Thyrotoxicosis presenting with headache

We report three cases of thyrotoxicosis who presented acutely with headache to our neurology service in a 1-year period. In two of these patients there was a pre-existing or subsequent history of migraine. With hindsight, there were other clinical features of thyrotoxicosis but this diagnosis had been missed in primary care. Severe headache can be a striking presenting feature of thyrotoxicosis, but these cases provide reassurance to the clinician that when this does occur, other clinical features of hyperthyroidism are usually present.     

Induction of HIV-1-specific T cell responses by administration of cytokines in late-stage patients receiving highly active anti-retroviral therapy.

Highly active anti-retroviral therapy (HAART) is associated with reduction in the morbidity and mortality of patients with advanced HIV-1 disease. The ability of such treatment to improve immune responses against HIV-1 and opportunistic pathogens is variable and limited. Addition of cytokine immunotherapy to this treatment may improve immune responses. IL-2 with or without granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered to HIV-1+ individuals receiving HAART with undetectable viral loads, and CD4 counts < 100 cells/microl. In one patient presenting with Mycobacterium avium complex (MAC) infection, we evaluated the effect of cytokine immunotherapy on lymphocyte phenotype; plasma viral load; proliferative responses to mitogens, recall and HIV-1 antigens; cytokine production and message in response to non-specific and specific stimuli; and natural killer (NK) cell activity. Proliferation assays were performed in two similar patients. Before cytokine immunotherapy the predominant CD8+ population was mainly CD28-. No proliferation or IL-2 production was seen in response to mitogens, recall or HIV-1 antigens; and no HIV-1 peptide-specific interferon-gamma (IFN-gamma)-secreting cells were present. Low levels of IL-4 were detected in response to antigens to which patients had been exposed, associated with up-regulated expression of costimulatory molecules influenced by IL-4. Following IL-2 administration, loss of IL-4 was associated with increased NK cell activity and HIV-1 peptide-specific and non-specific IFN-gamma-producing cells. Proliferative responses associated with IL-2 production and responsiveness were only seen after subsequent concomitant administration of GM-CSF with IL-2. These changes mirrored clinical improvement. An imbalance of lymphocyte subsets may account for immune unresponsiveness when receiving HAART. Restoration of responses following immunotherapy suggests a shift towards a lymphocyte profile with anti-pathogen activity.     

Transmol: repurposing a language model for molecular generation

Recent advances in convolutional neural networks have inspired the application of deep learning to other disciplines. Even though image processing and natural language processing have turned out to be the most successful, there are many other domains that have also benefited; among them, life sciences in general and chemistry and drug design in particular. In concordance with this observation, from 2018 the scientific community has seen a surge of methodologies related to the generation of diverse molecular libraries using machine learning. However to date, attention mechanisms have not been employed for the problem of de novo molecular generation. Here we employ a variant of transformers, an architecture recently developed for natural language processing, for this purpose. Our results indicate that the adapted Transmol model is indeed applicable for the task of generating molecular libraries and leads to statistically significant increases in some of the core metrics of the MOSES benchmark. The presented model can be tuned to either input-guided or diversity-driven generation modes by applying a standard one-seed and a novel two-seed approach, respectively. Accordingly, the one-seed approach is best suited for the targeted generation of focused libraries composed of close analogues of the seed structure, while the two-seeds approach allows us to dive deeper into under-explored regions of the chemical space by attempting to generate the molecules that resemble both seeds. To gain more insights about the scope of the one-seed approach, we devised a new validation workflow that involves the recreation of known ligands for an important biological target vitamin D receptor. To further benefit the chemical community, the Transmol algorithm has been incorporated into our cheML.io web database of ML-generated molecules as a second generation on-demand methodology.

A novel molecular generation pipeline employing an attention-based neural network.     

Prevalence and parental perceptions of complementary and alternative medicine use by children with cancer in a multi-ethnic Southeast Asian population

Background

The purpose of the current study was to determine the prevalence of use of complementary and alternative medicine (CAM) by children with cancer and to compare the characteristics of CAM users and CAM nonusers.

