Neuroscience

The new Diagnostics and Statistical Manual, DSM-V, is out. Not surprisingly, it has sparked some controversy. Psychiatry deniers are proclaiming that this is the collapse of the mental-illness fraud (I believe reports of the death of psychiatry are exaggerated). What the DSM-V does represent, to some degree, is an attempt to advance psychiatry to the next stage of our understanding of illness. It seems that we are not quite ready for this step in psychiatry, but the effort is sincere and interesting. For background, the DSM (now in the fifth edition) is essentially a list of official psychiatric diagnoses, based upon clinical criteria. For mental illness and disorders we mostly lack clear biological markers or pathology, and so we have had to make due with clinical descriptions – lists of signs and symptoms. This is very much a descriptive phase of scientific understanding. What almost every popular article I read on the subject gets terribly wrong, however, is in characterizing this as a unique feature of psychiatry, unlike the rest of medicine. A recent Wired article, for example, writes: In most areas of medicine, diagnoses are based on the cause of illness. Heartburn and heart attacks both cause chest pain, but they’re different diagnoses because they have different underlying causes. At least they added the qualifier “most”, but even that is misleading. In fact most disorders and medical illnesses begin their life as a description of signs and symptoms – a purely clinically defined entity. Scientists then investigate possible causes, with the full spectrum of success. Some illnesses we have very little idea, nothing but guesses, about the cause and pathology. In others we have a completely fleshed out model of what is happening, down to the most reductionist level. The Wired article also notes: What doctors now diagnose as schizophrenia may in fact be several disorders with different causes that happen to produce an overlapping set of symptoms. True, but his is also true of many medical illnesses. ALS (Lou Gehrig’s disease, which causes progressive weakness), for example, is a clinical syndrome. We don’t know the ultimate cause, so it is entirely defined clinically. It is very likely to be multiple pathophysiological diseases with a common manifestation. Migraine headaches are another favorite example. They are diagnosed by a list of symptoms, just like DSM diagnoses. Migraine is likely many different underlying biological entities that all manifest in a similar fashion. It is also possible that underlying biological traits manifest in some people as classic migraines, in others as a different type of headache, and in still others with no symptoms. Medical diagnoses span the entire spectrum from a pure description of clinical features, to some knowledge of mechanism, to fairly complete pathophysiologal description.  Mental illness is not unique for being at the clinical description end of the spectrum. What neuroscientists focusing on mental illness are seriously trying to do is advance pyshicatric diagnoses to the next step, from pure clinical description to at least classification by underlying mechanism. No one thinks this is going to be easy. The brain is very complex, and the higher cognitive manifestations of the brain are subject to a host of influences. Teasing apart those influences to determine their relative contribution to a mental disorder is a herculean task, but not impossible. Possible influence include genes, epigenetic factors, developmental factors, biological factors such as nutrition, and all possible environmental factors. Scientists understand this complexity, but you would not know that from reading many popular treatments of the current DSM and efforts to advance our understanding of mental illness. For example, a recent Slate article, Double Inanity, claims right in the subtitle that “twin studies are pretty much useless.” It opens with this howler

by Franziska Ruëff, Bernhard Przybilla, Maria Beatrice Biló, Ulrich Müller, Fabian Scheipl, Michael J. Seitz, Werner Aberer, Anna Bodzenta-Lukaszyk, Floriano Bonifazi, Paolo Campi, Ulf Darsow, Gabrielle Haeberli, Thomas Hawranek, Helmut Küchenhoff, Roland Lang, Oliviero Quercia, Norbert Reider, Peter Schmid-Grendelmeier, Maurizio Severino, Gunter Johannes Sturm, Regina Treudler, Brunello Wüthrich Background Treatment failure during venom immunotherapy (VIT) may be associated with a variety of risk factors. Objective Our aim was to evaluate the association of baseline serum tryptase concentration (BTC) and of other parameters with the frequency of VIT failure during the maintenance phase. Methods In this observational prospective multicenter study, we followed 357 patients with established honey bee or vespid venom allergy after the maintenance dose of VIT had been reached. In all patients, VIT effectiveness was either verified by sting challenge (n?=?154) or patient self-reporting of the outcome of a field sting (n?=?203). Data were collected on BTC, age, gender, preventive use of anti-allergic drugs (oral antihistamines and/or corticosteroids) right after a field sting, venom dose, antihypertensive medication, type of venom, side effects during VIT, severity of index sting reaction preceding VIT, and duration of VIT. Relative rates were calculated with generalized additive models. Results 22 patients (6.2%) developed generalized symptoms during sting challenge or after a field sting. A strong association between the frequency of VIT failure and BTC could be excluded. Due to wide confidence bands, however, weaker effects (odds ratios Interpretation It is unlikely that an elevated BTC has a strong negative effect on the rate of treatment failures. The magnitude of the latter, however, may depend on the method of effectiveness assessment. Failure rate is higher in patients suffering from bee venom allergy.

