Project description:Alzheimer's and Parkinson's disease are the two most common neurodegenerative disorders. They develop after a progressive death of many neurons in the brain. Although therapies are available to treat the signs and symptoms of both diseases, the progression of neuronal death remains relentless, and it has proved difficult to slow or stop. Hence, there is a need to develop neuroprotective or disease-modifying treatments that stabilize this degeneration. Red to infrared light therapy (? = 600-1070 nm), and in particular light in the near infrared (NIr) range, is emerging as a safe and effective therapy that is capable of arresting neuronal death. Previous studies have used NIr to treat tissue stressed by hypoxia, toxic insult, genetic mutation and mitochondrial dysfunction with much success. Here we propose NIr therapy as a neuroprotective or disease-modifying treatment for Alzheimer's and Parkinson's patients.
Project description:Poor handover between doctors is a recognised cause of error in hospitals.[1] Watford General Hospital is a busy acute trust in southern England, where high admission rates necessitate timely patient transfers from the acute admissions unit (AAU) to the medical wards. We found that doctors were infrequently informed of patient transfers, and they rarely handed over patient care when a patient was moved. Our aim was to minimise preventable harm to patients by prompting handover of clinically unstable patients, and patients with outstanding investigations or referrals, at the time of transfer. We introduced a traffic light tool to categorise patients on the medical take as red, amber, or green according to their clinical status at time of admission to AAU. The traffic light colour, which was assigned both on paper and electronically, was designed to prompt a verbal handover between doctors at the time of patient transfer from AAU.
Project description:Although not as common as other genetic renal diseases such as autosomal dominant polycystic kidney disease, patients with tuberous sclerosis complex frequently have significant renal involvement. Recent revelations in the cell biology of these renal disease manifestations as well as effective therapies for tuberous sclerosis complex-related renal issues have heralded hope of improved renal survival and improved quality of life for the TSC patient. This review specifically addresses some of the major renal manifestations of this disease.
Project description:Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice.
Project description:Tuberous sclerosis complex (TSC) is a genetic condition caused by a mutation in either the TSC1 or TSC2 gene. Disruption of either of these genes leads to impaired production of hamartin or tuberin proteins, leading to the manifestation of skin lesions, tumors, and seizures. TSC can manifest in multiple organ systems with the cutaneous and renal systems being the most commonly affected. These manifestations can secondarily lead to the development of hypertension, chronic kidney disease, and neurocognitive declines. The renal pathologies most commonly seen in TSC are angiomyolipoma, renal cysts, and less commonly, oncocytomas. In this review, we highlight the current understanding on the renal manifestations of TSC along with current diagnosis and treatment guidelines.
Project description:PurposeTo describe the finding of bright hyperautofluorescent streaks in the peripheral retina in tuberous sclerosis.ObservationsA woman with a pathogenic TSC1 mutation and cutaneous manifestations of tuberous sclerosis underwent fundus examination and was found to have a cluster of thin, yellowish streaks in the inferior peripheral fundus of her left eye. The streaks were hyperautofluorescent in blue light and associated with irregular thickening of the photoreceptor-pigment epithelium complex on optical coherence tomography.Conclusions and importanceThe cluster of outer retinal abnormalities in a sector of the peripheral retina in one eye of a TSC1 patient has features in common with the more centrally located and less numerous lesions called achromatic patches. The resemblance of the streak pattern with the pattern of hypoautofluorescence in X-linked retinopathies suggests that the streaks may represent a clone of cells derived from a single somatic mutation in TSC1. The identification of this lesion type expands the scope of conditions that can be diagnosed by fundus imaging.
Project description:Tuberous sclerosis complex (TSC) is an inheritable disorder characterized by the formation of benign yet disorganized tumors in multiple organ systems. Germline mutations in the TSC1 (hamartin) or more frequently TSC2 (tuberin) genes are causative for TSC. The malignant manifestations of TSC, pulmonary lymphangioleiomyomatosis (LAM) and renal angiomyolipoma (AML), may also occur as independent sporadic perivascular epithelial cell tumor (PEComa) characterized by somatic TSC2 mutations. Thus, discerning TSC from the copresentation of sporadic LAM and sporadic AML may be obscured in TSC patients lacking additional features. In this report, we present a case study on a single patient initially reported to have sporadic LAM and a mucinous duodenal adenocarcinoma deficient in DNA mismatch repair proteins. Moreover, the patient had a history of Wilms' tumor, which was reclassified as AML following the LAM diagnosis. Therefore, we investigated the origins and relatedness of these tumors. Using germline whole-genome sequencing, we identified a premature truncation in one of the patient's TSC2 alleles. Using immunohistochemistry, loss of tuberin expression was observed in AML and LAM tissue. However, no evidence of a somatic loss of heterozygosity or DNA methylation epimutations was observed at the TSC2 locus, suggesting alternate mechanisms may contribute to loss of the tumor suppressor protein. In the mucinous duodenal adenocarcinoma, no causative mutations were found in the DNA mismatch repair genes MLH1, MSH2, MSH6, or PMS2 Rather, clonal deconvolution analyses were used to identify mutations contributing to pathogenesis. This report highlights both the utility of using multiple sequencing techniques and the complexity of interpreting the data in a clinical context.
Project description:Tuberous sclerosis complex has manifestations in many organ systems, including brain, heart, kidney, skin, and lung. The primary manifestations in the lung are lymphangioleiomyomatosis (LAM) and multifocal micronodular pneumocyte hyperplasia (MMPH). LAM affects almost exclusively women, and causes cystic lung destruction, pneumothorax, and chylous pleural effusions. LAM can lead to dyspnea, oxygen dependence, and respiratory failure, with more rapid disease progression during the premenopausal years. In contrast, MMPH affects men and women equally, causing small nodular pulmonary deposits of type II pneumocytes that rarely progress to symptomatic disease. Here, we review the clinical features and pathogenesis of LAM and MMPH.
Project description:Chordoma associated with tuberous sclerosis complex (TSC) are an extremely rare tumor that was described only in 13 cases since 1975. Сhordomas themselves are malignant slow-growing bone tumors thought to arise from vestigial or ectopic notochordal tissue. In total, with CMA we found 180 regions with CNVs in the chordoma tumor sample. The longest section was 58,014 kbp long (arr[GRCh38] 9q21.31q34.3(79267492_137281464)x1-2), harboring region 9q34 that includes TSC1 gene. Also, 12 oncogenes including KRAS and CBX7 were in amplified regions and 92 tumor suppressor genes were in regions with loss status. Four genes that participate in epigenetic regulation, - ELP3, GTF3C4, MBD2, and PHF2 were found to be affected. Moreover, members of the APOBEC3 family were amplified.