Dystrophic Epidermolysis Bullosa: Secondary Disease Mechanisms and Disease Modifiers

The phenotypic presentation of monogenetic diseases is determined not only by the nature of the causative mutations but also is influenced by manifold cellular, microenvironmental, and external factors. Here, heritable extracellular matrix diseases, including dystrophic epidermolysis bullosa (DEB), are no exceptions. Dystrophic epidermolysis bullosa is caused by mutations in the COL7A1 gene encoding collagen VII. Deficiency of collagen VII leads to skin and mucosal fragility, which progresses from skin blistering to severe fibrosis and cancer. Clinical and pre-clinical studies suggest that targeting of secondary disease mechanisms or employment of natural disease modifiers can alleviate DEB severity and progression. However, since many of these mechanisms are needed for tissue homeostasis, informed, selective targeting is essential for safe and efficacious treatment. Here, we discuss a selection of key disease modifiers and modifying processes active in DEB, summarize the still scattered knowledge of them, and reflect on ways forward toward their utilization for symptom-relief or enhancement of curative therapies.

Treatment Options in Congenital Disorders of Glycosylation

Despite advances in the identification and diagnosis of congenital disorders of glycosylation (CDG), treatment options remain limited and are often constrained to symptomatic management of disease manifestations. However, recent years have seen significant advances in treatment and novel therapies aimed both at the causative defect and secondary disease manifestations have been transferred from bench to bedside. In this review, we aim to give a detailed overview of the available therapies and rising concepts to treat these ultra-rare diseases.

Incidence of community-acquired pneumonia in HIV-infected people, depending on the level of immunodeficiency and viral load

The aim of the study was to study the timing and frequency of community — acquired pneumonia in HIV-infected people, depending on the level of immunodeficiency and viral load.Materials and methods. Based on the materials of the Perm regional center for the fight and prevention of AIDS and infectious diseases, medical documentation was studied for 396 patients with HIV-associated pneumonia who died in 2014–2018 the frequency of community-acquired pneumonia (EAP) was estimated depending on the level of immunodeficiency and viral load.Results and discussion. It turned out that in most cases, EAP in relation to HIV infection is a secondary disease. The average duration of EAP after HIV infection was 4,6±3,7 years. With increasing immunodeficiency and viral load, the incidence of VP increases. Most often, VP is registered with CD4+ lymphocytes less than 200 cells/μl and viral load of 10 000–100 000 copies/ml.

A significant relationship between personality traits and adhesive capsulitis

SUMMARY OBJECTIVE We investigated the associations between adhesive capsulitis (AC) and a specific psychological profile. METHODS We assessed 72 patients with phase-II AC. In our study, 36 patients were affected by primary disease and 36 by secondary disease. The inclusion criteria were as follows: unilateral AC and pain in the shoulder for at least two months. The exclusion criteria were: psychiatric and neurological manifestations with a previous diagnosis and inability to comprehend the instruments. Outcomes were determined at 52 weeks. Shoulder pain severity was assessed with the Visual Analog Scale. We also measured the range of motion with a universal goniometer and the strength with the Medical Research Council. We assessed the personality traits of our patients with the Cloninger’s Temperament and Character Inventory and the Multidimensional Perfectionism Scale. RESULTS Patients with primary AC needed more time to improve the symptomatology compared to the group with the secondary disease (p<0.01). Patients with primary AC complained of severe and lasting pain more frequently than patients with the secondary disease (p< 0.01). In patients with primary disease, the prevalence of perfectionism, low levels of novelty seeking, and high levels of harm avoidance were 88.2 and 86.2%, and 80.4, respectively, and below 20 percent in patients with secondary AC disease. CONCLUSION We found a significant correlation between primary AC and particular personality traits, indicating an interaction between psychological and somatic factors.

Analisis kerusakan daun dan buah kelapa akibat serangan belalang Sexava

<p><em>Sexava</em>, the long-horned grasshopper, is an important pest of the coconut palm that destroys leaves and fruits. Study on analysis of damage to leaves and fruits of coconut palms due to being attacked by <em>Sexava</em> was aimed to determine the mechanism of the damage. Visual in situ observations were carried out in Salibabu Island, Talaud Islands Regency, North Sulawesi Province, while histological and chemical analyses of attacked young fruits and observation of symptoms of the secondary disease were carried out in the laboratory. The results showed that the process of damage to coconut-palm leaves and fruits due to bitten by the <em>Sexava</em> occurs mechanically. Phytotoxic symptoms due to bites of the long-horned grasshopper and symptoms of the secondary disease were not observed. Fruit tissue with a thickness of several millimeters appears to dry out and die while the tissue near the wound appears normal. Reduced sugar levels, cellulose, and lignin, between healthy fruit tissues (1.22%, 2.72%, 5.66%) and those attacked (1.22%, 2.85%, 4.84%) were relatively the same. The attacked young-fruits will fall out while attacked fruits on bunches more than 3 months old still keep to grow and develop until ripe.</p>

