Carrier detection in Duchenne muscular dystrophy

The identification of apparently healthy carriers of the lethal, X- linked gene for Duchenne muscular dystrophy (DMD) is of importance for genetic counselling purposes. At present the accepted most reliable test for determining DMD carrier status is the estimation of serum creatine kinase activity. However, approximately one third of genetic carriers remain undetected by this method. This study was designed to evaluate other possible methods of DMD heterozygote recognition with a view to improving the carrier detection rate.There is considerable evidence to suggest a generalised membrane defect is responsible for the degenerative muscle fibre alterations which occur in DMD. Increased intracellular calcium has been implicated as an early biochemical change which would account for many of the membrane abnormalities reported. Several changes exhibited by DMD erythrocytes could be attributed to an increased intraerythrocytic calcium content. If this increased calcium level is related to the primary defect then, according to the Lyon hypothesis, a proportion of erythrocytes from a genetic carrier of DMD should manifest this abnormality. The relative intraerythrocytic calcium content of individual erythrocytes within DMD patient, DMD carrier and control erythrocyte populations were examined. Quantitative measurement of the elemental content of single erythrocytes was carried out using electron probe X -ray microanalysis (EPXMA). However the extremely low level of intraerythrocytic calcium and the wide variation in relative calcium concentrations of each erythrocyte population render EPXMA insufficiently sensitive to be capable of distinguishing two erythrocyte populations within a DMD carrier.An alternate approach to the demonstration of cellular mosaicism is the additional measurement of secondary biochemical parameters which, if non -correlated, could improve the carrier detection rate over that obtained using serum creatine kinase estimation alone. Serum levels of haemopexin and myoglobin were found to be raised significantly in a series of 10 DMD patients compared to 10 age and sex matched, normal, healthy controls. Measurements of serum pyruvate kinase, haemopexin and myoglobin levels were then carried out in a series of 15 DF'T carriers and 15 age matched, normal, healthy women, in conjunction with serum creatine kinase estimation. The mean serum pyruvate kinase activity of the DMD carrier group was significantly higher than that of the control group but this test selected only 4/14 (28.5%) carriers and failed to identify 3 carriers whose serum creatine kinase levels were within normal limits. The mean serum haemopexin level of the carrier group was not significantly different from that of the control group. The mean serum myoglobin level of the carrier group was significantly higher than that of the control group. Nine of 15 (60%) carriers had myoglobin levels outside the 95% confidence limits. However serum myoglobin was within normal limits in all 3 carriers with normal serum creatine kinase levels. Discriminant analysis suggested that combining serum myoglobin and creatine kinase measurements might improve the detection rate. Serum levels of myoglobin and creatine kinase were measured in a series of 20 DMD carriers (all with serum creatine kinase activities within normal limits) and 20 age matched, normal, healthy women. Three of 20 (15 %) carriers had myoglobin levels outside the calculated 95% confidence limits but all 3 had serum creatine kinase activities close to the 95th percentile of the control series. The positive correlation between serum myoglobin and creatine kinase levels implies the combined use of these tests may be of value only in cases where the subjects' creatine kinase level is borderline normal. Otherwise the results of this study suggest the additional measurement of either serum pyruvate kinase of haemopexin in combination with serum creatine kinase estimation will have little value in DMD carrier detection