by Ashna D. Mohangoo, Béatrice Blondel, Mika Gissler, Petr Velebil, Alison Macfarlane, Jennifer Zeitlin, the Euro-Peristat Scientific Committee Background Fetal and neonatal mortality rates are essential indicators of population health, but variations in recording of births and deaths at the limits of viability compromises international comparisons. The World Health Organization recommends comparing rates after exclusion of births with a birth weight less than 1000 grams, but many analyses of perinatal outcomes are based on gestational age. We compared the effects of using a 1000-gram birth weight or a 28-week gestational age threshold on reported rates of fetal and neonatal mortality in Europe. Methods Aggregated data from 2004 on births and deaths tabulated by birth weight and gestational age from 29 European countries/regions participating in the Euro-Peristat project were used to compute fetal and neonatal mortality rates using cut-offs of 1000-grams and 28-weeks (2.8 million total births). We measured differences in rates between and within countries using the Wilcoxon signed rank test and 95% confidence intervals, respectively. Principal Findings For fetal mortality, rates based on gestational age were significantly higher than those based on birth weight (pp?=?0.370). Country rankings were comparable with both thresholds. Conclusions Neonatal mortality rates were not affected by the choice of a threshold. However, the use of a 1000-gram threshold underestimated the health burden of fetal deaths. This may in part reflect the exclusion of growth restricted fetuses. In high-income countries with a good measure of gestational age, using a 28-week threshold may provide additional valuable information about fetal deaths occurring in the third trimester.

by Ann Thuring, K. Jonas Brännström, Maria Ewerlöf, Edgar Hernandez-Andrade, David Ley, Göran Lingman, Karina Liuba, Karel Maršál, Tomas Jansson Objective An experienced sonographer can by listening to the Doppler audio signals perceive various timbres that distinguish different types of umbilical artery flow despite an unchanged pulsatility index (PI). Our aim was to develop an objective measure of the Doppler audio signals recorded from fetoplacental circulation in a sheep model. Methods Various degrees of pathological flow velocity waveforms in the umbilical artery, similar to those in human complicated pregnancies, were induced by microsphere embolization of the placental bed (embolization model, 7 lamb fetuses, 370 Doppler recordings) or by fetal hemodilution (anemia model, 4 lamb fetuses, 184 recordings). A subjective 11-step operator auditory scale (OAS) was related to conventional Doppler parameters, PI and time average mean velocity (TAM), and to sound frequency analysis of Doppler signals (sound frequency with the maximum energy content [MAXpeak] and frequency band at maximum level minus 15 dB [MAXpeak-15 dB] over several heart cycles). Results We found a negative correlation between the OAS and PI: median Rho ?0.73 (range ?0.35– ?0.94) and ?0.68 (range ?0.57– ?0.78) in the two lamb models, respectively. There was a positive correlation between OAS and TAM in both models: median Rho 0.80 (range 0.58–0.95) and 0.90 (range 0.78–0.95), respectively. A strong correlation was found between TAM and the results of sound spectrum analysis; in the embolization model the median r was 0.91 (range 0.88–0.97) for MAXpeak and 0.91 (range 0.82–0.98) for MAXpeak-15 dB. In the anemia model, the corresponding values were 0.92 (range 0.78–0.96) and 0.96 (range 0.89–0.98), respectively. Conclusion Audio-spectrum analysis reflects the subjective perception of Doppler sound signals in the umbilical artery and has a strong correlation to TAM-velocity. This information might be of importance for clinical management of complicated pregnancies as an addition to conventional Doppler parameters.