Primary Laryngeal Tuberculosis Masquerading Laryngeal Malignancy

Nowadays, tuberculosis (TB) infection shows re-emergence again in many other part of the world due to HIV/AIDS- related disease, low socioeconomic as well as insurgence of multidrug resistance tuberculosis. TB is a disease which is primarily affects a lung. However it also can affect other organs as a secondary disease in a body via hematogenous or lymphatic spread. As in ENT field, TB also can manifest as a solely ear, nose or throat (ENT) diseasea such as in primary laryngeal tuberculosis (TB). In the past, laryngeal TB typically presented as a secondary disease with ulcerated laryngeal lesions in advanced pulmonary tuberculosis patient. In our case, we report a case of primary laryngeal tuberculosis masquerading as laryngeal malignancy in adult patient without pulmonary tuberculosis. In conclusion, in a patient who presented with various laryngeal symptoms, physician should be aware of the reemergence of laryngeal tuberculosis and the various manisfestation of the disease. Bangladesh J Otorhinolaryngol; April 2016; 22(1): 53-57

Outcomes in Relapsed/Refractory Patients with FLT3-ITD Mutated AML Are Poor When Treated with Non-Targeted Therapy with a Potential Role for Stem Cell Transplantation: Results from the NCRI AML Trials

Introduction: Patients with Acute Myeloid Leukaemia (AML) who harbour a FLT3-ITD mutation have a worse prognosis characterised by increased early relapse. Outcomes following relapse in such patients are typically poor, not only because of earlier relapse, but also because of worse performance post-relapse than those who have the same remission duration but are FLT3-ITD WT. In a single centre retrospective study among relapsed patients, Ravandi et al [1] found a remission rate of 24% and median survival of only 13 weeks. There are therefore twin challenges in this population: first to reduce the early relapse rate, and also to develop more effective treatments post relapse. In the recent QUANTUM-R trial [2] for patients with relapsed or refractory disease, single agent quizartinib (AC220) was found to significantly improve median survival from 20.4 weeks to 27 weeks when compared to "doctor's choice" treatment (low-dose ara-C, MEC or FLAG-Ida). There is however, no directly comparable data for the population in the QUANTUM-R trial. To contextualise these results, especially given the potentially different outcomes by control treatment, we looked at outcomes in the UK NCRI AML15,16,17 trials in patients satisfying the eligibility criteria of QUANTUM-R. Methods: Patients aged 18+ in the UK NCRI AML15,16,17 trials were identified who harboured a FLT3 ITD mutation, were treated with intensive chemotherapy, and were either refractory to two courses of induction therapy, or relapsed within six months of transplant, or did not receive a prior transplant and had a remission duration of 6 months or less. Patients were grouped hierarchically as refractory, relapsed post transplant, or relapsed without prior transplant. Eligibility was established at the point a patient first became eligible for analysis. The primary outcome was overall survival (OS), measured from point of eligibility, with subsequent remission with or without count recovery as secondary outcome. A sensitivity analysis was performed excluding those who died within 21 days of eligibility to eliminate patients who might be thought of as too unwell to enter a post-relapse trial. Cox regression was used to identify prognostic factors for survival. Results: A total of 264 patients were identified (refractory n=58, relapsed post SCT n=49, relapsed without SCT n=157). The median age was 51 (range 18-84); 25% of patients were aged 60 or older; 44% were male, 95% had intermediate cytogenetics; 11% had secondary disease. Split by age, among those under 60 45 were refractory, 44 relapsed post SCT and 110 relapsed without SCT; for ages 60+ the figures were 13 vs 5 vs 47. Overall 17% of patients experienced a subsequent remission; with median survival of 86 days and 1 year OS of 13%. If deaths within 21 days were excluded, the remission rate improved to 21%; with a median survival of 133 days and 1 year OS of 16%. In multivariable Cox regression, age group HR for age>60 1.81 (1.33-2.47) p=0.0002) and route to eligibility (HR refractory vs relapsed no SCT 0.77 (0.55-1.07); relapsed post SCT vs no SCT 1.58 (1.11-2.25) p=0.003) were the only factors affecting survival - in particular sex, secondary disease, and ITD allelic burden were not significant. In the sensitivity analyses, only age was significant (HR 1.77 (1.24-2.53) p=0.001); with route to eligibility not significant (p=0.14). Among patients with post-relapse treatment information, 65% were treated intensively, 8% non-intensively, and 20% with palliation - other patients received experimental therapies. When restricting attention to those treated intensively, median survival was 130 days with 17% 1 year OS. Figures were not materially changed if early death was excluded. Of 215 patients who had not relapsed post transplant, 53 (25%) received a transplant post-eligibility. In these 56 patients, median survival was 301 days with 42% alive at one year. Conclusions: In relapsed/refractory AML, outcomes for FLT3-ITD mutated patients are generally poor and worse for older patients. Applying the eligibility criteria of QUANTUM-R and excluding early deaths gives outcomes comparable to the control group of the QUANTUM-R study. In the 25% of patients who proceeded to transplant survival was extended indicating that a treatment which can deliver patients to transplant has the potential to improve patient outcomes. References: [1] Ravandi F, et al. Leuk Res. 2010;34(6):752-756; [2] Cortes et al. EHA 2018, Abstr LB2600. Table. Table. Disclosures Hills: Daiichi Sankyo: Consultancy, Honoraria. Russell:Daiichi Sankyo: Consultancy; Pfizer: Consultancy, Honoraria, Speakers Bureau; Jazz Pharma: Speakers Bureau.