The use of neuralgia medications to treat sensory neuropathic cough: our experience in a retrospective cohort of thirty-two patients

Objective. This study sought to: (1) quantify response rate and efficacy of amitriptyline, desipramine, and gabapentin in treating sensory neuropathic cough; and (2) describe an efficient treatment protocol.Study Design. This study is a retrospective case series.Methods. Persons diagnosed with sensory neuropathic cough during a one-year period were potential study candidates. To bolster the diagnosis credibility, only persons who had been treated elsewhere for gastroesophageal reflux disease, asthma, and allergy with no reduction of cough were included. Upon diagnosis of sensory neuropathic cough, each person was treated with either amitriptyline, desipramine, or gabapentin, titrating the dose upward to desired benefit or the dose limit. If the benefit was insufficient, another of the medications was used next, using a similar dose escalation strategy. Data points included patient demographics, initial and final medication, final dose, and degree of improvement.Results. 32 patients met the diagnostic and inclusion criteria and had a complete data set. 94% (30 of 32) of the patients responded to at least one of the medications. The 32 patients undertook a total of 45 single-medication trials. Patients reported symptom relief during 78% (14 of 18) of amitriptyline trials, 73% (11 of 15) of desipramine trials, and 83% (10 of 12) of gabapentin trials. At final dosage, symptom reduction averaged 77% on amitriptyline, 73% on desipramine, and 69% on gabapentin.Conclusion. Amitriptyline, desipramine, and gabapentin appear to vary in their effectiveness for individual cases of sensory neuropathic cough; across a whole cohort, symptom relief was similar in frequency and degree on any of the three medications. More evidence is needed to demonstrate more convincingly the effectiveness of these medications, but this data set suggests that each of these three medications deserves consideration in the codified treatment protocol presented here

Extending the linear-noise approximation to biochemical systems influenced by intrinsic noise and slow lognormally distributed extrinsic noise

It is well known that the kinetics of an intracellular biochemical network is stochastic. This is due to intrinsic noise arising from the random timing of biochemical reactions in the network as well as due to extrinsic noise stemming from the interaction of unknown molecular components with the network and from the cell's changing environment. While there are many methods to study the effect of intrinsic noise on the system dynamics, few exist to study the influence of both types of noise. Here we show how one can extend the conventional linear-noise approximation to allow for the rapid evaluation of the molecule numbers statistics of a biochemical network influenced by intrinsic noise and by slow lognormally distributed extrinsic noise. The theory is applied to simple models of gene regulatory networks and its validity confirmed by comparison with exact stochastic simulations. In particular we show how extrinsic noise modifies the dependence of the variance of the molecule number fluctuations on the rate constants, the mutual information between input and output signalling molecules and the robustness of feed-forward loop motifs.Comment: 43 pages, 4 figure

Shortfalls and Solutions for Meeting National and Global Conservation Area Targets

Governments have committed to conserving greater than or equal to 17% of terrestrial and greater than or equal to 10% of marine environments globally, especially areas of particular importance for biodiversity through ecologically representative Protected Area (PA) systems or other area-based conservation measures , while individual countries have committed to conserve 3-50% of their land area. We estimate that PAs currently cover 14.6% of terrestrial and 2.8% of marine extent, but 59-68% of ecoregions, 77-78% of important sites for biodiversity, and 57% of 25,380 species have inadequate coverage. The existing 19.7 million km super(2) terrestrial PA network needs only 3.3 million km super(2) to be added to achieve 17% terrestrial coverage. However, it would require nearly doubling to achieve, cost-efficiently, coverage targets for all countries, ecoregions, important sites, and species. Poorer countries have the largest relative shortfalls. Such extensive and rapid expansion of formal PAs is unlikely to be achievable. Greater focus is therefore needed on alternative approaches, including community- and privately managed sites and other effective area-based conservation measures

FISH as an effective diagnostic tool for the management of challenging melanocytic lesions