by Magne Aldrin, Bård Storvik, Anja Bråthen Kristoffersen, Peder Andreas Jansen Parasitic salmon lice are potentially harmful to salmonid hosts and farm produced lice pose a threat to wild salmonids. To control salmon lice infections in Norwegian salmonid farming, numbers of lice are regularly counted and lice abundance is reported from all salmonid farms every month. We have developed a stochastic space-time model where monthly lice abundance is modelled simultaneously for all farms. The set of farms is regarded as a network where the degree of contact between farms depends on their seaway distance. The expected lice abundance at each farm is modelled as a function of i) lice abundance in previous months at the same farm, ii) at neighbourhood farms, and iii) other, unspecified sources. In addition, the model includes explanatory variables such as seawater temperature and farm-numbers of fish. The model gives insight into factors that affect salmon lice abundance and contributing sources of infection. New findings in this study were that 66% of the expected salmon lice abundance was attributed to infection within farms, 28% was attributed to infection from neighbourhood farms and 6% to non-specified sources of infection. Furthermore, we present the relative risk of infection between neighbourhood farms as a function of seaway distance, which can be viewed as a between farm transmission kernel for salmon lice. The present modelling framework lays the foundation for development of future scenario simulation tools for examining the spread and abundance of salmon lice on farmed salmonids under different control regimes.

by Kap Lim, Liudmila Kulakova, Andrey Galkin, Osnat Herzberg The parasite Giardia lamblia utilizes the L-arginine dihydrolase pathway to generate ATP from L-arginine. Carbamate kinase (CK) catalyzes the last step in this pathway, converting ADP and carbamoyl phosphate to ATP and ammonium carbamate. Because the L-arginine pathway is essential for G. lamblia survival and absent in high eukaryotes including humans, the enzyme is a potential target for drug development. We have determined two crystal structures of G. lamblia CK (glCK) with bound ligands. One structure, in complex with a nonhydrolyzable ATP analog, adenosine 5?-adenylyl-?,?-imidodiphosphate (AMP-PNP), was determined at 2.6 Å resolution. The second structure, in complex with citric acid bound in the postulated carbamoyl phosphate binding site, was determined in two slightly different states at 2.1 and 2.4 Å resolution. These structures reveal conformational flexibility of an auxiliary domain (amino acid residues 123–170), which exhibits open or closed conformations or structural disorder, depending on the bound ligand. The structures also reveal a smaller conformational change in a region associated the AMP-PNP adenine binding site. The protein residues involved in binding, together with a model of the transition state, suggest that catalysis follows an in-line, predominantly dissociative, phosphotransfer reaction mechanism, and that closure of the flexible auxiliary domain is required to protect the transition state from bulk solvent.

by Donard S. Dwyer, Eric J. Aamodt In C. elegans, pharyngeal pumping is regulated by the presence of bacteria. In response to food deprivation, the pumping rate rapidly declines by about 50–60%, but then recovers gradually to baseline levels on food after 24 hr. We used this system to study the role of insulin/IGF-1 signaling (IIS) in the recovery of pharyngeal pumping during starvation. Mutant strains with reduced function in the insulin/IGF-1 receptor, DAF-2, various insulins (INS-1 and INS-18), and molecules that regulate insulin release (UNC-64 and NCA-1; NCA-2) failed to recover normal pumping rates after food deprivation. Similarly, reduction or loss of function in downstream signaling molecules (e.g., ARR-1, AKT-1, and SGK-1) and effectors (e.g., CCA-1 and UNC-68) impaired pumping recovery. Pharmacological studies with kinase and metabolic inhibitors implicated class II/III phosphatidylinositol 3-kinases (PI3Ks) and glucose metabolism in the recovery response. Interestingly, both over- and under-activity in IIS was associated with poorer recovery kinetics. Taken together, the data suggest that optimum levels of IIS are required to maintain high levels of pharyngeal pumping during starvation. This work may ultimately provide insights into the connections between IIS, nutritional status and sarcopenia, a hallmark feature of aging in muscle.