The Sewing Ladies Meet

Title onlyhttps://scholarsjunction.msstate.edu/cht-sheet-music/1628/thumbnail.jp

Process improvement and analytics of commercial material substantiation

Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Engineering Systems Division; in conjunction with the Leaders for Global Operations Program at MIT, 2013.Cataloged from PDF version of thesis.Includes bibliographical references (p. 55-56).Sikorsky is currently negotiating the SDTA proposal for the CH-53K helicopter. Due to the Truth In Negotiations Act (TINA), when submitting a proposal to the government all suppliers with a total award greater than $700,000 need to have supporting documentation (material substantiation) showing that pricing is fair and reasonable. This can be accomplished through competition, a cost-price analysis (CPA), or commerciality. Each entity involved in the proposal prefers a different substantiation method: the government prefers CPA or competition, the suppliers prefer commerciality, and Sikorsky prefers competition. Because the government and suppliers have opposing views on commerciality, the government has increased the oversight and complexity of the commercial process. Previously, a proposal's commerciality claims required only a commerciality claim form and an invoice showing that the part had been sold to a commercial entity, but did not require the supplier to provide the commercial invoice price. For the SDTA proposal, an approved commerciality claim required a commerciality form, non-redacted invoices showing pricing information and the customer to which the part was sold, an escalated price analysis to support price reasonableness, a detailed list of modifications to the commercial part, an estimated cost of the modifications, and final commercial end user information. The commercial process involved roughly 90 Sikorsky employees and required roughly 11 months to fulfill all of the government's SDTA commercial requirements. As a comparison, CPA substantiation was completed 4 months prior to commerciality. Reasons for the long cycle time include labor time, a lengthy paper internal approval process including process downtime, lost or misprocessed documents, and insufficient employee training. To combat these inefficiencies, a formalized commercial substantiation process that uses an electronic workspace to provide process control is proposed in this thesis. The formalized commercial substantiation process decreases the required labor hours by an estimated 43%, decreases the internal approval cycle time by 74%, and provides secure document management. These improvements not only benefit the company internally, but also provide external benefits like an increase in government satisfaction which will help Sikorsky attain additional government contracts.by Carolyn Marie Freeman.S.M.M.B.A

Institutional experience with a rotational total skin electron irradiation (RTSEI) technique—A three decade review (1981–2012)

AbstractTotal skin electron irradiation (TSEI) for patients with cutaneous lymphomas is technically challenging, and numerous approaches have been developed to overcome the many field matching problems associated with such a large and complex treatment volume. Since 1981 we have delivered TSEI using a rotational total skin electron irradiation (RTSEI) technique in conjunction with patch, treat and boost fields in order to provide complete skin and dose coverage. Initially we used a 6MeV electron beam at an extended source-skin distance (SSD) on a modified linear accelerator. More recently we began using a high dose rate electron mode on a commercially available linear accelerator. The RTSEI technique allows the delivery of a seamless surface dose to the majority of the patient's skin surface in a single treatment. In this review paper we present our three-decade experience with the technical development, dosimetry, treatment delivery and clinical outcomes of our RTSEI technique

Incidence and Severity of Lymphoedema following Limb Salvage of Extremity Soft Tissue Sarcoma

Background and Purpose. Lymphoedema is a serious complication following limb salvage for extremity soft tissue sarcomas (STSs) for which little is known. We aimed to evaluate its incidence, its, severity and its associated risk factors. Material and Method. Patient and tumor characteristics, treatment modalities and complications and functional outcomes (MSTS 1987, TESS), and lymphoedema severity (Stern) were all collected from prospective databases. Charts were retrospectively abstracted for BMI and comorbidities. Results. There were 289 patients (158 males). Mean age was 53 (16–88). Followup ranged between 12 and 60 months with an average of 35 and a median of 36 months. Mean BMI was 27.4 (15.8–52.1). 72% had lower extremity tumors and 38% upper extremity. Mean tumor size was 8.1 cm (1.0–35.6 cm). 27% had no adjuvant radiation, 62% had 50 Gy, and 11% received 66 Gy. The incidence of lymphoedema was 28.8% (206 none, 58 mild, 22 moderate, 3 severe, and 0 very severe). Mean MSTS score was 32 (11–35) and TESS was 89.4 (32.4–100). Radiation dose was significantly correlated with tumor size > 5 cm (P = 0.0001) and TESS score (P = 0.001), but not MSTS score (P = 0.090). Only tumor size > 5 cm and depth were found to be independent predictors of significant lymphoedema. Conclusion. Nine percent of STS patients in our cohort developed significant (grade ≥ 2) lymphoedema. Tumor size > 5 cm and deep tumors were associated with an increased occurrence of lymphoedema but not radiation dosage

Institutional experience with a rotational total skin electron irradiation (RTSEI) technique—A three decade review (1981–2012)

