Significance of endothelial dysfunction in sleep‐related breathing disorder

The endothelium functions not only as a semi‐selective barrier between body tissue and circulation; it also plays an active role in the maintenance of a healthy vasculature. Endothelial dysfunction is increasingly found to play a pivotal role in the pathogenesis of atherosclerosis. Impaired endothelium‐dependent vasodilation, as a marker of endothelial dysfunction, predates and predicts cardiovascular disease. Endothelial dysfunction is thought to result from oxidative stress, inflammatory gene activation and cytokine cascade, as well as impairment of endothelial repair mechanisms. In the context of sleep‐related breathing disorders, obstructive sleep apnoea (OSA) is postulated to contribute independently to cardiovascular morbidity and mortality. Thus, endothelial dysfunction is an important target of research in vascular pathogenesis and also serves as an intermediary outcome indicator in clinical trials evaluating cardiovascular sequelae in OSA. Basic or translational studies have identified cellular and molecular mechanisms of potential relevance to endothelial dysfunction in OSA, while epidemiological or clinical studies have shown endothelial dysfunction attributable to sleep‐disordered breathing, which could improve with effective treatment of OSA. Endothelial dysfunction is poised to serve as a call for timely intervention with possibility of halting or even reverting vascular injury in sleep‐related breathing disorders. Much remains to be explored about the complex pathways of endothelial dysfunction and its clinical manifestations in subjects with OSA, which are likely to involve multiple contributing factors. Evidence‐based information will allow us to construct the framework for guiding individualized clinical management and public health strategies for OSA, as well as cardiometabolic diseases.     

Evolutionary evidence of the effect of rare variants on disease etiology

Gorlov IP, Gorlova OY, Frazier ML, Spitz MR, Amos CI. Evolutionary evidence of the effect of rare variants on disease etiology. The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single‐nucleotide polymorphisms (SNPs), i.e. those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common diseases from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, and the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk‐associated rare SNPs.     

Role of 'atypical pathogens' among adult hospitalized patients with community-acquired pneumonia

Background and objective: Agents such as Mycoplasma pneumoniae, Chlamydophila pneumoniae and Legionella pneumophila are recognized as important causes of community‐acquired pneumonia (CAP) worldwide. This study examined the role of these ‘atypical pathogens’ (AP) among adult hospitalized patients with CAP. Methods: A prospective, observational study of consecutive adult CAP (clinico‐radiological diagnosis) patients hospitalized during 2004–2005 was conducted. Causal organisms were determined using cultures, antigen testing and paired serology. Clinical/laboratory/radiological variables and outcomes were compared between different aetiologies, and a clinical prediction rule for AP was constructed. Results: There were 1193 patients studied (mean age 70.8 ± 18.0 years, men 59.3%). Causal organisms were identified in 468 (39.2%) patients: ‘bacterial’ (48.7%), ‘viral’ (26.9%), ‘AP’ (28.6%). The AP infections comprised Mycoplasma or Chlamydophila pneumoniae (97.8%) and co‐infection with bacteria/virus (30.6%). The majority of AP infections involved elderly patients (63.4%) with comorbidities (41.8%), and more than one‐third of patients were classified as ‘intermediate’ or ‘high’ risk CAP on presentation (pneumonia severity index IV–V (35.1%); CURB‐65 2–5 (42.5%)). Patients with AP infections had disease severities and outcomes similar to patients with CAP due to other organisms (oxygen therapy 29.1% vs 29.8%; non‐invasive ventilation 3.7% vs 3.3%; admission to the intensive care unit 4.5% vs 2.7%; length of hospitalization 6 day vs 7 day; 30‐day mortality: 2.2% vs 6.0%; overall P > 0.05). Age <65 years, female gender, fever ≥38.0°C, respiratory rate <25/min, pulse rate <100/min, serum sodium >130 mmol/L, leucocyte count <11 × 10⁹/L and Hb < 11 g/dL were features associated with AP infection, but the derived prediction rule failed to reliably discriminate CAP caused by AP from bacterial CAP (area under the curve 0.75). Conclusions: M. pneumoniae and C. pneumoniae as single/co‐pathogens are important causes of severe pneumonia among older adults. No reliable clinical indicators exist, so empirical antibiotic coverage for hospitalized CAP patients may need to be considered.     

Peritoneo-Venous Shunting for Ascites

A new minor surgical procedure for ascites has been devised wherein a specially designated one way pressure activated valve is implanted to create a permanent peritoneo-venous shunt. The normally closed valves opens only when the peritoneal pressure rises 3-5 cm higher than the intrathoracic venous pressure thus preventing backflow of blood and closing the valve should the venous pressure rise from the over-infusion of ascitic fluid. The procedure has been performed on 45 patients but nine were terminal at the time of surgery. Prolonged relief of ascites occurred in 28 of 37 cases.     

