Human epididymis protein 4 (HE4) levels inversely correlate with lung function improvement (delta FEV1) in cystic fibrosis patients receiving ivacaftor treatment

Background

We have recently shown that human epididymis protein 4 (HE4) levels correlate with the severity of cystic fibrosis (CF) lung disease. However, there are no data on how HE4 levels alter in patients receiving CFTR modulating therapy.

Subclinical course of adult visceral Niemann–Pick type C1 disease. A rare or underdiagnosed disorder?

Summary  We present the third case of Niemann–Pick disease type C without neurological symptoms. The patient was a 53-year-old woman without significant prior health problems who died of acute pulmonary embolism. Autopsy findings of hepatosplenomegaly, lymphadenopathy and ceroid-rich foam cells raised the suspicion of the visceral form of acid sphingomyelinase deficiency (Niemann–Pick disease type B; NPB) or a much rarer disorder, variant adult visceral form of Niemann–Pick disease type C (NPC). To verify the histopathological findings, SMPD1, NPC1 and NPC2 genes were analysed. Two novel sequence variants, c.1997G>A (S666N) and c.2882A>G (N961S) were detected in the NPC1 gene. No pathogenic sequence variants were found either in the SMPD1 gene mutated in NPB or in NPC2 gene. The pathogenicity of both NPC1 variants was supported by their location in regions important for the protein function. Both variations were not found in more than 300 control alleles. Identified sequence variations confirm the diagnosis of the extremely rare adult visceral form of Niemann–Pick disease type C, which is otherwise dominated by neurovisceral symptoms. Although only three patients have been reported, this (most probably underdiagnosed) form of NPC should be considered in differential diagnosis of isolated hepatosplenomegaly with foam cells in adulthood. Electronic supplementary material  Supplementary material is available for this article at     

Cough and paradoxical vocal fold motion

OBJECTIVES: The differential diagnosis and treatment of patients with chronic cough, paradoxical vocal fold motion, and disordered breathing can be a challenge to most practicing otolaryngologists. Tracheobronchial (ie, asthma, bronchitis, and tracheal stenosis), laryngeal (ie, vocal fold paralysis and neoplasms), and rhinologic (ie, allergies and rhinosinusitis) etiologies are commonly diagnosed and treated effectively. However, occasionally one is faced with patients who are refractory to medical treatment and have no obvious rhinologic, laryngeal or pulmonary cause. STUDY DESIGN AND SETTING: We conducted a review of the literature. METHODS: We present a thorough review of the current medical literature exploring the complex neurologic mechanisms involved in the production of cough and the relationship between gastroesophageal reflux disease, vagal neurapathy, and paradoxical vocal fold motion. RESULTS: The diagnosis and successful treatment of chronic cough can be complex. It requires a thorough understanding of the neurologic mechanisms behind cough excitation and suppression. Successful treatment strategies include aggressive management of the patient's reactive airway disease, gastroesophageal reflux disease, and, in select cases, paradoxical vocal fold motion. This may involve a well-coordinated effort among pulmonologists, otolaryngologists, gastroenterologists, and speech pathologists. CONCLUSION: Gastroesophageal reflux disease, vagal neuropathy, and paradoxical vocal fold motion are additional causes of chronic cough and disordered breathing that need to be considered, in the absence of obvious laryngotracheal and/or rhinologic pathology. A high index of suspicion is essential in making the diagnosis and formulating an effective multidisciplinary treatment plan for these patients.     