Total skin electron irradiation (TSEI) for patients with cutaneous lymphomas is technically challenging, and numerous approaches have been developed to overcome the many field matching problems associated with such a large and complex treatment volume. Since 1981 we have delivered TSEI using a rotational total skin electron irradiation (RTSEI) technique in conjunction with patch, treat and boost fields in order to provide complete skin and dose coverage. Initially we used a 6[[ce:hsp sp="0.25"/]]MeV electron beam at an extended source-skin distance (SSD) on a modified linear accelerator. More recently we began using a high dose rate electron mode on a commercially available linear accelerator. The RTSEI technique allows the delivery of a seamless surface dose to the majority of the patient's skin surface in a single treatment. In this review paper we present our three-decade experience with the technical development, dosimetry, treatment delivery and clinical outcomes of our RTSEI technique

Ascaris lumbricoides Infection Following School-Based Deworming in Western Kenya: Assessing the Role of Pupils' School and Home Water, Sanitation, and Hygiene Exposures.

Water, sanitation, and hygiene (WaSH) technologies and behaviors can prevent infection by soil-transmitted helminth species independently, but may also interact in complex ways. However, these interactions are poorly understood. The purpose of this study was to characterize how school and home WaSH exposures were associated with Ascaris lumbricoides infection and to identify relevant interactions between separate WaSH technologies and behaviors. A study was conducted among 4,404 children attending 51 primary schools in western Kenya. We used multivariable mixed effects logistic regression to characterize how various WaSH exposures were associated with A. lumbricoides infection after annual school-based deworming. Few WaSH behaviors and technologies were independently associated with A. lumbricoides infection. However, by considering relevant interdependencies between variables, important associations were elucidated. The association between handwashing and A. lumbricoides depended largely upon the pupils' access to an improved water source. Among pupils who had access to improved water sources, A. lumbricoides prevalence was lower for those who handwashed both at school and home compared with neither place (odds ratio: 0.38, 95% confidence interval: 0.18-0.83; P = 0.01). This study contributes to a further understanding of the impact of WaSH on A. lumbricoides infection and shows the importance of accounting for interactions between WaSH technologies and behaviors

Integrins Form an Expanding Diffusional Barrier that Coordinates Phagocytosis

Phagocytosis is initiated by lateral clustering of receptors, which in turn activates Src-family kinases (SFKs). Activation of SFKs requires depletion of tyrosine phosphatases from the area of particle engagement. We investigated how the major phosphatase CD45 is excluded from contact sites, using single-molecule tracking. The mobility of CD45 increased markedly upon engagement of Fcγ receptors. While individual CD45 molecules moved randomly, they were displaced from the advancing phagocytic cup by an expanding diffusional barrier. By micropatterning IgG, the ligand of Fcγ receptors, we found that the barrier extended well beyond the perimeter of the receptor-ligand engagement zone. Second messengers generated by Fcγ receptors activated integrins, which formed an actin-tethered diffusion barrier that excluded CD45. The expanding integrin wave facilitates the “zippering” of Fcγ receptors onto the target and integrates the information from sparse receptor-ligand complexes, coordinating the progression and ultimate closure of the phagocytic cup

Revisiting Neurofibromatosis type 2 diagnostic criteria to exclude LZTR1 related schwannomatosis

OBJECTIVE: To determine the specificity of the current clinical diagnostic criteria for neurofibromatosis type 2 (NF2) relative to the requirement for unilateral vestibular schwannoma (VS) and at least 2 other NF2-related tumors. METHODS: We interrogated our Manchester NF2 database, which contained 205 individuals meeting NF2 criteria who initially presented with a unilateral VS. Of these, 83 (40.7%) went on to develop a contralateral VS. We concentrated our genetic analysis on a group of 70 who initially fulfilled NF2 criteria with a unilateral vestibular schwannoma and at least 2 additional nonintradermal schwannomas. RESULTS: Overall, 5/70 (7%) individuals with unilateral VS and at least 2 other schwannomas had a pathogenic or likely pathogenic LZTR1 mutation. Twenty of the 70 subsequently developed bilateral disease. Of the remaining 50, 5 (10%) had a germline LZTR1 mutation, equivalent to the number (n = 5) with a germline NF2 mutation. CONCLUSIONS: The most common etiology for unilateral VS and 2 additional NF2-associated tumors in this cohort was mosaic NF2. Germline LZTR1 and germline NF2 mutations were equally common in our cohort. This indicates that LZTR1 must be considered when making a diagnosis of NF2 in the presence of unilateral VS in individuals without a germline NF2 mutation