by D'Angelo Carlo Magliano, Thereza Cristina Lonzetti Bargut, Simone Nunes de Carvalho, Marcia Barbosa Aguila, Carlos Alberto Mandarim-de-Lacerda, Vanessa Souza-Mello Aim The aim of the present study was to evaluate whether activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma by Bezafibrate (BZ) could attenuate hepatic and white adipose tissue (WAT) abnormalities in male offspring from diet-induced obese dams. Materials and Methods C57BL/6 female mice were fed a standard chow (SC; 10% lipids) diet or a high-fat (HF; 49% lipids) diet for 8 weeks before mating and during gestation and lactation periods. Male offspring received SC diet at weaning and were subdivided into four groups: SC, SC/BZ, HF and HF/BZ. Treatment with BZ (100 mg/Kg diet) started at 12 weeks of age and was maintained for three weeks. Results The HF diet resulted in an overweight phenotype and an increase in oral glucose intolerance and fasting glucose of dams. The HF offspring showed increased body mass, higher levels of plasmatic and hepatic triglycerides, higher levels of pro-inflammatory and lower levels of anti-inflammatory adipokines, impairment of glucose metabolism, abnormal fat pad mass distribution, higher number of larger adipocytes, hepatic steatosis, higher expression of lipogenic proteins concomitant to decreased expression of PPARalpha and carnitine palmitoyltransferase I (CPT-1) in liver, and diminished expression of PPARgamma and adiponectin in WAT. Treatment with BZ ameliorated the hepatic and WAT abnormalities generated by diet-induced maternal obesity, with improvements observed in the structural, biochemical and molecular characteristics of the animals' livers and epididymal fat. Conclusion Diet-induced maternal obesity lead to alterations in metabolism, hepatic lipotoxicity and adverse liver and WAT remodeling in the offspring. Targeting PPAR with Bezafibrate has beneficial effects reducing the alterations, mainly through reduction of WAT inflammatory state through PPARgamma activation and enhanced hepatic beta-oxidation due to increased PPARalpha/PPARgamma ratio in liver.

by Zhongji Meng, Xiaoyong Zhang, Jun Wu, Rongjuan Pei, Yang Xu, Dongliang Yang, Michael Roggendorf, Mengji Lu Background & Aims Our previous results showed that the knockdown of woodchuck hepatitis virus (WHV) by RNA interference (RNAi) led to upregulation of interferon stimulated genes (ISGs) in primary hepatocytes. In the present study, we tested the hypothesis that the cellular signaling pathways recognizing RNA molecules may be involved the ISG stimulation by RNAi. Methods Primary murine hepatocytes (PMHs) from wild type mice and WHV transgenic (Tg) mice were prepared and treated with defined siRNAs. The mRNA levels of target genes and ISGs were detected by real-time RT-PCR. The involvement of the signaling pathways including RIG-I/MDA5, PKR, and TLR3/7/8/9 was examined by specific inhibition and the analysis of their activation by Western blotting. Results In PMHs from WHV Tg mice, specific siRNAs targeting WHV, mouse ?-actin, and GAPDH reduced the levels of targeted mRNAs and increased the mRNA expression of IFN-?, MxA, and IP-10. The enhanced ISG expression by siRNA transfection were abolished by siRNA-specific 2?-O-methyl antisense RNA and the inhibitors 2-AP and chloroquine blocking PKR and other TLR-mediated signaling pathways. Furthermore, Western blotting revealed that RNAi results in an increase in PKR phosphorylation and nuclear translocation of IRF3 and NF-êB, indicating the possible role of IRF3 in the RNAi-directed induction of ISGs. In contrast, silencing of RIG-I and MDA5 failed to block RNAi-mediated MxA induction. Conclusions RNAi is capable of enhancing innate immune responses through the PKR- and TLR-dependent signaling pathways in primary hepatocytes. The immune stimulation by RNAi may contribute to the antiviral activity of siRNAs in vivo.

by Xiao-Qin Sun, Mao-Xin Zhang, Jing-Ya Yu, Yu Jin, Bing Ling, Jin-Ping Du, Gui-Hua Li, Qing-Ming Qin, Qing-Nian Cai Plants have evolved complex processes to ward off attacks by insects. In parallel, insects have evolved mechanisms to thwart these plant defenses. To gain insight into mechanisms that mediate this arms race between plants and herbivorous insects, we investigated the interactions between gramine, a toxin synthesized by plants of the family Gramineae, and glutathione S transferase (GST), an enzyme found in insects that is known to detoxify xenobiotics. Here, we demonstrate that rice (Oryza sativa), a hydrophytic plant, also produces gramine and that rice resistance to brown planthoppers (Nilaparvata lugens, BPHs) is highly associated with in planta gramine content. We also show that gramine is a toxicant that causes BPH mortality in vivo and that knockdown of BPH GST gene nlgst1-1 results in increased sensitivity to diets containing gramine. These results suggest that the knockdown of key detoxification genes in sap-sucking insects may provide an avenue for increasing their sensitivity to natural plant-associated defense mechanisms.