Utility of the new gold classification for COPD in alpha one antitrypsin deficiency

Background The revised 2011 GOLD strategy presented a new classification and treatment of usual Chronic Obstructive Pulmonary disease (COPD) based on symptom assessment by CAT or mMRC and risk assessment based on exacerbations estimated from the spirometric grade or number of exacerbations in previous year (1). This new strategy has not previously been applied to patients with Alpha one antitrypsin deficiency (AATD). Aims To apply new GOLD strategy/categories in AATD and assess comparable symptom thresholds and predictability of mortality, future exacerbations and lung function decline (FEV1, Kco) and the role of comorbidities. Results The results have validated the strategy/classification in AATD with a suggested threshold of 13 rather than 10 for CAT to match with mMRC 1. Mortality and Kco decline was worse in the more severe category D which also had patients with more comorbidity. Applying COTE index to patients with AATD did not help in predicting mortality. Conclusion The new GOLD classification helps identify AATD patients who are at risk of poorer outcome based on lung function decline, mortality and exacerbation risk with patients in group D being most at risk. Presence of comorbidities does not appear to influence outcomes in AATD although they do tend to indicate a poorer quality of life. References 1. Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, et a!. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. American journal of respiratory and critical care medicine. 2013;187(4):347-65

Cervical length measurement by transvaginal sonography in predicting preterm labour in low risk women

Background: Preterm birth is the leading cause of perinatal morbidity and mortality. Transvaginal sonographic measurement of the cervix is a reliable alternative method for the assessment of cervical length as it allows better quality and more accurate visualization of the uterine cervix. Several studies have reported that cervical assessment on transvaginal sonography may be useful in the prediction of preterm delivery. The objective of this study was to assess cervical length at 20 to 24 weeks of gestation in low risk women and correlate with the gestational age at delivery.Methods: A prospective cohort study conducted in a tertiary care Military Hospital in Pune, India. 354 asymptomatic low risk antenatal women with gestational age of 20 to 24 weeks were studied. Cervical assessment with transvaginal sonography for the measurement of cervical length was performed using a 10 MHz transvaginal probe.Results: 7 percent women delivered preterm. The incidence of short cervix in low risk women was only 0.56%. 100% women with short cervix delivered preterm and, only 6.9% patients who had cervical length more than 25 mm delivered preterm. Cervical length 25 mm has got sensitivity and NPV of 100% and a specificity of 93.46%. However, the PPV was only 8%.Conclusions: The study reported significant inverse relation between short cervix and the occurrence of preterm delivery. Our findings suggest that cervical length can be used as a screening method for preterm labour in low risk women. However strong evidences from large randomized control trials would be required to assess its cost-effectiveness.

Individualised lung function trends in AATD: a need for patience in order to provide patient centred management?

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction and accelerated decline of forced expired volume in 1 second (FEV(1)). Alpha-1-antitrypsin deficiency is a genetic cause of COPD and associated with more rapid decline in lung function, even in some never smokers (NS) but the potential for individualized assessment to reveal differences when compared to group analyses has rarely been considered. METHODS: We analyzed decline in post-bronchodilator FEV(1) and gas transfer (% predicted) over at least 3 years (mean= 6.11, 95% CI 5.80–6.41) in our unique data set of 482 patients with alpha-1-antitrypsin deficiency (PiZ) to determine individual rates of decline, implications for prognosis, and potential clinical management. FINDINGS: There was a marked variation in individual rates of FEV(1) decline from levels consistent with normal aging (observed in 23.5% of patients with established COPD, 57.5% of those without) to those of rapidly declining COPD. Gas transfer did not decline in 12.8% of NS and 20.7% of ex-smokers with established COPD (33.3% and 25.0%, respectively, for those without COPD). There was no correlation between decline in gas transfer and FEV(1) for those with COPD, although a weak relationship existed for those without (r=0.218; P<0.025). CONCLUSION: These data confirm differing individual rates of lung function decline in alpha-1-antitrypsin deficiency, indicating the importance of comprehensive physiological assessment and a personalized approach to patient management