<p>Abstract</p> <p>Background</p> <p>The accuracy of melanoma diagnosis continues to challenge the pathology community, even today with sophisticated histopathologic techniques. Melanocytic lesions exhibit significant morphological heterogeneity. While the majority of biopsies can be classified as benign (nevus) or malignant (melanoma) using well-established histopathologic criteria, there exists a cohort for which the prediction of clinical behaviour and invasive or metastatic potential is difficult if not impossible to ascertain on the basis of morphological features alone. Multiple studies have shown that there is significant disagreement between pathologists and even expert dermatopathologists in the diagnosis of this subgroup of difficult melanocytic lesions.</p> <p>Methods</p> <p>A four probe FISH assay was utilized to analyse a cohort of 500 samples including 157 nevus, 176 dysplastic nevus and 167 melanoma specimens.</p> <p>Results</p> <p>Review of the lesions determined the assay identified genetic abnormalities in a total of 83.8% of melanomas, and 1.9% of nevus without atypia, while genetic abnormalities were identified in 6.3%, 6.7%, and 10.3% of nevus identified with mild, moderate and severe atypia, respectively.</p> <p>Conclusions</p> <p>Based on this study, inheritable genetic damage/instability identified by FISH testing is a hallmark of a progressive malignant process, and a valuable diagnostic tool for the identification of high risk lesions.</p

A rare sequence variant in intron 1 of THAP1 is associated with primary dystonia

Although coding variants in THAP1 have been causally associated with primary dystonia, the contribution of noncoding variants remains uncertain. Herein, we examine a previously identified Intron 1 variant (c.71+9C>A, rs200209986). Among 1672 subjects with mainly adult-onset primary dystonia, 12 harbored the variant in contrast to 1/1574 controls (P < 0.01). Dystonia classification included cervical dystonia (N = 3), laryngeal dystonia (adductor subtype, N = 3), jaw-opening oromandibular dystonia (N = 1), blepharospasm (N = 2), and unclassified (N = 3). Age of dystonia onset ranged from 25 to 69 years (mean = 54 years). In comparison to controls with no identified THAP1 sequence variants, the c.71+9C>A variant was associated with an elevated ratio of Isoform 1 (NM_018105) to Isoform 2 (NM_199003) in leukocytes. In silico and minigene analyses indicated that c.71+9C>A alters THAP1 splicing. Lymphoblastoid cells harboring the c.71+9C>A variant showed extensive apoptosis with relatively fewer cells in the G2 phase of the cell cycle. Differentially expressed genes from lymphoblastoid cells revealed that the c.71+9C>A variant exerts effects on DNA synthesis, cell growth and proliferation, cell survival, and cytotoxicity. In aggregate, these data indicate that THAP1 c.71+9C>A is a risk factor for adult-onset primary dystonia

Intermixing-Driven Surface and Bulk Ferromagnetism in the Quantum Anomalous Hall Candidate MnBi6Te10

The recent realizations of the quantum anomalous Hall effect (QAHE) in MnBi2Te4 and MnBi4Te7 benchmark the (MnBi2Te4)(Bi2Te3)n family as a promising hotbed for further QAHE improvements. The family owes its potential to its ferromagnetically (FM) ordered MnBi2Te4 septuple layers (SLs). However, the QAHE realization is complicated in MnBi2Te4 and MnBi4Te7 due to the substantial antiferromagnetic (AFM) coupling between the SLs. An FM state, advantageous for the QAHE, can be stabilized by interlacing the SLs with an increasing number n of Bi2Te3 quintuple layers (QLs). However, the mechanisms driving the FM state and the number of necessary QLs are not understood, and the surface magnetism remains obscure. Here, robust FM properties in MnBi6Te10 (n = 2) with Tc ≈ 12 K are demonstrated and their origin is established in the Mn/Bi intermixing phenomenon by a combined experimental and theoretical study. The measurements reveal a magnetically intact surface with a large magnetic moment, and with FM properties similar to the bulk. This investigation thus consolidates the MnBi6Te10 system as perspective for the QAHE at elevated temperatures