Niemann-Pick disease

Results of the investigation carried out during this decade brought unambigous evidence of biochemical heterogeneity inside the complex of Niemann-Pick disease according to which two entirely different metabolic disorders can be recognized. 1. Niemann-Pick sphingomyelinosis, a clear-cut enzymopathy, the pivotal lesion of which is the deficiency of lysosomal spingomyelinase leading to widespread lysosomal deposition of sphingomyelin liquid crystals. Two main allelic variants are known. The first one, neuronopathic (former type A) known as infantile with rapid course, may also manifest considerably prolonged course or an atypical course with predominantly visceral symptomatology. Patients with the second, visceral, variant (former type B), display mainly slow clinical course and often reach adulthood. With rare exceptions the neuronopathic variant can be biochemically recognized from the visceral one by much lower values of the in vivo sphingomyelin degradation test in the former. 2. The rest of the complex comprising types C-D differs substantially from the sphingomyelinase deficiency group by the remarkable heterogeneity in the lysosomal stored lipid pattern given by differences among the affected cell populations. Sphingomyelin storage could be proved histochemically solely in the histiocytic population together with cholesterol, neutral glycosphingolipids and lysobisphosphatidic acid, whereas the brain neurons displayed only neutral glycosphingolipid storage. There is an increasing evidence of the crucial biochemical lesion in this group being an altered intracellular traffic of exogenously derived cholesterol caused probably by its deficient translocation from lysosomes to other intracellular membrane sites. This leads to decreased cholesterol esterification rate which is the basis of the newly developed diagnostic test. Inconstant depression of sphingomyelinase activity is considered to be a secondary phenomenon. The so-called lactosylceramidosis is a rare variant pertinent to this group. The biochemical nature of type E still awaits clarification. Both groups of Niemann-Pick disease display clinical and especially histochemical features which allows to establish diagnosis in a highly efficient way already at the clinicopathological level.     

Causality Between the Amplitude and Frequency of Cardiac Oscillations

Using an information-theoretic approach, causality between the systolic amplitude in blood pressure and the frequency of the heart beat was analyzed. Blood pressure and ECG were noninvasively recorded in young, healthy subjects. Three successive measurements were performed: during spontaneous breathing and during paced respiration—at frequencies both higher and lower than that of spontaneous respiration. We demonstrate that the amplitude and frequency of the cardiac rhythm are synchronized for most of the time. The synchronization is stronger during paced respiration at a frequency lower than that of spontaneous breathing. Episodes where the cardiac frequency was driven by the systolic pressure were also detected during slow, paced respiration.     

Wear of the Christiansen hip prosthesis

The wear was examined in 39 Christiansen total hip prostheses, which were removed because of mechanical loosening after being used 5 (3-11) years. In the polyacetal acetabular cups, the head had made an eccentric defect, the mean volume of which was 680 (180-3310) mm³. The mean penetration of the head into the wall of the cup was 0.8 (0.1-3.2) mm. In two additional cups the head had penetrated right through the wall of the cup. In three prostheses the polyacetal sleeve of the trunnion was so worn that the head bore directly on the stem. There was a positive correlation between wear and the time the prostheses had been used before symptoms of loosening presented.     

Increased in vitro uptake of the complement C3b in the serum of patients with Guillain-Barré syndrome, myasthenia gravis and dermatomyositis

To examine the role of complement in certain autoimmune neuromuscular diseases, we used an in-vitro quantitative complement uptake assay that allows measurement of the capacity of patients' sera to deposit fragments of the third complement component onto sensitized targets. C3 uptake was significantly higher in patients with active dermatomyositis, Guillain-Barré syndrome and myasthenia gravis, compared to inclusion body myositis and controls. The in-vitro C3 uptake assay supports the role of C3b neoantigen and Membranolytic Attack Complex deposition in the target tissues and may be a useful tool to monitor disease activity in patients with complement-mediated neurological disorders.     

High dose melphalan and total body irradiation with autologous marrow rescue in childhood acute lymphoblastic leukaemia after relapse

High dose melphalan (HDM 110-140 mg/m2) and total body irradiation (TBI, 10.5 Gy, single fraction) followed by infusion of autologous bone marrow (ABMT) was evaluated for toxicity and efficacy in 24 children with acute lymphoblastic leukaemia (ALL) in second (CR2) or third remission (CR3). Marrow was purged with Campath 1 in six children (four were children in CR3). All children had engraftment with a median of 30 days (range 18-70 days) to neutrophil count greater than 0.5 x 10(9)/l. Four children (16%) died from toxicity 1-4 months after autograft, two from pneumonitis, one from an intracerebral haemorrhage and one from sepsis. Apart from fever and mucositis the procedure was well tolerated. Nine of 17 children treated in CR2 remain in complete remission 6-72 months after ABMT (median 25 months). Seven of these have a follow-up of greater than 12 months. Three of the seven children treated in CR3 are alive 17, 22 and 29 months post ABMT. Seven children relapsed within 10 months (median 4 months) of the autograft. Only one relapse has occurred beyond 10 months. HDM and TBI followed by ABMT is a relatively well tolerated regimen and may contribute to survival in children with relapsed ALL.