Axonal Ensheathment and Septate Junction Formation in the Peripheral Nervous System of Drosophila

Axonal insulation is critical for efficient action potential propagation and normal functioning of the nervous system. I

Plasma Amyloid-β dynamics in late-life major depression: a longitudinal study

Depressed individuals are twice as likely to develop Alzheimer’s disease (AD) as compared to controls. Brain amyloid-β (Aβ) deposition is believed to have a major role in AD pathogenesis but studies also suggest associations of Aβ dynamics and depression. The aim of this study was to test if plasma Aβ levels are longitudinally associated to late-life depression. We measured plasma levels of amyloid-β1-40 (Aβ40) and amyloid-β1-42 (Aβ42) peptides longitudinally for three consecutive years in 48 cognitively intact elderly subjects with late-life major depressive disorder (LLMD) and 45 age-matched cognitively healthy controls. We found that the Aβ42/Aβ40 plasma ratio was significantly and steadily lower in depressed subjects compared to controls (p < 0.001). At screening, Aβ42/Aβ40 plasma did not correlate with depression severity (as measured with Hamilton Depression Scale) or cognitive performance (as measured with Mini-Mental State Examination) but was associated to depression severity at 3 years after adjustment for age, education, cognitive performance, and antidepressants use. This study showed that reduced plasma Aβ42/Aβ40 ratio is consistently associated with LLMD diagnosis and that increased severity of depression at baseline predicted low Aβ42/Aβ40 ratio at 3 years. Future studies are needed to confirm these findings and examine if the consistently lower plasma Aβ42/Aβ40 ratio in LLMD reflects increased brain amyloid deposition, as observed in AD subjects, and an increased risk for progressive cognitive decline and AD

Nodes of Ranvier Act as Barriers to Restrict Invasion of Flanking Paranodal Domains in Myelinated Axons

Accumulation of voltage gated sodium (Nav) channels at nodes of Ranvier is paramount for action potential propagation along myelinated fibers, yet the mechanisms governing nodal development, organization and stabilization remain unresolved. Here, we report that genetic ablation of the neuron-specific isoform of Neurofascin (NfascNF186) in vivo results in nodal disorganization, including loss of Nav channel and ankyrin-G (AnkG) enrichment at nodes in the peripheral (PNS) and central (CNS) nervous systems. Interestingly, the presence of paranodal domains failed to rescue nodal organization in the PNS and the CNS. Most importantly, using ultrastructural analysis, we demonstrate that the paranodal domains invade the nodal space in NfascNF186 mutant axons and occlude node formation. Our results suggest that NfascNF186-dependent assembly of the nodal complex acts as a molecular boundary to restrict the movement of flanking paranodal domains into the nodal area, thereby facilitating the stereotypic axonal domain organization and saltatory conduction along myelinated axons

Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155 ) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains

The evolutionary demand for rapid nerve impulse conduction led to the process of myelination-dependent organization of axons into distinct molecular domains. These domains include the node of Ranvier flanked by highly specialized paranodal domains where myelin loops and axolemma orchestrate the axoglial septate junctions. These junctions are formed by interactions between a glial isoform of neurofascin (NfascNF155) and axonal Caspr and Cont. Here we report the generation of myelinating glia-specific NfascNF155 null mouse mutants. These mice exhibit severe ataxia, motor paresis, and death before the third postnatal week. In the absence of glial NfascNF155, paranodal axoglial junctions fail to form, axonal domains fail to segregate, and myelinated axons undergo degeneration. Electrophysiological measurements of peripheral nerves from NfascNF155 mutants revealed dramatic reductions in nerve conduction velocities. By using inducible PLP-CreER recombinase to ablate NfascNF155 in adult myelinating glia, we demonstrate that paranodal axoglial junctions disorganize gradually as the levels of NfascNF155 protein at the paranodes begin to drop. This coincides with the loss of the paranodal region and concomitant disorganization of the axonal domains. Our results provide the first direct evidence that the maintenance of axonal domains requires the fence function of the paranodal axoglial junctions. Together, our studies establish a central role for paranodal axoglial junctions in both the organization and the maintenance of axonal domains in myelinated axons

