Steroids for Migraine Headaches: A Randomized Double-Blind, Two-Armed, Placebo-Controlled Trial

Background: Recurrence of migraine headache after treatment in the emergency department (ED) is common. Conflicting evidence exists regarding the utility of steroids in preventing migraine headache recurrence at 24–48 h. Objective: To determine if steroids decrease the headache recurrence in patients treated for migraine headaches in the ED. Methods: Double-blind placebo-controlled, two-tailed randomized trial. Patients aged >17 years with a moderately severe migraine headache diagnosed by treating Emergency Physician were approached for participation. Enrollees received either dexamethasone (10 mg i.v.) if intravenous access was utilized or prednisone (40 mg by mouth × 2 days) if no intravenous access was obtained. Each medication was matched with an identical-appearing placebo. Patients were contacted 24–72 h after the ED visit to assess headache recurrence. Results: A total of 181 patients were enrolled. Eight were lost to follow-up, 6 in the dexamethasone group and 2 in the prednisone arm. Participants had a mean age of 37 years (±10 years), with 86% female. Eighty-six percent met the International Headache Society Criteria for migraine headache. Of the 173 patients with completed follow-up, 20/91 (22%) (95% confidence interval [CI] 13.5–30.5) in the steroid arm and 26/82 (32%) (95% CI 21.9–42.1) in the placebo arm had recurrent headaches (p = 0.21). Conclusion: We did not find a statistically significant decrease in headache recurrence in patients treated with steroids for migraine headaches.     

Genetic and environmental control of host-gut microbiota interactions

Genetics provides a potentially powerful approach to dissect host-gut microbiota interactions. Toward this end, we profiled gut microbiota using 16s rRNA gene sequencing in a panel of 110 diverse inbred strains of mice. This panel has previously been studied for a wide range of metabolic traits and can be used for high-resolution association mapping. Using a SNP-based approach with a linear mixed model, we estimated the heritability of microbiota composition. We conclude that, in a controlled environment, the genetic background accounts for a substantial fraction of abundance of most common microbiota. The mice were previously studied for response to a high-fat, high-sucrose diet, and we hypothesized that the dietary response was determined in part by gut microbiota composition. We tested this using a cross-fostering strategy in which a strain showing a modest response, SWR, was seeded with microbiota from a strain showing a strong response, A×B19. Consistent with a role of microbiota in dietary response, the cross-fostered SWR pups exhibited a significantly increased response in weight gain. To examine specific microbiota contributing to the response, we identified various genera whose abundance correlated with dietary response. Among these, we chose Akkermansia muciniphila, a common anaerobe previously associated with metabolic effects. When administered to strain A×B19 by gavage, the dietary response was significantly blunted for obesity, plasma lipids, and insulin resistance. In an effort to further understand host-microbiota interactions, we mapped loci controlling microbiota composition and prioritized candidate genes. Our publicly available data provide a resource for future studies.Studies carried out over the last decade have revealed that gut microbiota contribute to a variety of common disorders, including obesity and diabetes (Musso et al. 2011), colitis (Devkota et al. 2012), atherosclerosis (Wang et al. 2011), rheumatoid arthritis (Vaahtovuo et al. 2008), and cancer (Yoshimoto et al. 2013). The evidence for metabolic interactions is particularly strong, as a large body of data now supports the conclusion that gut microbiota influence the energy harvest from dietary components, particularly complex carbohydrates, and that metabolites such as the short-chain fatty acids produced by gut bacteria can perturb metabolic traits, including adiposity and insulin resistance (Turnbaugh et al. 2006, 2009; Backhed et al. 2007; Wen et al. 2008; Ridaura et al. 2013). Gut microbiota communities are assembled each generation, influenced by maternal seeding, environmental factors, host genetics, and age, resulting in substantial variations in composition among individuals in human populations (Eckburg et al. 2005; Costello et al. 2009; Human Microbiome Project Consortium 2012; Goodrich et al. 2014). Most experimental studies of host-gut microbiota interactions have employed large perturbations, such as comparisons of germ-free versus conventional mice, and the significance of common variations in gut microbiota composition for disease susceptibility is still poorly understood. Furthermore, while studies with germ-free mice have clearly implicated microbiota in clinically relevant traits, it has proven difficult to identify the responsible taxa of bacteria.We now report a population-based analysis of host-gut microbiota interactions in the mouse. One of the issues we explore is the role of host genetics. Although some evidence is consistent with significant heritability of gut microbiota composition, the extent to which the host controls microbiota composition under controlled environmental conditions is unclear. We also examined the role of common variations in gut microbiota in metabolic traits such as obesity and insulin resistance and mapped loci contributing to the abundance of certain microbiota. We performed our study using a resource termed the Hybrid Mouse Diversity Panel (HMDP), consisting of about 100 inbred strains of mice that have been either sequenced or subjected to high-density genotyping (Bennett et al. 2010). The resource has several advantages for genetic analysis as compared to traditional genetic crosses. First, it allows high-resolution mapping by association rather than linkage analysis, and it has now been used for the identification of a number of novel genes underlying complex traits (Farber et al. 2011; Lavinsky et al. 2015; Parks et al. 2015; Rau et al. 2015). Second, since the strains are permanent, the data from separate studies can be integrated, allowing the development of large, publicly available databases of physiological and molecular traits relevant to a variety of clinical disorders (systems.genetics.ucla.edu and phenome.jax.org). Third, the panel is ideal for examining gene-by-environment interactions, since it is possible to examine individuals of a particular genotype under a variety of conditions (Orozco et al. 2012; Parks et al. 2013).     

