Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis

Data from the International Collaborative Gaucher Group Gaucher Registry were analysed to assess the relationship between enzyme replacement therapy with imiglucerase (ERT) and incidence of avascular necrosis (AVN) in type 1 Gaucher disease (GD1), and to determine whether the time interval between diagnosis and initiation of ERT influences the incidence rate of AVN. All patients with GD1 enrolled in the Gaucher Registry who received ERT and did not report AVN prior to starting therapy (n = 2700) were included. The incidence rate of AVN following initiation of ERT was determined. An incidence rate of AVN of 13·8 per 1000 person-years was observed in patients receiving ERT. Patients who initiated ERT within 2 years of diagnosis had an incidence rate of 8·1 per 1000 person-years; patients who started ERT ≥2 years after diagnosis had an incidence rate of 16·6 per 1000 person-years. The adjusted incidence rate ratio was 0·59 [95% confidence interval (CI) 0·36–0·96, P = 0·0343]. Splenectomy was an independent risk factor for AVN (adjusted incidence rate ratio 2·23, 95% CI 1·61–3·08, P < 0·0001). In conclusion, the risk of AVN was reduced among patients who initiated ERT within 2 years of diagnosis, compared to initiating treatment ≥2 years after diagnosis. A higher risk of AVN was observed among patients who had previously undergone splenectomy

Polymorphous low-grade adenocarcinoma of the upper lip: 11 cases of an uncommon diagnosis

ObjectiveThe aim of this case study was to describe an international case series of polymorphous low-grade adenocarcinoma (PLGA) affecting the upper lip.Material and MethodsOver a 30-year-period, the files of five pathology services were reviewed for PLGA affecting the upper lip. Hematoxylin and eosin–stained slides were reviewed by three oral and maxillofacial pathologists, and microscopic features were described. Clinical data were retrieved from patients' medical records.ResultsThe review identified 11 cases of upper lip PLGAs, with a complete set of clinical data available for 5 cases. There was a male predominance (1.2:1), and the mean age was 58.7 years. Most cases presented as small asymptomatic swellings that resembled benign tumors. All patients underwent surgery, and no recurrences or metastases were reported in the 8 cases from which follow-up data were available. Microscopically, the typical polymorphic architectural arrangement of PLGA was seen in all cases, with lobular, trabecular, papillary, and cribriform patterns identified. Perineural invasion, normal gland entrapment, Indian filing, and concentric growth were frequently identified.ConclusionPLGA must be included in the list of differential diagnoses of tumors affecting the upper lip because of its similar clinical presentation to benign entities. The follow-up data available from 8 of 11 cases suggest that these tumors follow a low-grade clinical course, similar to the majority of palatal cases of PLGA

Corneal topographic changes in premenopausal and postmenopausal women

<p>Abstract</p> <p>Background</p> <p>To asses the effect of menopause on the corneal curvature changes using corneal computerized videokeratography (CVK) in premenopausal and postmenopausal healthy women.</p> <p>Methods</p> <p>Thirty-six postmenopausal women with mean ages of 49.2 (range 39 to 57) were enrolled in this randomized, prospective study, comparing with 26 healthy controls with mean ages of 38.5 +/- 4.9 (range 32 to 49). Subjects were determined to be postmenopausal, by the Gynecology and Obstetrics Department, based on blood Follicular Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estradiol, Progesterone levels and clinical complaints. Complete ophthalmic examination and CVK using Haag-Streit System was performed in both premenopausal and postmenopausal women.</p> <p>Results</p> <p>Mean horizontal curvature and vertical curvature of central corneal power in premenopausal women were 43.5 +/- 1.25 Diopter (D), and 44.1 +/- 1.53 D. Mean horizontal curvature and vertical curvature of central corneal power in postmenopausal women were 43.9 +/- 1.4 D, and 44.6 +/- 1.3 D. The mean keratometric astigmatisms of premenopausal and postmenopausal women were 0.81 +/- 0.57 D (4–179 degrees), 0.74 degrees +/- 0.5 D (1–180 degrees) respectively. No significant corneal curvature changes were detected between premenopausal and postmenopausal groups (P > 0.05). On the other hand, we only found negative but significant correlation between horizontal corneal curvature and estrogen level of postmenopausal women (r = -0.346, p = 0.038).</p> <p>Conclusion</p> <p>Menopause is physiologic process and may also affect corneal topographic changes. In postmenopausal women, corneal steeping was observed minimally compared to premenopausal women. The results suggest that changes in estrogen level of women with menopause are associated with slightly alteration of horizontal curvature of cornea.</p

