In vitro pharmacological profiling of selected small molecules compound using recombinant human iduronate-2-sulphatase

Background: Mucopolysaccharidoses type II (MPS II) is an X-linked lysosomal storage disease (LSD). It is due to mutation in IDS gene encoding iduronate-2-sulphatase (IDS) involved in the catabolism of dermatan sulphate and heparan sulphate. Currently, the treatments for MPS II patients are enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). However, ERT is not effectively reducing the central nervous system manifestation and finding the suitable donor maybe quite challenging in BMT. Over the past decades, pharmacological chaperone has been an alternative approach for management of MPS II patient. Here, we described the in vitro profiling of small molecules in group of chondroitin/dermatan (CD) sulphate disaccharide, heparin oligosaccharides, unsaturated heparin disaccharides and 6-O-desulphated heparin oligosaccharide, using recombinant human iduronate-2-sulphatase (rhIDS). Twenty-one small molecule compounds with several concentrations were each screened by inhibition and thermal stability assays. Results: Our study revealed that condroitin dermatan trisulphate (CD3S), heparin tetrasaccharide (H4Sac), heparin octasaccharide (H8Sac) and heparin octadecasaccharide (H18Sac) showed high inhibition constant, Ki and low inhibition concentration, IC50 in comparison to others. In the thermal stability study, only rhIDS incubated with CD3S was found to preserve enzyme activity (20%) after incubated at 67oC. Conclusion: Overall, our experiments discovered that CD3S was able to bind, inhibit and chaperone rhIDS. These features suggest a potential pharmacological chaperone for MPS II.

A Patient with Limbic Encephalitis, Ear Perichondritis, and Episcleritis – An Unusual Presentation of Relapsing Polychondritis

Relapsing polychondritis (RPC) is a rare autoimmune disease that is characterized by recurrent inflammation and destruction of cartilaginous tissues. Limbic encephalitis is a rare central nervous system manifestation of RPC that has been mentioned in case reports. Recognition of this association, and reliable methods of diagnosis, including the utility of neuroimaging modalities such as positron emission tomography/computed tomography (PET/CT) can be useful in the evaluation of this diagnostic challenge. We report a patient with limbic encephalitis associated with RPC, where PET/CT was effectively used in the diagnosis, and monitoring of response to treatment. We also demonstrate that it can be a useful modality in certain situations when brain magnetic resonance imaging cannot be done.

A study of neurological problems in HIV infection

Background: Knowledge of central nervous system manifestation (CS) is crucial for clinical practitioners, which is why this study was conducted to identify the neurological manifestations in HIV patient is crucial problems with HIV and the difficulties in managing these patients.Methods: The present study was conducted on patients of HIV infection who were either admitted or being treated in OPD during study period. The cases were selected based seropositivity for HIV on two consecutive occasions by ELISA and presence of WHO surveillance definition criteria. Based on a detailed history account including high risk behaviour to HIV infection was obtained from patients or relatives. Then each patient was subjected to thorough physical examination with specific attention to any clinical evidence of immunosuppression viz oral thrush. Thorough neurological examination was done to localize the part of central nervous system affected. Patients were then categorized into various clinical neurological syndromes.Results: Commonest finding was single or multiple ring enhancing lesions seen in 21(35%) patients followed by basal exudates (21.6%). Hydrocephalus was seen in 5 patients (8.3%) and infarct due to vascular lesion in 4(7%) patients. Oral thrush was more commonly seen in patients with cryptococcal meningitis. CSF analysis was useful and revealed abnormalities in most of the patients with infective disorders.Conclusions: In conclusion, variety of neurologic manifestations occur and any part of nervous system can be affected in HIV infection and high index of euspicion is required to pick up the cases early in the course which may help to improve the quality and life span of these suspicion patients.

Glioneuronal and other epilepsy-associated tumours

Patients with (glio)neuronal brain tumours are rare. The most common variants, hat is, gangliogliomas and dysembryoplastic neuroepithelial tumours (DNTs), frequently present with pharmacoresistant epilepsy. Together with certain other tumour types associated with chronic epilepsy (including selected cases with diffuse gliomas WHO grade II/III) these entities have historically been referred to as LEATs (long-term epilepsy-associated tumours). LEATs share a very benign clinical course and rarely recur following a gross total resection. More than 80% of patients can expect to become seizure-free following epilepsy surgery (i.e. resection of the epileptogenic zone rather than tumour removal only). Hippocampal resections may improve the seizure outcome in cases with mesial temporal lobe epilepsy, but may also carry a concurrent risk of neuropsychological deficits. In contrast, oncological issues dominate the clinical course of LEATs and glioneuronal tumour variants if encountered outside the setting of refractory epilepsy. The dysplastic cerebellar gangliocytoma (L’Hermitte-Duclos disease, LDD) is the major central nervous system manifestation of Cowden disease. Its neoplastic nature is questionable.

Limbic encephalitis with relapsing polychondritis: persistent white matter lesions and brain atrophy

Relapsing polychondritis (RP) is a rare autoimmune disorder affecting cartilage. Limbic encephalitis is a rare central nervous system manifestation of RP. This current case report describes a 66-year-old Chinese male patient who complained of developing myoclonus in the left leg, ataxia and speech difficulties 3 weeks prior to hospital admission. The patient presented with cognitive impairment, sleep disorder and extrapyramidal symptoms. The patient was diagnosed with RP that affected auricular cartilage, which also manifested as limbic encephalitis. Magnetic resonance imaging showed bilateral temporal lobe lesions involving the hippocampi and basal ganglia. Signal abnormalities in the white matter persisted during the 15-month follow-up period after treatment with corticosteroids and intravenous immunoglobulin. Over the same period, the bilateral hippocampi showed significant atrophy.

Rheumatoid leptomeningitis presenting with an acute neuropsychiatric disorder

Leptomeningitis is a rare central nervous system manifestation of rheumatoid arthritis, generally in patients with established chronic rheumatoid disease. We report a 41-year-old man without previous rheumatoid arthritis or psychiatric disorder who presented with an acute neuropsychiatric disturbance and polyarthralgia. His MR scan of brain showed asymmetric bifrontal leptomeningitis, confirmed on (18F)-fluoro-D-glucose-positron emission tomography. Other investigations showed highly positive serum and cerebrospinal fluid anti-cyclic citrullinated peptide. A leptomeningeal biopsy showed necrotising leptomeningeal inflammation with ill-defined granulomas and lymphoplasmacytic infiltrate without organisms. Prolonged high-dose corticosteroids and then rituximab resulted in recovery. Chronic leptomeningitis can present with an acute neuropsychiatric disorder. We highlight that early rheumatoid disease can, rarely, cause a chronic leptomeningitis, reversible with immunotherapy.