Chronic headaches related to post-dural puncture headaches: a scoping review.

Post-dural puncture headache (PDPH) is a well-recognised complication of neuraxial procedures. Although it is generally considered to be self-limiting, there is mounting evidence suggesting an association between PDPH and chronic headaches. In this review, chronic headache after dural puncture was defined as the reporting of persistent headaches more than 1 month after the index dural puncture. This scoping review aims to: (1) review the relationship between PDPH and chronic headaches, (2) explore the pathophysiology of chronic headache arising from a dural puncture, and (3) make recommendations about the follow-up and treatment of these patients. The pooled relative risk of chronic headache from 15 863 patients reported in 12 cohort studies in patients with an accidental dural puncture compared with those without accidental dural puncture were 1.9 (95% confidence interval [CI], 1.2-2.9), 2.5 (95% CI, 2.0-3.2), and 3.6 (95% CI, 1.9-7.1) at 2, 6, and 12 months, respectively. We also identified 20 case reports of 49 patients who developed chronic headache after a dural puncture. Epidural blood patch and fibrin glue injection and surgery have been used to treat chronic postural headaches. Overall, the level of evidence is low for all reported outcomes (aetiology, intervention and outcome) by virtue of the type of studies available (cohort and case reports) and significant risk of bias in the cohort studies. Based on findings from this review, we recommend that the risk of chronic headache is included in the informed consent discussion for all neuraxial procedures. Patients with PDPH should be closely followed up after hospital discharge.

Mechanical Strain Alters Cellular and Nuclear Dynamics at Early Stages of Oligodendrocyte Differentiation.

Mechanical and physical stimuli including material stiffness and topography or applied mechanical strain have been demonstrated to modulate differentiation of glial progenitor and neural stem cells. Recent studies probing such mechanotransduction in oligodendrocytes have focused chiefly on the biomolecular components. However, the cell-level biophysical changes associated with such responses remain largely unknown. Here, we explored mechanotransduction in oligodendrocyte progenitor cells (OPCs) during the first 48 h of differentiation induction by quantifying the biophysical state in terms of nuclear dynamics, cytoskeleton organization, and cell migration. We compared these mechanophenotypic changes in OPCs exposed to both chemical cues (differentiation factors) and mechanical cues (static tensile strain of 10%) with those exposed to only those chemical cues. We observed that mechanical strain significantly hastened the dampening of nuclear fluctuations and decreased OPC migration, consistent with the progression of differentiation. Those biophysical changes were accompanied by increased production of the intracellular microtubule network. These observations provide insights into mechanisms by which mechanical strain of physiological magnitude could promote differentiation of progenitor cells to oligodendrocytes via inducing intracellular biophysical responses over hours to days post induction.

Molecular profiling of colorectal pulmonary metastases and primary tumours: implications for targeted treatment.

This study aimed to molecularly characterise colorectal pulmonary metastases (PM) and investigate whether their molecular profiles were concordant with those of the primary tumour. Clinical data and archival formalin fixed paraffin embedded tissue samples were retrospectively collected from patients who underwent ≥ 1 pulmonary metastasectomies for colorectal cancer between 1997-2012. Primary tumour and metastatic samples were analysed using a targeted capture sequencing panel of 46 cancer-associated genes. The 5-year progression-free and overall survival rates for the 81 patients in this study were 32% (95% CI 22-42%) and 77% (95% CI 66-85%) respectively. Fifty-four patients had samples available from ≥ 1 PM, and sequencing data were successfully obtained from 33 PM from 24 patients. The most frequently mutated genes were APC (71%), KRAS (58%) and TP53 (46%). Seventy-three percent of the 15 patients with matched primary and PM samples and 6 of the 7 patients (86%) with data from ≥ 2 PM had concordant molecular profiles. The concordance for KRAS and NRAS was 100%. At our institutions, patients with resectable colorectal PM had a favourable prognosis. RAS mutations were commonly detected in PM and the molecular profiles of colorectal PM were highly concordant with the primary tumour.

Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib.

