Global macroeconomic burden of epilepsy and the role for neurosurgery: a modelling study based upon the 2016 Global Burden of Disease data.

BACKGROUND AND PURPOSE: Although the significant morbidity and mortality burden associated with epilepsy is well understood, associated economic consequences are yet to be estimated on a global scale. We sought to: (i) estimate the value of lost economic welfare attributable to epilepsy among countries included in the 2016 Global Burden of Disease study, (ii) evaluate differences in disease burden between countries of varied income classification and location, and (iii) understand the proportion of this burden that requires neurosurgical consultation and intervention. METHODS: Publicly available morbidity and mortality data were incorporated into a 'full-income' model to generate estimates of the cumulative value of lost economic welfare (VLW) related to epilepsy. Results from a survey of neurosurgeons were then used to estimate the VLW attributable to the proportion of disease requiring neurosurgical consultation and intervention. RESULTS: A total of 195 countries and territories were included in this analysis. We estimate that the cumulative VLW related to epilepsy was $647.37 billion [2016 US dollars (USD), purchasing power parity (PPP)]. Economic welfare losses were equivalent to a mean of 1.45% (±1.00%) of gross domestic product. The value of economic losses attributable to the proportion of the burden necessitating neurosurgical consultation and intervention was $258.95 billion (2016 USD, PPP) and $155.37 billion (2016 USD, PPP) respectively. CONCLUSIONS: Our results indicate that the economic consequences of epilepsy-related morbidity and mortality are substantial. When considered with evidence supporting the cost-effectiveness of various interventions for improved epilepsy diagnosis and management, our findings suggest that the implementation of simple and affordable measures may avert significant economic loss.

Methodological quality and reporting of systematic reviews in hand and wrist pathology.

The objective of this study was to assess methodological and reporting quality of systematic reviews in hand and wrist pathology. MEDLINE, EMBASE and Cochrane Library were searched from inception to November 2016 for relevant studies. Reporting quality was evaluated using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and methodological quality using a measurement tool to assess systematic reviews, the Assessment of Multiple Systematic Reviews (AMSTAR). Descriptive statistics and linear regression were used to identify features associated with improved methodological quality. A total of 91 studies were included in the analysis. Most reviews inadequately reported PRISMA items regarding study protocol, search strategy and bias and AMSTAR items regarding protocol, publication bias and funding. Systematic reviews published in a plastics journal, or which included more authors, were associated with higher AMSTAR scores. A large proportion of systematic reviews within hand and wrist pathology literature score poorly with validated methodological assessment tools, which may affect the reliability of their conclusions. LEVEL OF EVIDENCE: I.

Calcium mobilisation and CCK secretion induced by modified fatty acids and latex microspheres reveal dual receptor mechanisms for lipid stimulation of STC-1 cells.

How fatty acids stimulate enteroendocrine cells to release cholecystokinin (CCK) is largely unknown. Recently, we proposed that the murine enteroendocrine cell line, STC-1, responds to insoluble fatty acid aggregates rather than fatty acid monomers in solution. This hypothesis led to two testable predictions. First, other insoluble particles of similar size but unrelated to fatty acid may be able to stimulate STC-1 cells in a similar fashion to dodecanoic acid and second, fatty acid sensing in STC-1 cells should be fairly insensitive to chemical modifications of the fatty acid as long as these modifications do not greatly alter the ability of the molecule to form insoluble aggregates. We used several analogues of dodecanoic acid and several varieties of latex microsphere (varying in size and surface charge) to see whether the predictions of our model hold. We found that while there was at least one latex microsphere that could induce CCK secretion and calcium mobilisation in STC-1 cells, there was a very poor correlation between the presence of insoluble aggregates and a cellular response. Instead the most important property, determining the potency of fatty acid analogues as stimulants of CCK secretion, was their amphipathicity. Removal of either the polar head or lipophilic tail completely abolished the ability of a given fatty acid analogue to stimulate STC-1 cells. These data suggested that while fatty acids can stimulate cells as aggregates, they may also be acting in monomeric form with the oil:water partitioning coefficient playing a crucial role. We finally resolved this issue with the observation that the sulfate ion greatly altered the response of STC-1 cells to monomeric dodecanoic acid. In the presence of sulfate, STC-1 cells will only respond to dodecanoic acid aggregates whereas when sulfate is replaced with chloride the cells clearly respond to dodecanoic acid monomers which are completely in solution. In summary, we propose that dodecanoic acid can stimulate STC-1 cells via two separate pathways one involving fatty acid monomers in solution and one involving fatty acid aggregates. Which pathway dominates depends on the presence of sulfate in the extracellular medium.

An alternatively spliced long form of Fas apoptosis inhibitory molecule (FAIM) with tissue-specific expression in the brain.

The gene encoding Fas apoptosis inhibitory molecule (FAIM) was cloned by differential display using RNA obtained from Fas-resistant and Fas-sensitive primary murine B lymphocytes. FAIM is highly evolutionarily conserved and broadly expressed, suggesting that its gene product plays a key role in cellular physiology. Here we report the identification of a new, longer form of FAIM (FAIM-L) and characterization of the genomic locus that clarifies its origin. The murine FAIM gene is located at chromosome 9f1, a region syntenic to the corresponding location of the human FAIM gene. The gene consists of six exons and contains putative translation initiation sites within exons II and III. The long form of FAIM is generated by all six exons, whereas the originally cloned form of FAIM, now termed FAIM-Short (FAIM-S) is generated from five exons by alternative splicing. FAIM-L is dominantly expressed in the brain whereas FAIM-S is widely expressed in many tissues.

Partial reduction of annulated heterocycles as a general route to medium rings containing oxygen and nitrogen.

