A study of acute respiratory disease in families exposed to different levels of Air pollution in the Great Salt Lake basin, Utah, 1971-1972 and 1972-1973.

The reported incidence of acute respiratory illness in families exposed to different concentrations of air pollution was studied during two consecutive school years. The purpose of the study was to determine the effect of increased exposure to sulfur dioxide and suspended particulate matter. In each of four study communities, the mothers of approximately 250 white families were contacted biweekly to obtain information regarding the occurrence of respiratory symptoms in each family member. Annual mean ambient sulfur dioxide concentrations in one community for the three years included in the study (1971-1973) were well above the current air quality standard of 80 micrograms/m3, while in the other three communities the annual sulfur dioxide concentrations were much lower (usually less than 40 micrograms/m3). Suspended particulate matter concentrations in high sulfur dioxide community were close to the limit designated by the annual standard (75 micrograms/m3) but actual exposures in the four communities probably were not excessive. Regression analyses of the data collected showed inconsistent associations between illness rates and educational attainment of the head of household, crowding in the home, bronchitis in parents or smoking of parents. However, once the effects of these factors were removed the adjusted rates showed little association with community of residence. It was concluded that the higher concentrations of sulfur dioxide in the Utah atmosphere could not be the cause of increases in acute respiratory illness in the exposed populations

Two novel missense mutations in the myelin protein zero gene causes Charcot-Marie-Tooth type 2 and Déjérine-Sottas syndrome

<p>Abstract</p> <p>Background</p> <p>The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the <it>myelin protein zero (MPZ) </it>gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P₀) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P₀ex) is known, while the transmembrane and intracellular structure is unknown.</p> <p>Findings</p> <p>One novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome.</p> <p>Conclusions</p> <p>The phenotypic variation caused by different missense mutations in the <it>MPZ </it>gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.</p

Non-surgical spinal decompression therapy: does the scientific literature support efficacy claims made in the advertising media?

<p>Abstract</p> <p>Background</p> <p>Traction therapy has been utilized in the treatment of low back pain for decades. The most recent incarnation of traction therapy is non-surgical spinal decompression therapy which can cost over $100,000. This form of therapy has been heavily marketed to manual therapy professions and subsequently to the consumer. The purpose of this paper is to initiate a debate pertaining to the relationship between marketing claims and the scientific literature on non-surgical spinal decompression.</p> <p>Discussion</p> <p>Only one small randomized controlled trial and several lower level efficacy studies have been performed on spinal decompression therapy. In general the quality of these studies is questionable. Many of the studies were performed using the VAX-D^®unit which places the patient in a prone position. Often companies utilize this research for their marketing although their units place the patient in the supine position.</p> <p>Summary</p> <p>Only limited evidence is available to warrant the routine use of non-surgical spinal decompression, particularly when many other well investigated, less expensive alternatives are available.</p

The Diversity and Variability of Star Formation Histories in Models of Galaxy Evolution

Understanding the variability of galaxy star formation histories (SFHs) across a range of timescales provides insight into the underlying physical processes that regulate star formation within galaxies. We compile the SFHs of galaxies at $z=0$ from an extensive set of models, ranging from cosmological hydrodynamical simulations (Illustris, IllustrisTNG, Mufasa, Simba, EAGLE), zoom simulations (FIRE-2, g14, and Marvel/Justice League), semi-analytic models (Santa Cruz SAM) and empirical models (UniverseMachine), and quantify the variability of these SFHs on different timescales using the power spectral density (PSD) formalism. We find that the PSDs are well described by broken power-laws, and variability on long timescales ($\gtrsim1$ Gyr) accounts for most of the power in galaxy SFHs. Most hydrodynamical models show increased variability on shorter timescales ($\lesssim300$ Myr) with decreasing stellar mass. Quenching can induce $\sim0.4-1$ dex of additional power on timescales $>1$ Gyr. The dark matter accretion histories of galaxies have remarkably self-similar PSDs and are coherent with the in-situ star formation on timescales $>3$ Gyr. There is considerable diversity among the different models in their (i) power due to SFR variability at a given timescale, (ii) amount of correlation with adjacent timescales (PSD slope), (iii) evolution of median PSDs with stellar mass, and (iv) presence and locations of breaks in the PSDs. The PSD framework is a useful space to study the SFHs of galaxies since model predictions vary widely. Observational constraints in this space will help constrain the relative strengths of the physical processes responsible for this variability.Comment: 31 pages, 17 figures (+ appendix). Resubmitted to MNRAS after responding to referee's comments. Comments are welcome

Liberalization of Opening Hours With Free Entry

This paper studies competition in prices and opening hours in a model with free entry. It is shown that under free competition a market failure arises: Entry is excessive and opening hours are under-provided. Restrictions on opening hours aggravate this failure. I analyze the impact of a liberalization of opening hours. The model predicts that in the short run prices will remain constant, but increase in the long run. Concentration in the retail sector will rise and opening hours will increase in two steps, immediately after deregulation and further over time. Finally, employment in the retail sector increases

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

BACKGROUND: The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. METHODS: We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). RESULTS: 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. CONCLUSIONS: Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT0119307

Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

OBJECTIVE—Abnormal small nerve fiber function may be an early feature of diabetic neuropathy and may also underlie painful symptoms. Methods for assessing small-fiber damage include quantitative sensory testing (QST) and determining intraepidermal nerve fiber density. We recently described a reproducible physiological technique, the LDIflare, which assesses small-fiber function and thus may reflect early dysfunction before structural damage. The value of this technique in painful neuropathy was assessed by comparing it with QST and dermal nerve fiber density (NFD)

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores

Objective: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Methods: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. Results: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4–87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99–1.97, p < 0.0001, for baseline CMTES-R score 0–9). Conclusion: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. ClinicalTrials.gov identifier NCT01193075

A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement

The CADM family of proteins consists of four neuronal specific adhesion molecules (CADM1, CADM2, CADM3 and CADM4) that mediate the direct contact and interaction between axons and glia. In the peripheral nerve, axon-Schwann cell interaction is essential for the structural organization of myelinated fibres and is primarily mediated by the binding of CADM3, expressed in axons, to CADM4, expressed by myelinating Schwann cells. We have identified—by whole exome sequencing—three unrelated families, including one de novo patient, with axonal Charcot-Marie-Tooth disease (CMT2) sharing the same private variant in CADM3, Tyr172Cys. This variant is absent in 230 000 control chromosomes from gnomAD and predicted to be pathogenic. Most CADM3 patients share a similar phenotype consisting of autosomal dominant CMT2 with marked upper limb involvement. High resolution mass spectrometry analysis detected a newly created disulphide bond in the mutant CADM3 potentially modifying the native protein conformation. Our data support a retention of the mutant protein in the endoplasmic reticulum and reduced cell surface expression in vitro. Stochastic optical reconstruction microscopy imaging revealed decreased co-localization of the mutant with CADM4 at intercellular contact sites. Mice carrying the corresponding human mutation (Cadm3Y170C) showed reduced expression of the mutant protein in axons. Cadm3Y170C mice showed normal nerve conduction and myelin morphology, but exhibited abnormal axonal organization, including abnormal distribution of Kv1.2 channels and Caspr along myelinated axons. Our findings indicate the involvement of abnormal axon-glia interaction as a disease-causing mechanism in CMT patients with CADM3 mutations. A correction has been published: Brain, Volume 144, Issue 7, July 2021, Page e64, https://doi.org/10.1093/brain/awab18