A point mutation in the granulocyte colony-stimulating factor receptor (G-CSF-R) gene in a case of acute myeloid leukemia results in the overexpression of a novel G-CSF-R isoform

A novel human granulocyte colony-stimulating factor (G-CSF) receptor isoform, designated SD, has been identified in which the distal C- terminal cytoplasmic region, previously shown to be essential for maturation signalling, is substituted by an altered C-terminus. The SD receptor has a high affinity for G-CSF and retains the membrane- proximal cytoplasmic region known to be sufficient for proliferative signalling. Nonetheless, the SD isoform lacks the ability to transduce growth signals in murine BAF3 cells and, in contrast to the wild-type G- CSF receptor, is scarcely capable of activating JAK2 kinase. Expression of SD receptor was found to be low in normal granulocytes, but was significantly increased in a patient with acute myeloid leukemia (AML). The leukemic cells of this patient harbour a point mutation in the SD splice donor site of the G-CSF receptor gene. These findings provide the first evidence that mutations in the G-CSF receptor gene can occur in certain cases of clinical de novo AML. The possible contribution of defective G-CSF receptor signalling to leukemogenesis is discussed.     

How many different headaches do you have?

Patients with migraine attending a specialist clinic often have more than one type of headache. One hundred and two patients attending the City of London Migraine Clinic for the first time were asked: "What type(s) of headache do you think you have?" A separate diagnosis was made by the doctor, who was blinded to the self-diagnosis. On clinic diagnosis, 27 (26.5%) patients were found to have migraine plus an additional non-migraine headache. When compared with the self-diagnosis, 15 (56%) of these had correctly self-diagnosed two types of headache. Many migraineurs can distinguish migraine from non-migraine headaches when they have both.     

How useful is glucose detection in diagnosing cerebrospinal fluid leak? The rational use of CT and Beta-2 transferrin assay in detection of cerebrospinal fluid fistula

BACKGROUND: This report describes the sensitivity and specificity of glucose detection using Glucostix test strips and computed tomography (CT) of the skull base for confirming cerebrospinal fluid (CSF) fistulae in patients with persistent rhinorrhoea or otorrhoea, and comparing them with the beta-2 transferrin assay as the gold standard for CSF detection. METHODS: Fluid samples from the nose were collected from 18 patients with suspected CSF fistulae. The samples were assayed for beta-2 transferrin using the Western blotting and immunostaining technique. CT (5mm axial slice) of the skull base was performed for evidence of skull base fracture. The glucose levels and Glucostix results were compared. RESULTS: Out of the 18 samples, 15 were positive for beta-2 transferrin adn the leaks were validated surgically in 10 patients. Give leaks healed spontaneously with conservative management. Glucostix tests produced three false positive results from blood and nasal mucus contaminated fluid. Glucostix failed to detect another three CSF leaks resulting from false negative tests because of low CSF glucose levels. The Glucostix glucose test was nonspecific and insensitive compared with the beta-2 transferrin assay. CT failed to detect three of the 15 beta-2 transferrin-positive leaks but there were no false positive results. CT produced six negative results, of which three were false negatives. CONCLUSIONS: Glucose detection using Glucostix test strips is not recommended as a confirmatory test due to its lack of specificity and sensitivity. In the presence of a skull bas fracture on CT and a clinical CSF leak, there is no need for a further confirmatory test. In cases where a confirmatory test is needed, the beta-2 transferrin assay is the test of choice because of its high sensitivity and specificity.     

CLONIDINE IN THE TREATMENT OF ALCOHOL WITHDRAWAL IN THE INTENSIVE CARE UNIT

We present two cases of patients with a past history of alcoholabuse admitted to the Intensive Care Unit (ICU) for treatmentof respiratory problems, after multiple trauma and after sub-totalcolectomy, respectively. In both patients, features of alcoholwithdrawal were prominent after sedation had been discontinued.Both were treated successfully with an infusion of clonidine.     

Clinicopathologic features of antineutrophil cytoplasm autoantibody (ANCA)-associated acute renal failure in Chinese patients

Summary: The clinical course and renal pathologic features of anti-neutrophil cytoplasm auto-antibody (ANCA)-associated renal disease were studied among Chinese patients from a single centre. Eight ANCA positive patients with acute renal impairment were studied, four of whom required dialysis shortly after presentation. Their mean age at presentation was 61.6 ± 4.2 years. Renal histology, obtained in seven patients, showed paucummune crescentic glomerulonephritis in five patients, interstitial nephritis in two patients, and small vessel vasculitis in one patient. Pulmonary baemorrhage was the other common disease manifestation, present in four of the eight patients, necessitating ventilatory support in three patients. Neurologic, cutaneous, and gastrointestinal involvement were also observed. Seven of the eight patients tested positive for pANCA and anti-myeloperoxidase, while cANCA was detected in one patient of the eight patients, six (75%) responded to therapy, consisting of prednisolone and cyclophosphamide in five patients, and antibacterial therapy alone in one patient, who had interstitial nephritis but no evidence of vasculitis. Two patients died from sepsis and severe debilitation one month after presentation. of the other six patients, five had significant improvement of renal function, while one became dialysis-dependent. the levels of ANCA and C-reactive protein remained normal, and disease reactivation was not observed during follow-up for 32.4 ± 6.1 months. Patient and renal survival rates at one year were 75% and 62.5%, respectively. It was concluded that the clinical and pathologic features of ANCA-associated renal disease in Chinese patients are, in general, similar to those described in Caucasians. Nevertheless, cANCA-positivity is distinctly uncommon. the demonstration of interstitial nephritis in two of the eight patients underlines the importance of renal biopsy for correct histologic diagnosis. Early institution of aggressive immunosuppression and supportive therapies are essential for the achievement of favourable outcome in patients with vasculitis.