The preparation of annulated furans and pyrroles is described as part of a general strategy for the synthesis of medium ring heterocycles. After Birch reduction, the corresponding dihydro compounds were oxidatively cleaved to produce medium ring ethers and amines in an efficient manner. This methodology was successfully applied to the formation of eight- and nine-membered cyclic ethers and nine-membered cyclic amines. Attaching a chiral auxiliary (bismethoxymethylpyrrolidine) to the furan allowed the formation of nine-membered ethers in 95% ee.

The regioselective aminohydroxylation of allylic carbamates.

The synthesis and aminohydroxylation of a series of acyclic allylic carbamates is described: the formation of a putative O=Os=NR linkage between the transition metal and substrate is proposed to account for the high levels of regioselectivity that were observed; proof of the structure of one of the aminohydroxylation products was obtained through X-ray crystallography.

Receptor-specific regulation of B-cell susceptibility to Fas-mediated apoptosis and a novel Fas apoptosis inhibitory molecule.

The susceptibility of primary B cells to Fas (APO-1, CD95)-mediated apoptosis is modulated by signals derived from additional surface receptors: CD40 engagement produces upregulation of Fas expression and marked sensitivity to Fas-induced cell death, whereas antigen receptor engagement, or interleukin-4 receptor (IL-4R) engagement, inhibits Fas killing and thereby produces Fas resistance, even in otherwise susceptible, CD40-stimulated targets. Surface immunoglobulin (sIg) and IL-4R utilize distinct signaling pathways to produce Fas resistance that rely on protein kinase C and signal transducer and activator of transcription 6, respectively sIg signaling for inducible Fas resistance requires nuclear factor-kappaB and depends on new macromolecular synthesis. Proximate mediators for Fas resistance include the known anti-apoptotic gene products Bcl-xL and FLIP (but not Btk), and a novel anti-apoptotic gene that encodes Fas apoptosis inhibitory molecule (FAIM). FAIM was identified by differential display and was cloned as two alternatively spliced forms: FAIM-S is broadly expressed, whereas faim-L expression is tissue specific. faim is highly evolutionarily conserved, suggesting an important function throughout phylogeny. Inducible resistance to Fas-mediated apoptosis is speculated to protect antigen-specific B cells during potentially dangerous interactions with FasL-bearing T cells; the elevated sIg-signaling threshold for inducible Fas resistance in autoreactive, tolerant B cells would insure against autoimmunity. However, aberrant acquisition of Fas resistance may allow autoreactive B cells to escape Fas deletion and malignant lymphocytes to thwart antitumor immunity.

Changing sources of care for HIV infection in California.

A telephone survey was conducted of random samples of primary care physicians in Los Angeles County and in the 26 rural counties of California to assess changes in medical practices that may have occurred with the development of new pharmacological agents and recent changes in the management of infection with the HIV. Seventy-two to seventy-three percent of the physicians selected participated in the survey in both areas. The results indicate a reduction by almost two thirds of the number of primary care physicians who plan to continue to provide care to HIV-infected patients, both in Los Angeles County and the nonmetropolitan counties of California. Although some were no longer caring for HIV patients because of deaths or patient relocation, the overwhelming majority had referred their patients to infectious disease specialists and HIV clinics because of the growing complexity of the management of these patients.

A novel gene coding for a Fas apoptosis inhibitory molecule (FAIM) isolated from inducibly Fas-resistant B lymphocytes.

The sensitivity of primary splenic B cells to Fas-mediated apoptosis is modulated in a receptor-specific fashion. Here we used a differential display strategy to detect cDNAs present in B cells rendered Fas resistant but absent in those rendered Fas sensitive. This led to the cloning and characterization of a novel 1.2-kb gene that encodes a Fas apoptosis inhibitory molecule (FAIM). faim-transfected BAL-17 B lymphoma cells were less sensitive by half or more to Fas-mediated apoptosis than were vector-transfected controls, using Fas ligand-bearing T cells or a cytotoxic anti-Fas antibody to trigger Fas, and this was associated with inhibition of Fas- induced poly-ADP ribose polymerase (PARP) cleavage. In primary B cells, the time course of faim mRNA and FAIM protein expression correlated with the induction of Fas resistance by surface (s)Ig engagement. Thus, FAIM is an inducible effector molecule that mediates Fas resistance produced by sIg engagement in B cells. However, faim is broadly expressed in various tissues and the faim sequence is highly conserved evolutionarily, suggesting that its role extends beyond lymphocyte homeostasis. As FAIM has no significant regions of homology to other gene products that modulate Fas killing, it appears to represent a distinct, new class of antiapoptotic protein.

Growth and differentiation in the Drosophila eye coordinated by hedgehog.

Differentiation of the Drosophila retina is asynchronous: it starts at the posterior margin of the eye imaginal disc and progresses anteriorly over two days. During this time the disc continues to grow, increasing in size by approximately eightfold. An indentation in the epithelium, the morphogenetic furrow, marks the front edge of the differentiation wave. Anterior progression of the furrow is thought to be driven by signals emanating from differentiating photoreceptor cells in the posterior eye disc. A good candidate for such a signal is the product of the hedgehog (hh) gene; it is expressed, and presumably secreted, by differentiating photoreceptors and its function is required for continued furrow movement. Here we show that ectopic expression of hedgehog sets in motion ectopic furrows in the anterior eye disc. In addition to changes in cell shape, these ectopic furrows are associated with a tightly orchestrated series of events, including proliferation, cell cycle synchronization and pattern formation, that parallel normal furrow progression. We propose that the morphogenetic furrow coincides with a transient boundary that coordinates growth and differentiation of the eye disc, and that hedgehog is necessary and sufficient to propagate this boundary across the epithelium.