Native diversity buffers against severity of non-native tree invasions

Determining the drivers of non-native plant invasions is critical for managing native ecosystems and limiting the spread of invasive species. Tree invasions in particular have been relatively overlooked, even though they have the potential to transform ecosystems and economies. Here, leveraging global tree databases, we explore how the phylogenetic and functional diversity of native tree communities, human pressure and the environment influence the establishment of non-native tree species and the subsequent invasion severity. We find that anthropogenic factors are key to predicting whether a location is invaded, but that invasion severity is underpinned by native diversity, with higher diversity predicting lower invasion severity. Temperature and precipitation emerge as strong predictors of invasion strategy, with non-native species invading successfully when they are similar to the native community in cold or dry extremes. Yet, despite the influence of these ecological forces in determining invasion strategy, we find evidence that these patterns can be obscured by human activity, with lower ecological signal in areas with higher proximity to shipping ports. Our global perspective of non-native tree invasion highlights that human drivers influence non-native tree presence, and that native phylogenetic and functional diversity have a critical role in the establishment and spread of subsequent invasions

Recurrence in oral and pharyngeal cancer is associated with quantitative MGMT promoter methylation

<p>Abstract</p> <p>Background</p> <p>Biomarkers that predict clinical response, tumor recurrence or patient survival are severely lacking for most cancers, particularly for oral and pharyngeal cancer. This study examines whether gene-promoter methylation of tumor DNA correlates with survival and recurrence rates in a population of patients with oral or pharyngeal cancer.</p> <p>Methods</p> <p>The promoter methylation status of the DNA repair gene <it>MGMT </it>and the tumor suppressor genes <it>CDKN2A and RASSF1 </it>were evaluated by methylation-specific PCR in 88 primary oral and pharyngeal tumors and correlated with survival and tumor recurrence. Quantitative <it>MGMT </it>methylation was also assessed.</p> <p>Results</p> <p>29.6% of the tumors presented with <it>MGMT </it>methylation, 11.5% with <it>CDKN2A </it>methylation and 12.1% with <it>RASSF1 </it>methylation. <it>MGMT </it>promoter methylation was significantly associated with poorer overall and disease-free survival. No differences in methylation status of <it>MGMT </it>and <it>RASSF1 </it>with HPV infection, smoking or drinking habits were observed. A significant inverse trend with the amount of <it>MGMT </it>methylation and overall and disease-free survival was observed (p_trend= 0.002 and 0.001 respectively).</p> <p>Conclusion</p> <p>These results implicate <it>MGMT </it>promoter methylation as a possible biomarker for oral and pharyngeal cancer prognosis. The critical role of MGMT in DNA repair suggests that defective DNA repair may be correlative in the observed association between <it>MGMT </it>promoter methylation and tumor recurrence. Follow-up studies should include further quantitative MSP-PCR measurement, global methylation profiling and detailed analysis of downstream DNA repair genes regulated by promoter methylation.</p

High-throughput mutational analysis of TOR1A in primary dystonia

<p>Abstract</p> <p>Background</p> <p>Although the c.904_906delGAG mutation in Exon 5 of <it>TOR1A </it>typically manifests as early-onset generalized dystonia, DYT1 dystonia is genetically and clinically heterogeneous. Recently, another Exon 5 mutation (c.863G>A) has been associated with early-onset generalized dystonia and some ΔGAG mutation carriers present with late-onset focal dystonia. The aim of this study was to identify <it>TOR1A </it>Exon 5 mutations in a large cohort of subjects with mainly non-generalized primary dystonia.</p> <p>Methods</p> <p>High resolution melting (HRM) was used to examine the entire <it>TOR1A </it>Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known ΔGAG DYT1 dystonia and 88 subjects with ΔGAG-negative dystonia.</p> <p>Results</p> <p>HRM of <it>TOR1A </it>Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the <it>TOR1A </it>ΔGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic ΔGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia.</p> <p>Conclusion</p> <p>First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in <it>TOR1A </it>are rarely associated with non-generalized primary dystonia.</p