BACKGROUND & AIMS: The availability of non-tumorigenic and tumorigenic liver progenitor cell (LPC) lines affords a method to screen putative anti-liver cancer agents to identify those that are selectively effective. To prove this principle we tested thalidomide and a range of its derivatives and compared them to lenalidomide and sorafenib, to assess their growth-inhibitory effects. METHODS: Cell growth, the mitotic and apoptotic index of cell cultures were measured using the Cellavista instrument (SynenTec) using commercially available reagents. RESULTS: Neither lenalidomide nor thalidomide (100 µM) affected tumorigenic LPCs but killed their non-tumorigenic counterparts. Sorafenib arrested growth in both cell types. All but two derivatives of thalidomide were ineffective; of the two effective derivatives, one (thalidomide C1) specifically affected the tumorigenic cell line (10 µM). Mitotic and apoptotic analyses revealed that thalidomide C1 induced apoptotic cell death and not mitotic arrest. CONCLUSIONS: This study shows that screens incorporating non-tumorigenic and tumorigenic liver cell lines are a sound approach to identify agents that are effective and selective. A high throughput instrument such as the Cellavista affords robust and reproducible objective measurements with a large number of replicates that are reliable. These experiments show that neither lenalidomide nor thalidomide are potentially useful for anti-liver cancer therapy as they kill non-tumorigenic liver cells and not their tumorigenic counterparts. Sorafenib in contrast, is highly effective, but not selective. One tested thalidomide derivative has potential as an anti-tumor drug since it induced growth arrest; and importantly, it selectively induced apoptotic cell death only in tumorigenic liver progenitor cells.

Results of surgery for chronic pulmonary Aspergillosis, optimal antifungal therapy and proposed high risk factors for recurrence--a National Centre's experience.

BACKGROUND: Surgery for pulmonary aspergillosis is infrequent and often challenging. Risk assessment is imprecise and new antifungals may ameliorate some surgical risks. We evaluated the medical and surgical management of these patients, including perioperative and postoperative antifungal therapy. METHODS: Retrospective study of patients who underwent surgery for pulmonary aspergillosis between September 1996 and September 2011. RESULTS: 30 patients underwent surgery with 23 having a preoperative tissue diagnosis while 7 were confirmed post-resection. The median age was 57 years (17-78). The commonest presenting symptoms were cough (40%, n = 12) and haemoptysis (43%, n = 13). Twelve (40%) patients had simple aspergilloma (including 2 with Aspergillus nodules) while the remaining 18 (60%) had chronic cavitary pulmonary aspergillosis (CCPA) (complex aspergilloma). Most of the patients had underlying lung disease: tuberculosis (20%, n = 6), asthma (26%, n = 8) and COPD (20%, n = 6). The procedures included lobectomy 50% (n = 15), pneumonectomy 10% (n = 3), sublobar resection 27% (n = 8), decortication 7% (n = 2), segmentectomy 3% (n = 1), thoracoplasty 3% (n = 1), bullectomy and pleurectomy 3% (n = 1), 6% (n = 2) lung transplantation for associated disease. Median hospital stay was 9.5 days (3-37). There was no operative and 30 day mortality. Main complications were prolonged air leak (n = 7, 23%), empyema (n = 6, 20%), respiratory failure requiring tracheostomy /reintubation (n = 4, 13%). Recurrence of CCPA was noted in 8 patients (26%), most having prior CCPA (75%). Taurolidine 2% was active against all 9 A. fumigatus isolates and used for pleural decontamination during surgery. CONCLUSIONS: Surgery in patients with chronic pulmonary aspergillosis offered good outcomes with an acceptable morbidity in a difficult clinical situation; recurrence is problematic.

Spinal cord compression in children with Wilms' tumour.

PURPOSE: To document the clinical, imaging and histopathological features of five children with paraplegia due to Wilms' tumour (WT), highlighting therapeutic options and patient outcome in a developing country. METHODS: Patients with WT and paraplegia seen at the Department of Paediatric Surgery since 1984 form the study cohort. Patient demographics, duration of neurological symptoms, stage of primary tumour, therapeutic intervention and outcome were recorded. Histology of the primary tumours and paraspinal or epidural biopsies were reviewed. RESULTS: Five patients with WT and paraplegia were identified. Imaging showed epidural masses with paraspinal disease, cord displacement and compression. Four patients have died. Of the two patients with neurological recovery, one relapsed 4 months later. Histology revealed triphasic WT with one case showing anaplasia. Paraspinal or epidural biopsies confirmed WT with post-treatment changes. Three biopsies showed lymphovascular, perineurial and intraneural tumour invasion and one showed epidural venous invasion. CONCLUSION: Although rare, WT-associated spinal disease may cause permanent neurological deficit, adding considerably to the burden of disease. In developing countries where patients present late, the prognosis is poor, however surgery may provide immediate relief of compression symptoms and biopsy material. The treatment of choice will depend on the facilities available and the clinical circumstances.

Factors which influence the cardiac surgeon's decision not to operate on patients referred for consideration of surgery.