Methods

A cross‐sectional study was performed at a pediatric oncology center in Kuala Lumpur, Malaysia. The parents of 97 children with cancer were interviewed using a structured questionnaire.

Results

Overall, 84.5% of the respondents had used CAM, and most of them believed that CAM provided a boost to the immune system, and used CAM with the intention to complement conventional treatment. The most frequently used CAM was water therapy (78%), followed by spirulina (33%), vitamin C (27%), multivitamin (23%), visit to traditional healers (22%), sea cucumber (Stichopus horrens) (15%), and Chinese traditional medicine (12%). The Malay (n = 67) were using more often (93%) CAM than non‐Malay (n = 30, use 67%, P = 0.001).

Conclusions

CAM use is common among Malaysian children with cancer. Understanding the sociocultural dimension of patients' health beliefs is important to a successful treatment, and pediatric oncologists should ask for the use of CAM. Pediatr Blood Cancer 2009;52:70–74. © 2008 Wiley‐Liss, Inc.     

Dissimilar Friction Stir Welding of AA2519 and AA5182

In this study, the friction-stir welding (FSW) technique was successfully applied for joining of AA2519 to AA5181 alloy. Microstructure and mechanical properties of dissimilar FSW joints were investigated by optical microscopy, microhardness, and tensile testing. The deformation behaviour of the welded joints was elucidated via the digital image correlation technique. After welding, the ultimate tensile strength of joints was ~300 MPa and ductility was ~16%. The microhardness values observed at the stir zone were higher than those in the base material AA5182. The produced welds demonstrate nearly 100% (based on AA5182) joint efficiency.     

Unlocking the 'locked-in syndrome'

We present a case of a 48-year-old man who was initially thought to have had a brainstem stroke and was clinically 'locked-in'. Upon investigation, a petrous apex dural atriovenous fistula was identified causing profound brainstem venous hypertension. Surgical clipping lead to complete neurological recovery.     

European research priorities for intracerebral haemorrhage

Over 2 million people are affected by intracerebral haemorrhage (ICH) worldwide every year, one third of them dying within 1 month, and many survivors being left with permanent disability. Unlike most other stroke types, the incidence, morbidity and mortality of ICH have not declined over time. No standardised diagnostic workup for the detection of the various underlying causes of ICH currently exists, and the evidence for medical or surgical therapeutic interventions remains limited. A dedicated European research programme for ICH is needed to identify ways to reduce the burden of ICH-related death and disability. The European Research Network on Intracerebral Haemorrhage EURONICH is a multidisciplinary academic research collaboration that has been established to define current research priorities and to conduct large clinical studies on all aspects of ICH.     

Age-related loss of calcium buffering and selective neuronal vulnerability in Alzheimer's disease

The reasons for the selective vulnerability of distinct neuronal populations in neurodegenerative disorders are unknown. The cholinergic neurons of the basal forebrain are vulnerable to pathology and loss early in Alzheimer’s disease and in a number of other neurodegenerative disorders of the elderly. In the primate, including man, these neurons are rich in the calcium buffer calbindin-D_28K. Here, we confirm that these neurons undergo a substantial loss of calbindin in the course of normal aging and report a further loss of calbindin in Alzheimer’s disease both at the level of RNA and protein. Significantly, cholinergic neurons that had lost their calbindin in the course of normal aging were those that selectively degenerated in Alzheimer’s disease. Furthermore, calbindin-containing neurons were virtually resistant to the process of tangle formation, a hallmark of the disease. We conclude that the loss of calcium buffering capacity in these neurons and the resultant pathological increase in intracellular calcium are permissive to tangle formation and degeneration.     

Autoimmune limbic encephalitis

Autoimmune limbic encephalitis is an increasingly recognised cause of cognitive decline and confusion. The typical presentation is with subacute cognitive decline, behavioural disturbance and seizures. Magnetic resonance imaging may show characteristic changes in the medial temporal regions. The diagnosis is confirmed by identification of elevated voltage-gated potassium channel antibody (VGKC-Ab) titres. It is a highly treatable condition, often responding well to intravenous immunoglobulin or steroids. Recognition of autoimmune limbic encephalitis is sometimes delayed--usually because the diagnosis has not been considered--which can result in long-term neurological consequences.