Concurrent use of intranasal and orally inhaled fluticasone propionate does not affect hypothalamic-pituitary-adrenal-axis function.

Two double-blind, randomized, placebo-controlled, parallel group safety and efficacy studies included evaluation of the hypothalamic-pituitary-adrenal (HPA)-axis effects of concurrent treatment with intranasal and orally inhaled fluticasone propionate (FP). In the first study, patients with asthma who were > or =12 years of age were assigned randomly to receive twice-daily doses (either 88 or 220 microg) of orally inhaled FP delivered from a metered-dose inhaler (MDI). In the second study, patients were assigned randomly to receive either orally inhaled FP 250 microg or orally inhaled FP 250 microg/salmeterol 50 microg delivered via the Diskus device. In both studies, patients with rhinitis were allowed to continue the use of intranasal FP at their usual dosing. Treatment periods were 26 weeks and 12 weeks for the MDI and Diskus studies, respectively. HPA-axis effects were assessed using response to short cosyntropin stimulation testing. The number and percentage of patients with an abnormal cortisol response, defined as a morning plasma cortisol of <5 microg/dL, a poststimulation peak of <18 microg/dL, or a poststimulation rise of <7 microg/dL, were summarized in two subgroups: patients who used intranasal FP and those who did not. The concurrent administration of intranasal FP and orally inhaled FP via an MDI or Diskus or via Diskus with salmeterol was not associated with HPA-axis effects compared with orally inhaled FP alone. The results of these two studies suggest that concurrent use of intranasal FP with orally inhaled FP administered via MDI or Diskus for treatment of comorbid rhinitis and asthma does not increase the risk of HPA-axis abnormalities.     

Primary gallbladder cancer: recognition of risk factors and the role of prophylactic cholecystectomy

The objective of this article is to review the available literature on the epidemiology, predisposing factors, and conditions associated with primary gallbladder cancer, and to discuss the role of prophylactic cholecystectomy in high-risk patient populations. Gallbladder cancer is a highly malignant tumor with a poor 5-yr-survival rate. It is a tumor of the elderly and has striking genetic, racial, and geographic characteristics, with an extremely high prevalence in Native Americans and Chileans. Cholelithiasis is a well-established risk factor for gallbladder cancer and the risk seems to correlate with stone size. Polyps that are >1 cm, single, sessile, and echopenic are associated with a higher risk of malignancy. Anomalous junction of pancreaticobiliary ducts (AJPBD), especially without choledochal cyst, and porcelain gallbladder are additional factors that predispose to gallbladder cancer. Lesser associations include chronic bacterial infections of the gallbladder, typhoid carrier state, certain occupational and environmental carcinogens, hormonal changes in women, and certain social, dietary, and familial factors. It is important to identify high-risk groups for gallbladder cancer because of the dismal nature of this tumor. In patients with porcelain gallbladder and anomalous junction of the pancreatic and biliary ducts, cholecystectomy is recommended provided that the patient is a good operative candidate. Patients with large solitary polyps or gallstones require close ultrasonic follow-up. With the advent of endoscopic ultrasound it is expected that early changes of malignancy in polyps will be reliably detected, and more patients will potentially be cured with a simple cholecystectomy. Through a MEDLINE/PAPERCHASE search we identified and reviewed articles regarding gallbladder cancer published in English-language journals between 1966 and 1999, using the key words biliary tract and gallbladder diseases, cancer, neoplasms, surgery, cholelithiasis, gallstones, cholecystitis, gallbladder polyps, risk factors, chemical industry, occupational diseases, typhoid, porcelain gallbladder, bacteremia, and precancerous conditions. We also used the bibliography of relevant articles to increase our search. A total of 122 publications were selected using the mentioned data source.     

Early changes in phosphatidylcholine metabolism in human acute promyelocytic leukemia cells stimulated to differentiate by phorbol ester

The HL-60 leukemia cell line derived from a human acute promyelocytic leukemia is stimulated to differentiate into macrophages within 24-28 hr after exposure to the phorbol ester, 12-O-tetradecanoylphorbol-13- acetate (TPA). We studied early alterations (within 90 min of exposure to TPA) in phosphatidylcholine metabolism in HL-60 cells and found that phosphatidylcholine synthesis by methylation is phosphatidylethanolamine was inhibited in a dose-dependent fashion. In contrast, synthesis of phosphatidylcholine from endogenous choline was enhanced and correlated inversely with the degree of inhibition of the methylation pathway. Phorbol ester congeners of TPA caused similar alterations in phosphatidylcholine metabolism in direct relationship to their capacity to induce differentiation in HL-60 cells. Perturbation of phosphatidylcholine metabolism is an early membrane even in TPA- induced HL-60 cell differentiation.     

Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.     

An alternative extrinsic pathway of human blood coagulation

To study the interrelationships of the major human coagulation pathways, factor X activation in normal and various deficient human plasmas was evaluated when clotting was triggered by dilute rabbit or human thromboplastin. Various dilutions of thromboplastin were added to plasma samples containing 3H-labeled factor X, and the time course of factor X activation was determined. At a 1/250 dilution of rabbit brain thromboplastin the rate of factor X activation in factor VIII or factor IX deficient plasma was only 10% of the activation rate seen for normal or factor XI deficient plasma. Reconstitution of the deficient plasmas with factors VIII or IX, respectively, restored normal factor X activation. Similar results were obtained when various dilutions of human thromboplastin replaced the rabbit thromboplastin. From these experiments, it is inferred that normal activation of factor X in plasma due to dilute thromboplastin requires factors VII, IX and VIII. An alternative extrinsic pathway that involves factors VII, IX, and VIII may be a major physiologic extrinsic pathway, and this pathway may help to explain the clinical observations of bleeding diatheses in patients deficient in factors IX or VIII.     

Establishing and managing a periodontal biobank for research: the sharing of experience

Periodontal bio‐repositories, which allow banking of clinically validated human data and biological samples, provide an opportunity to derive biomarkers for periodontal diagnosis, prognosis and therapeutic activities which are expected to improve patient management. This article presents the establishing of the Malaysian Periodontal Database and Biobank System (MPDBS) which was initiated in 2011 with the aim to facilitate periodontal research. Partnerships were established with collaborating centres. Policies on specimen access, authorship and acknowledgement policies were agreed upon by all participating centres before the initiation of the periodontal biobank. Ethical approval for the collection of samples and data were obtained from institutional ethics review boards. A broad‐based approach for informed consent was used, which covered areas related to quality of life impacts, genetics and molecular aspects of periodontal disease. Sample collection and processing was performed using a standardized protocol. Biobanking resources such as equipment and freezers were shared with the Malaysian Oral Cancer Database and Tissue Bank System (MOCDTBS). In the development of the MPDBS, challenges that were previously faced by the MOCDTBS were considered. Future challenges in terms of ethical and legal issues will be faced when international collaborations necessitate the transportation of specimens across borders.