Sclerosing angiomatoid nodular transformation of the spleen: CT, MR, PET, and 99mTc-sulfur colloid SPECT CT findings with gross and histopathological correlation

Sclerosing angiomatoid nodular transformation (SANT) is a benign, proliferative vascular lesion affecting the spleen. Few reports detailing the cross sectional and PET appearance of this lesion are available, and the lesion’s behavior with 99mTc-sulfur colloid scintigraphy is previously unreported. Sclerosing nodular transformation of the spleen shows increased tracer accumulation on positron emission tomography, and a central scar-like appearance with an enhancing capsule and radiating septae on CT and MR studies that reflects the gross and histopathological features of the lesion may be visible. An understanding of this pathological finding may allow prospective recognition of the sclerosing nodular transformation of the spleen on cross sectional imaging studies

Characteristics of Mothers Caring for Children During Episodes of Homelessness

This study provides a description of the physical, psychological, and substance use problems of adult homeless women who are and are not caring for children. We also examined differences in the characteristics of these two groups of women. Interviews were conducted with 148 homeless women from three mid-sized U.S. cities, 24.3% of whom were caring for at least one child. Our results showed that women caring for children were more likely to be sheltered and have health insurance. Homeless women caring for children and solitary homeless women were generally similar in terms of substance abuse problems. However, rates of Borderline Personality Disorder were higher among women caring for children than among solitary homeless women. Our results are somewhat consistent with previous research, with the exception of substance abuse problems and mental health problems, which were shown to be equally problematic for all women, regardless of current caregiving status

Inhibiting α-Synuclein Oligomerization by Stable Cell-Penetrating β-Synuclein Fragments Recovers Phenotype of Parkinson's Disease Model Flies

The intracellular oligomerization of α-synuclein is associated with Parkinson's disease and appears to be an important target for disease-modifying treatment. Yet, to date, there is no specific inhibitor for this aggregation process. Using unbiased systematic peptide array analysis, we indentified molecular interaction domains within the β-synuclein polypeptide that specifically binds α-synuclein. Adding such peptide fragments to α-synuclein significantly reduced both amyloid fibrils and soluble oligomer formation in vitro. A retro-inverso analogue of the best peptide inhibitor was designed to develop the identified molecular recognition module into a drug candidate. While this peptide shows indistinguishable activity as compared to the native peptide, it is stable in mouse serum and penetrates α-synuclein over-expressing cells. The interaction interface between the D-amino acid peptide and α-synuclein was mapped by Nuclear Magnetic Resonance spectroscopy. Finally, administering the retro-inverso peptide to a Drosophila model expressing mutant A53T α-synuclein in the nervous system, resulted in a significant recovery of the behavioral abnormalities of the treated flies and in a significant reduction in α-synuclein accumulation in the brains of the flies. The engineered retro-inverso peptide can serve as a lead for developing a novel class of therapeutic agents to treat Parkinson's disease

Mechanism of copper(II)-induced misfolding of Parkinson's disease protein

α-synuclein (aS) is a natively unfolded pre-synaptic protein found in all Parkinson's disease patients as the major component of fibrillar plaques. Metal ions, and especially Cu(II), have been demonstrated to accelerate aggregation of aS into fibrillar plaques, the precursors to Lewy bodies. In this work, copper binding to aS is investigated by a combination of quantum and molecular mechanics simulations. Starting from the experimentally observed attachment site, several optimized structures of Cu-binding geometries are examined. The most energetically favorable attachment results in significant allosteric changes, making aS more susceptible to misfolding. Indeed, an inverse kinematics investigation of the configuration space uncovers a dynamically stable β-sheet conformation of Cu-aS that serves as a nucleation point for a second β-strand. Based on these findings, we propose an atomistic mechanism of copper-induced misfolding of aS as an initial event in the formation of Lewy bodies and thus in PD pathogenesis

