-motif in controlling microtubule growth rates and anaphase onset, without grossly disrupting spindle function. Thus, we provide the first comprehensive map of temporal changes in EB1 interactors during mitosis and highlight the importance of EB protein interactions in ensuring normal mitosis.

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Aneuploidy is a hallmark of human solid cancers that arises from errors in mitosis and results in gain and loss of oncogenes and tumor suppressors. Aneuploidy poses a growth disadvantage for cells grown in vitro, suggesting that cancer cells adapt to this burden. To understand better the consequences of aneuploidy in a rapidly proliferating adult tissue, we engineered a mouse in which chromosome instability was selectively induced in T cells. A flanked by Lox mutation was introduced into the monopolar spindle 1 (Mps1) spindle-assembly checkpoint gene so that Cre-mediated recombination would create a truncated protein (Mps1(DK)) that retained the kinase domain but lacked the kinetochore-binding domain and thereby weakened the checkpoint. In a sensitized p53(+/-) background we observed that Mps1(DK/DK) mice suffered from rapid-onset acute lymphoblastic lymphoma. The tumors were highly aneuploid and exhibited a metabolic burden similar to that previously characterized in aneuploid yeast and cultured cells. The tumors nonetheless grew rapidly and were lethal within 3-4 mo after birth.

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OBJECTIVE: Multiple sclerosis (MS) is a chronic neurodegenerative disease of the CNS. Recently a controversial vascular hypothesis for MS, termed chronic cerebrospinal venous insufficiency (CCSVI), has been advanced. The objective of this study was to evaluate the relative prevalence of the venous abnormalities that define CCSVI. METHODS: A case-control study was conducted in which 100 MS patients aged between 18-65 y meeting the revised McDonald criteria were randomly selected and stratified into one of four MS subtypes: relapsing/remitting, secondary progressive, primary progressive and benign. Control subjects (16-70 y) with no known history of MS or other neurological condition were matched with the MS cases. All cases and controls underwent ultrasound imaging of the veins of the neck plus the deep cerebral veins, and magnetic resonance imaging of the neck veins and brain. These procedures were performed on each participant on the same day. RESULTS: On ultrasound we found no evidence of reflux, stenosis or blockage in the internal jugular veins (IJV) or vertebral veins (VV) in any study participant. Similarly, there was no evidence of either reflux or cessation of flow in the deep cerebral veins in any subject. Flow was detected in the IJV and VV in all study participants. Amongst 199 participants there was one MS subject who fulfilled the minimum two ultrasound criteria for CCSVI. Using MRI we found no significant differences in either the intra- or extra-cranial venous flow velocity or venous architecture between cases and controls. CONCLUSION: This case-control study provides compelling evidence against the involvement of CCSVI in multiple sclerosis.

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Stormwater ponds have become common features of modern development and often represent significant amounts of open space in urbanized areas. Although stormwater ponds may provide habitat for wildlife, factors responsible for producing variation in wildlife use of ponds have received limited attention. To investigate the role of variation in species tolerances of pollutants in structuring pond-breeding amphibian assemblages, we exposed species tolerant (Bufo americanus) and not tolerant (Rana sylvatica) of urbanization to pond sediments in laboratory microcosms. Pond microcosms had elevated sediment metal levels and chloride water concentrations. Among R. sylvatica embryos, exposure to pond sediments resulted in 100% mortality. In contrast, B. americanus embryos and larvae experienced only sublethal effects (i.e., reduced size at metamorphosis) due to pond sediment exposure. Our results suggest variation in pollutant tolerance among early developmental stages of amphibians may act in concert with terrestrial habitat availability to structure amphibian assemblages associated with stormwater ponds.

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Orbital teratomas are rare embryonic tumors composed of a wide diversity of tissues derived from the three germinal layers. The presenting features include, a healthy newborn with extreme unilateral proptosis; marked stretching of the eyelids over a tense, fluctuating mass, with elongation of the palpebral fissure; enlargement of the bony orbit (two to three times normal size) with subsequent nasal and malar deformities; and transillumination of all or part of the orbital mass. Commonly the eye is normally developed but often vision is not preserved either due to exposure or secondary optic atrophy. The objective in the management of orbital teratoma is to save the eye to encourage orbitofacial development, maintain cosmesis and retain some vision. We report a case of massive congenital orbital teratoma successfully removed by an eyelid-sparing exenteration technique.

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The roots of Epipremnum aureum, though not synthesizing nicotine themselves, take up exogenously fed nicotine as a xenobiotic. The alkaloid is subsequently translocated to the leaves, via the xylem path, where it accumulates in the mesophyll up to levels comparable with nicotine-rich Nicotiana species. The Epipremnum plants accept nicotine only up to a distinct level; saturation is reached after about 10 days. All mature, non-senescent leaves accumulate the same amount of nicotine. By different experimental approaches, unequivocal evidence could be provided that root pressure is the 'translocative force' for nicotine transport in E. aureum. Xylem sap exudates, collected from shoot stumps that were connected to an intact root system immersed in nicotine solution were analyzed for nicotine content. Nicotine uptake from the medium by the root and its subsequent transfer into the xylem of the shoot persisted for more than 10h without measurable decline of the transport rate, provided the nicotine concentrations applied were < or =0.05%. In intact plants, where both components of water transport in the xylem--root pressure and transpirative water flow--are in operation, no surplus transport of nicotine from the roots into the leaves took place beyond the level observed in amputated plants. Under the influence of inhibitors of root respiration, nicotine uptake was halted slowly in case of oxygen deprivation and in case of cyanide, or it stopped very rapidly when CCCP, an uncoupler of mitochondrial ATP formation, was applied to the roots. This threshold of toxicity against the xenobiotic was established by dose effect curves for nicotine sensitivity of the roots for root respiration and by transpiration measurements. Leaves, bearing a heavy 'nicotine load', showed symptoms of senescence only after 3-6 weeks, as indicated by a decline in the chlorophyll content, the chl a/b ratio, and the maximal quantum yield efficiency (Fv/Fm), and by an increase in catalase activity. Our results provide insight into the mechanisms of uptake, transport and storage of nicotine as a xenobiotic.

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