A proposed staging system for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by progressive loss of upper and lower motor neurons, with a median survival of 2–3 years. Although various phenotypic and research diagnostic classification systems exist and several prognostic models have been generated, there is no staging system. Staging criteria for amyotrophic lateral sclerosis would help to provide a universal and objective measure of disease progression with benefits for patient care, resource allocation, research classifications and clinical trial design. We therefore sought to define easily identified clinical milestones that could be shown to occur at specific points in the disease course, reflect disease progression and impact prognosis and treatment. A tertiary referral centre clinical database was analysed, consisting of 1471 patients with amyotrophic lateral sclerosis seen between 1993 and 2007. Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration. Milestones occurred at predictable proportions of the disease course. Diagnosis occurred at 35% through the disease course, involvement of a second region at 38%, a third region at 61%, need for gastrostomy at 77% and need for non-invasive ventilation at 80%. We therefore propose a simple staging system for amyotrophic lateral sclerosis. Stage 1: symptom onset (involvement of first region); Stage 2A: diagnosis; Stage 2B: involvement of second region; Stage 3: involvement of third region; Stage 4A: need for gastrostomy; and Stage 4B: need for non-invasive ventilation. Validation of this staging system will require further studies in other populations, in population registers and in other clinic databases. The standardized times to milestones may well vary between different studies and populations, although the stages themselves and their meanings are likely to remain unchanged

Mixing to monsoons: Air-sea interactions in the bay of Bengal

More than 1 billion people depend on rainfall from the South Asian monsoon for their livelihoods. Summertime monsoonal precipitation is highly variable on intraseasonal time scales, with alternating "active" and "break" periods. These intraseasonal oscillations in large-scale atmospheric convection and winds are closely tied to 1°C-2°C variations of sea surface temperature in the Bay of Bengal

The risk to relatives of patients with sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons with a median survival of 2 years. Most patients have no family history of amyotrophic lateral sclerosis, but current understanding of such diseases suggests there should be an increased risk to relatives. Furthermore, it is a common question to be asked by patients and relatives in clinic. We therefore set out to determine the risk of amyotrophic lateral sclerosis to first degree relatives of patients with sporadic amyotrophic lateral sclerosis attending a specialist clinic. Case records of patients with sporadic amyotrophic lateral sclerosis seen at a tertiary referral centre over a 16-year period were reviewed, and pedigree structures extracted. All individuals who had originally presented with sporadic amyotrophic lateral sclerosis, but who subsequently had an affected first degree relative, were identified. Calculations were age-adjusted using clinic population demographics. Probands (n = 1502), full siblings (n = 1622) and full offspring (n = 1545) were identified. Eight of the siblings and 18 offspring had developed amyotrophic lateral sclerosis. The unadjusted risk of amyotrophic lateral sclerosis over the observation period was 0.5% for siblings and 1.0% for offspring. Age information was available for 476 siblings and 824 offspring. For this subset, the crude incidence of amyotrophic lateral sclerosis was 0.11% per year (0.05–0.21%) in siblings and 0.11% per year (0.06–0.19%) in offspring, and the clinic age-adjusted incidence rate was 0.12% per year (0.04–0.21%) in siblings. By age 85, siblings were found to have an 8-fold increased risk of amyotrophic lateral sclerosis, in comparison to the background population. In practice, this means the risk of remaining unaffected by age 85 dropped from 99.7% to 97.6%. Relatives of people with sporadic amyotrophic lateral sclerosis have a small but definite increased risk of being affected

Constructive Hybrid Games

Hybrid games are models which combine discrete, continuous, and adversarial dynamics. Game logic enables proving (classical) existence of winning strategies. We introduce constructive differential game logic (CdGL) for hybrid games, where proofs that a player can win the game correspond to computable winning strategies. This is the logical foundation for synthesis of correct control and monitoring code for safety-critical cyber-physical systems. Our contributions include novel static and dynamic semantics as well as soundness and consistency.Comment: 60 pages, preprint, under revie

Toward Regional Characterizations of the Oceanic Internal Wavefield

Many major oceanographic internal wave observational programs of the last 4 decades are reanalyzed in order to characterize variability of the deep ocean internal wavefield. The observations are discussed in the context of the universal spectral model proposed by Garrett and Munk. The Garrett and Munk model is a good description of wintertime conditions at Site-D on the continental rise north of the Gulf Stream. Elsewhere and at other times, significant deviations in terms of amplitude, separability of the 2-D vertical wavenumber - frequency spectrum, and departure from the model's functional form are noted. Subtle geographic patterns are apparent in deviations from the high frequency and high vertical wavenumber power laws of the Garrett and Munk spectrum. Moreover, such deviations tend to co-vary: whiter frequency spectra are partnered with redder vertical wavenumber spectra. Attempts are made to interpret the variability in terms of the interplay between generation, propagation and nonlinearity using a statistical radiative balance equation. This process frames major questions for future research with the insight that such integrative studies could constrain both observationally and theoretically based interpretations

Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1

<p>Abstract</p> <p>Background</p> <p><it>Cinnamomum cassia </it>bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8⁺T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model.</p> <p>Methods</p> <p>Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer <it>in vitro </it>and <it>in vivo </it>mouse melanoma model.</p> <p>Results</p> <p>Cinnamon extract strongly inhibited tumor cell proliferation <it>in vitro </it>and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as <it>Bcl-2</it>, <it>BcL-xL </it>and <it>survivin</it>. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed <it>in vitro</it>.</p> <p>Conclusion</p> <p>Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes <it>in vitro </it>and <it>in vivo </it>mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers.</p

Analysis of Severity and Anatomical Distribution of Diabetic Foot Ulcers; A Single Unit Experience

Diabetes is the commonest cause of foot ulceration in developing countries leading to severe morbidity and mortality. The main aim of this study was to assess anatomical distribution of diabetic foot lesions, categorize it according to Wagner wound grading, find any association between smoking packs years and the severity of the foot lesions. Also to assess the relationship between the bony deformities and anatomical distribution of the ulcers. This was a cross sectional descriptive study conducted in a casualty surgical unit in a tertiary care teaching hospital for a period of 4 months. 91 diabetic patients with a diabetes related foot lesion were enrolled after simple randomization. Pretested interviewer administered questionnaire was used to gather data. Variety of soft tissue and bony changes of diabetic foot were assessed. Lesions were classified according to Wagner classification. Data was analysed using Epidata software. From the 91 participants, 55 (61 %) were males and 36 (39%) females. Mean age was at 60. 12 ± 10. 19 years. Median diabetes duration was 10 years (Interquartile range = 4.25 – 16.75). Wagner grade 1, 2, 3, 4 and 5 were17.7%, 40.65%, 28.8%, 13.3% and 0% respectively. Commonest ulcer location was margins of foot (31.87%). There was no statistically significant association between the pack years of cigarette smoking males and severity of foot lesions (Spearman’s rank correlation coefficient = - 0.037, p = 0.82). Patients with claw and hammer toe deformities had their ulcers located in fingertips and toes (p = 0.0185). But there was no statistically significant association with flat foot deformity and ulcer distribution on any particular anatomical area in the foot (p = 0.0511). In conclusion there is a statistically significant association between toe deformities and ulcer occurrence in finger tips. No significant correlation between severity of smoking and severity of foot lesions among males is present.  KEYWORDS: Diabetic ulcers, Diabetic foot lesions, Wagner classification, Dlcer distributio

Genetic Biomarkers for ALS Disease in Transgenic SOD1G93A Mice

The pathophysiological mechanisms of both familial and sporadic Amyotrophic Lateral Sclerosis (ALS) are unknown, although growing evidence suggests that skeletal muscle tissue is a primary target of ALS toxicity. Skeletal muscle biopsies were performed on transgenic SOD1G93A mice, a mouse model of ALS, to determine genetic biomarkers of disease longevity. Mice were anesthetized with isoflurane, and three biopsy samples were obtained per animal at the three main stages of the disease. Transcriptional expression levels of seventeen genes, Ankrd1, Calm1, Col19a1, Fbxo32, Gsr, Impa1, Mef2c, Mt2, Myf5, Myod1, Myog, Nnt, Nogo A, Pax7, Rrad, Sln and Snx10, were tested in each muscle biopsy sample. Total RNA was extracted using TRIzol Reagent according to the manufacturer's protocol, and variations in gene expression were assayed by real-time PCR for all of the samples. The Pearson correlation coefficient was used to determine the linear correlation between transcriptional expression levels throughout disease progression and longevity. Consistent with the results obtained from total skeletal muscle of transgenic SOD1G93A mice and 74-day-old denervated mice, five genes (Mef2c, Gsr, Col19a1, Calm1 and Snx10) could be considered potential genetic biomarkers of longevity in transgenic SOD1G93A mice. These results are important because they may lead to the exploration of previously unexamined tissues in the search for new disease biomarkers and even to the application of these findings in human studies