Nutritional Status,Body Surface,and Low Lean Body Mass/Body Mass Index Are Related to Dose Reduction and Severe Gastrointestinal Toxicity Induced by Afatinib in Patients With Non‐Small Cell Lung Cancer

Background.

The main reason for dose reduction of afatinib is gastrointestinal toxicity (GT). In a phase II study, we analyzed anthropometrical, nutritional, and biochemical factors associated with GT induced by afatinib.

Materials and Methods.

Patients diagnosed with non-small cell lung cancer who progressed to prior chemotherapy received 40 mg of afatinib. Malnutrition was determined by Subjective Global Assessment, and lean body mass (LBM) was determined by computed tomography scan analysis using a pre-established Hounsfield unit threshold. Toxicity was obtained during four cycles by Common Terminology Criteria for Adverse Events.

Results.

Eighty-four patients were enrolled. Afatinib was administered as the second, third, and fourth line of treatment in 54.8%, 38.1%, and 7.12% of patients, respectively. Severe diarrhea, mucositis, and overall severe GT were present in 38.9%, 28.8%, and 57.5%, respectively. Of the patients, 50% developed dose-limiting toxicity (DLT). Patients with malnutrition have higher risk for severe GT. Patients with lower LBM and body mass index developed more DLT (71.4% vs. 18.8%).

Conclusion.

Malnutrition is associated with a higher risk of severe GT induced by afatinib. Determination of nutritional status and body composition are helpful in identifying patients at higher risk of severe GT and could allow initiating treatment with lower doses according to tolerance.

Implications for Practice:

Body composition analysis, specifically lean body mass quantification, and nutritional status assessment are significant clinical variables to take into account when assessing oncological patients. This study on patients with non-small cell lung cancer treated with afatinib showed the important impact that malnutrition and low lean body mass have on the risk for developing dose-limiting toxicity and severe gastrointestinal toxicity. Still more research needs to be done to explore dose adjustment according to lean body mass, especially in drugs that are given at fixed doses, such as afatinib. However, this study presents evidence for the clinical oncologist to have a closer follow-up with malnourished patients and even to consider a lower starting dose until therapeutic dose is achieved.     

The Lidcombe Hospital Memory (Cognitive Disorders) Clinic: Review of Clinical Experience

Objective: A retrospective review of clinical experience of the Memory (Cognitive Disorders) Clinic at Lidcombe Hospital. Method: 100 available records of patients seen consecutively in the clinic were reviewed. The following information was extracted: demographics, clinical diagnosis, investigations and results. Follow-up contact was made by phone where possible and the patients' status established in terms of mortality, domicile, dependency, use of basic community services and any significant deterioration in function. Results: 11% of patients were found not to be suffering from dementia and most of these were suffering from potentially reversible conditions, particularly depression and delirium which could be detected clinically rather than on the basis of investigations. Discussion: The clinic was felt to be useful in providing education and support to the families and others caring for those suffering from dementia, in providing a sound basis for case management of dementia sufferers, and in providing a focus for the development and dissemination of skills and knowledge among health professionals.     

Long-term regulation of neuronal high-affinity glutamate and glutamine uptake in Aplysia

An increase in transmitter release accompanying long-term sensitization and facilitation occurs at the glutamatergic sensorimotor synapse of Aplysia. We report that a long-term increase in neuronal Glu uptake also accompanies long-term sensitization. Synaptosomes from pleural-pedal ganglia exhibited sodium-dependent, high-affinity Glu transport. Different treatments that induce long-term enhancement of the siphon-withdrawal reflex, or long-term synaptic facilitation increased Glu uptake. Moreover, 5-hydroxytryptamine, a treatment that induces long-term facilitation, also produced a long-term increase in Glu uptake in cultures of sensory neurons. The mechanism for the increase in uptake is an increase in the V(max) of transport. The long-term increase in Glu uptake appeared to be dependent on mRNA and protein synthesis, and transport through the Golgi, because 5,6-dichlorobenzimidazole riboside, emetine, and brefeldin A inhibited the increase in Glu uptake. Also, injection of emetine and 5,6-dichlorobenzimidazole into Aplysia prevented long-term sensitization. Synthesis of Glu itself may be regulated during long-term sensitization because the same treatments that produced an increase in Glu uptake also produced a parallel increase in Gln uptake. These results suggest that coordinated regulation of a number of different processes may be required to establish or maintain long-term synaptic facilitation.     

Bile duct confluence: anatomic variations and its classification

Accurate knowledge of the anatomy of the bile ducts is critical for successfully hepato-biliary surgery. We describe the anatomical variations of the confluence of the bile ducts, their branches patterns, frequency and classification. From 1996 to 2011, we have collected data of the bile duct confluence. 2,032 and 1,014 anatomical variations of right and left bile ducts, respectively, were reviewed and classified according to the branching pattern. The frequencies of each type of the right hepatic duct (RHD) were as follows: Type A1—1,247 (61.3 %); Type A2—296 (14.5 %); Type A3—272 (13.3 %); Type A4—124 (6.1 %); Type A5—21 (1 %) and others—72 (3.5 %) and, for the left hepatic duct (LHD) was as follows: Type B1—773 (76.2 %); Type B2—153 (15 %); Type B3—38 (3.7 %); Type B4—9 (0.8 %); Type B5—29 (2.8 %) and others—12 (1.1 %). Atypical branching patterns of both the right and left hepatic ducts were found in 14 and 8 %, respectively. The two most common variations of the RHD were right anterior and posterior hepatic ducts join together to form the RHD and trifurcation where the RHD is absent and right anterior and posterior hepatic ducts join directly to the confluence with the LHD to form the common hepatic duct. The two most common variations in the LHD were segment IV drainage to the left and right hepatic ducts.