No effect of genetic deletion of contactin-associated protein (CASPR) on axonal orientation and synaptic plasticity

Myelinated axons are endowed with a specialized domain structure that is essential for saltatory action potential conduction. The paranodal domain contains the axoglial junctions and displays a unique ultrastructure that resembles the invertebrate septate junctions (SJs). Biochemical characterizations of the paranodal axoglial SJs have identified several molecular components that include Caspr and contactin (Cont) on the axonal side and neurofascin 155 kDa (NF155) isoform on the glial side. All these proteins are essential for the formation of the axoglial SJs. Based on the interactions between Caspr and Cont and their colocalization in the CA1 synaptic areas, it was proposed that the synaptic function of Cont requires Caspr. Here we have extended the phenotypic analysis of CASPR mutants to address further the role of Caspr at the axoglial SJs and also in axonal orientation and synaptic plasticity. We report that, in CASPR mutants, the smooth endoplasmic reticulum (SER) forms elongated membranous complexes that accumulate at the nodal/ paranodal region and stretch into the juxtaparanodal region, a defect that is consistent with the paranodal disorganization. We show that the cerebellar microorganization is unaffected in CASPR mutants. We also demonstrate that Caspr function is not essential for normal CA1 synaptic transmission and plasticity. Taken together with previous findings, our results highlight that the Caspr/ Cont complex is essential for the formation of axoglial SJs, whereas Cont may regulate axonal orientation and synaptic plasticity independent of its association with Caspr

Cysteamine Attenuates the Decreases in TrkB Protein Levels and the Anxiety/Depression-Like Behaviors in Mice Induced by Corticosterone Treatment

OBJECTIVE: Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of anxiety-like behaviors observed in many neuropsychiatric disorders. Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB plays an important role in stress-mediated changes in structural as well as functional neuroplasticity. Studies designed to elucidate the mechanisms whereby TrkB signaling is regulated in chronic stress might provide valuable information for the development of new therapeutic strategies for several stress-related psychiatric disorders. MATERIALS AND METHODS: We examined the potential of cysteamine, a neuroprotective compound to attenuate anxiety and depression like behaviors in a mouse model of anxiety/depression induced by chronic corticosterone exposure. RESULTS: Cysteamine administration (150 mg/kg/day, through drinking water) for 21 days significantly ameliorated chronic corticosterone-induced decreases in TrkB protein levels in frontal cortex and hippocampus. Furthermore, cysteamine treatment reversed the anxiety and depression like behavioral abnormalities induced by chronic corticosterone treatment. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in behavioral tests, suggesting that TrkB signaling plays an important role in the antidepressant effects of cysteamine. CONCLUSIONS: The animal studies described here highlight the potential use of cysteamine as a novel therapeutic strategy for glucocorticoid-related symptoms of psychiatric disorders

Inter-annual variations of selected oceanographic parameters and its relation to fishery of small pelagics off Kochi, southwest coast of India

The availability as well as abundance of selected small pelagics along Kerala coast (south west coast of India) was highly variable during the past three decades. During the period 1980-2012 there have been several periods of abundance as well as population crashes in the oil sardine fishery. The present study revealed that the occurrence of low sea level during the month of May implies either early wind driven upwelling or early intensification of equator-ward coastal current and consequent upsloping of isopycnals. The occurrence of low sea level (6857) as early as in May and upwelled water in August with low dissolved oxygen (0.68 ml l-1) with low sea water temperature (24˚C) at the bottom at 10 m depth, off Kochi was found to affect the sardine fishery in the year 1994, when the landing at Kochi was only 15 t. Mean sea level was found to be a sign of upwelling and the real time observations of dissolved oxygen indicated wide variations during the upwelling period