Effect of Spermidine on Misfolding and Interactions of Alpha-Synuclein

Alpha-synuclein (α-Syn) is a 140 aa presynaptic protein which belongs to a group of natively unfolded proteins that are unstructured in aqueous solutions. The aggregation rate of α-Syn is accelerated in the presence of physiological levels of cellular polyamines. Here we applied single molecule AFM force spectroscopy to characterize the effect of spermidine on the very first stages of α-Syn aggregation – misfolding and assembly into dimers. Two α-Syn variants, the wild-type (WT) protein and A30P, were studied. The two protein molecules were covalently immobilized at the C-terminus, one at the AFM tip and the other on the substrate, and intermolecular interactions between the two molecules were measured by multiple approach-retraction cycles. At conditions close to physiological ones at which α-Syn misfolding is a rare event, the addition of spermidine leads to a dramatic increase in the propensity of the WT and mutant proteins to misfold. Importantly, misfolding is characterized by a set of conformations, and A30P changes the misfolding pattern as well as the strength of the intermolecular interactions. Together with the fact that spermidine facilitates late stages of α-Syn aggregation, our data demonstrate that spermidine promotes the very early stages of protein aggregation including α-Syn misfolding and dimerization. This finding suggests that increased levels of spermidine and potentially other polyamines can initiate the disease-related process of α-Syn

Biochemical profile and in vitro neuroprotective properties of Carpobrotus edulis L., a medicinal and edible halophyte native to the coast of South Africa

This work reports the nutritional profile and in vitro neuroprotective properties of leaves of Carpobrotus edulis L, a medicinal and edible succulent species native to the coast of South Africa. Biomass was evaluated for proximate composition and for contents in carotenoids, liposoluble pigments and minerals. Hexane, dichloromethane, ethyl acetate and methanol extracts were prepared by Soxhlet extraction from dried biomass and evaluated for in vitro inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), capacity to attenuate hydrogen peroxide (H2O2)-induced injury in the human dopaminergic cell line SH-SY5Y and for anti-neuroinflammatory potential on lipopolysaccharide (LPS)-stimulated microglia cells. Extracts were evaluated for antioxidant activity by four complementary methods, total content of phenolics, tannins and flavonoids. Finally the profile of the main phenolic compounds was determined by high performance liquid chromatography with diode array detection (HPLC-DAD). C edulis has a high moisture content, high levels of crude protein, fibre, ash, carotenoids, calcium and iron and a low fat level. The extracts were able to efficiently scavenge the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH), reduce iron and chelate copper and iron ions, and exhibited different levels of phenolic compounds in the order ethyl acetate > methanol > dichloromethane > hexane. The main compounds detected were gallic and salicylic acids and quercetin, all in the ethyl acetate extract. The extracts allowed a dual and potent inhibition of AChE and BuChE. The dichloromethane and methanol extracts had the strongest capacity to prevent cell death induced by H2O2, and the methanol extract had anti-neuronflammatory properties. All together our results suggest that consumption of leaves of C edulis can contribute for a balanced diet, and that they may add to the improvement of cognitive functions. It also suggests possible novel biotechnological applications of C. edulis such as source of molecules and/or products for the food and/or pharmaceutical industries. Studies aiming to the isolation and identification of the bioactive compounds are already in progress. (C) 2017 SAAB. Published by Elsevier B.V. All rights reserved.Portuguese National BudgetXtremeGourmet project [ALG-01-0247-FEDER-017676]FCT Investigator Programme [IF/00049/2012]info:eu-repo/semantics/publishedVersio