BACKGROUND: The aim of this study was to document what proportion of patients referred for consideration of cardiac surgery are turned down, the reasons given for not operating and also to evaluate what happens to those patients who do not undergo surgery. METHODS: 382 elective patients referred for consideration of cardiac surgery to one of six consultant cardiac surgeons at Wythenshawe Hospital during a one year period from were included in the study. Data for those patients who underwent an operation were collected prospectively in a cardiac surgery database. The case notes of those patients who did not undergo an operation were reviewed to establish reasons given by surgeons for not operating. Patients were followed up to determine vital status at the end of the study period. RESULTS: 333 (87.2%) patients underwent an operation and 49 (12.8%) did not. 68% of patients turned down were thought to be too high-risk. 14% of patients did not fulfill symptomatic or prognostic criteria for surgery and in 8% of patients coronary artery surgery was thought ineffective due to poor distal vessels. 6% of patients declined an operation and 4% were thought to be more suitable for coronary angioplasty. Patients turned down for surgery had more renal dysfunction (p = 0.017), respiratory disease (p < 0.001) and peripheral vascular disease (p < 0.001), were more likely to have undergone prior heart surgery (p < 0.001) and to have poor left ventricular function (p = 0.003). Patients turned down for surgery had significantly higher EuroSCORE values compared to patients who underwent an operation: 5 versus 4 (p = 0.006). Freedom from death in the patients turned down for surgery at 1-, 6-, 12- and 24-months was 95.9%, 91.8%, 83.7% and 71.4% respectively, compared with 97.9%, 96.7%, 96.4% and 94.5% for the patients who underwent an operation (p < 0.001 [log-rank]). 14 of the 15 deaths that occurred in the turned down group occurred in the category considered too high-risk for surgery. CONCLUSION: 12.8% of patients referred for consideration of cardiac surgery did not undergo an operation. Two thirds of patients not accepted for surgery were thought too high risk. Those patients who did not undergo an operation had a significantly worse mortality.

Sertoli cell nodules in the undescended testis: a histochemical, immunohistochemical, and ultrastructural study of hyaline deposits.

AIMS: To document the morphology, immunohistochemical staining properties, and ultrastructural features of hyaline material in Sertoli cell nodules of undescended testis and contrast them with those of sex cord tumour with annular tubules (SCTAT), which is histologically similar. To highlight the need to distinguish these nodules from other Sertoli cell hyperplasias, such as intratubular Sertoli cell proliferations, which occur in specific clinical contexts. MATERIALS/METHODS: A retrospective study of 46 orchidectomy specimens from cryptorchid testes, 27 of which contained Sertoli cell nodules. Special histochemical stains, immunohistochemical stains for type IV collagen and fibronectin, and ultrastructural examination of the hyaline material were performed using tissue from paraffin wax embedded tissue blocks. RESULTS: The hyaline deposits in SCTAT and Sertoli cell nodules had similar staining patterns-periodic acid Schiff (PAS) and PAS-diastase positivity with variable staining of Martius scarlet blue and Masson trichrome. Type IV collagen immunoreactivity was seen in hyaline areas, although fibronectin was negative. Electron microscopy of hyaline areas confirmed a compact matrix identical to components of the basement membrane in the adjacent seminiferous tubules. CONCLUSION: This study describes an unusual form of Sertoli cell proliferation in undescended testes, which must be distinguished from Sertoli cell tumours and other forms of proliferation. In addition, the hyaline material within Sertoli cell nodules in the cryptorchid testis is histochemically, immunohistochemically, and ultrastructurally consistent with both matrix and fibrous components of seminiferous tubule basement membranes. Increased production of basement membrane material, with subsequent invagination into tubules, is the most likely origin of this material.

Eplerenone: a selective aldosterone receptor antagonist (SARA).

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.

High-performance hydrophobic interaction chromatography of proteins on reversed-phase supports coated with non-ionic surfactants of polyoxyethylene type. Purification of a fungal aspartic proteinase.

On coating reversed-phase supports with polyoxyethylene-type non-ionic surfactants, proteins are no longer retained on such supports at moderate or low ionic strength, but they are retained at high ionic strength and can be desorbed by a decreasing ionic strength gradient. These reversibly modified supports were used for hydrophobic interaction chromatography (HIC). The proteins probably interact with the polyoxyethylene tail of the non-ionic surfactant while the hydrophobic part of the surfactant anchors the surfactant to the reversed-phase support by interactions with its alkane coverage. Although the interactions between non-ionic surfactant and reversed-phase support are non-covalent and the HIC mobile phases contained no surfactant, the modified columns were stable and could be used repeatedly. A surfactant-modified reversed-phase column provided a rapid, efficient, one-step purification of a fungal aspartic proteinase from a commercial crude preparation.