From nature versus nurture, via nature and nurture, to gene x environment interaction in mental disorders

It is now generally accepted that complex mental disorders are the results of interplay between genetic and environmental factors. This holds out the prospect that by studying G x E interplay we can explain individual variation in vulnerability and resilience to environmental hazards in the development of mental disorders. Furthermore studying G x E findings may give insights in neurobiological mechanisms of psychiatric disorder and so improve individualized treatment and potentially prevention. In this paper, we provide an overview of the state of field with regard to G x E in mental disorders. Strategies for G x E research are introduced. G x E findings from selected mental disorders with onset in childhood or adolescence are reviewed [such as depressive disorders, attention-deficit/hyperactivity disorder (ADHD), obesity, schizophrenia and substance use disorders]. Early seminal studies provided evidence for G x E in the pathogenesis of depression implicating 5-HTTLPR, and conduct problems implicating MAOA. Since then G x E effects have been seen across a wide range of mental disorders (e.g., ADHD, anxiety, schizophrenia, substance abuse disorder) implicating a wide range of measured genes and measured environments (e.g., pre-, peri- and postnatal influences of both a physical and a social nature). To date few of these G x E effects have been sufficiently replicated. Indeed meta-analyses have raised doubts about the robustness of even the most well studied findings. In future we need larger, sufficiently powered studies that include a detailed and sophisticated characterization of both phenotype and the environmental risk.

International survey of primary and revision total knee replacement

Purpose Total knee arthroplasty (TKA) is currently the international standard of care for treating degenerative and rheumatologic knee joint disease, as well as certain knee joint fractures. We sought to answer the following three research questions: (1) What is the international variance in primary and revision TKA rates around the world? (2) How do patient demographics (e.g., age, gender) vary internationally? (3) How have the rates of TKA utilization changed over time? Methods The survey included 18 countries with a total population of 755 million, and an estimated 1,324,000 annual primary and revision total knee procedures. Ten national inpatient databases were queried for this study from Canada, the United States, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, and Switzerland. Inpatient data were also compared with published registry data for eight countries with operating arthroplasty registers (Denmark, England & Wales, Norway, Romania, Scotland, Sweden, Australia, and New Zealand). Results The average and median rate of primary and revision (combined) total knee replacement was 175 and 149 procedures/100,000 population, respectively, and ranged between 8.8 and 234 procedures/100,000 population. We observed that the procedure rate significantly increased over time for the countries in which historical data were available. The compound annual growth in the incidence of TKA ranged by country from 5.3% (France) to 17% (Portugal). We observed a nearly 27-fold range of TKA utilization rates between the 18 different countries included in the survey. Conclusion It is apparent from the results of this study that the demand for TKA has risen substantially over the past decade in countries around the world.

Neuroimaging Auditory Hallucinations in Schizophrenia: From Neuroanatomy to Neurochemistry and Beyond

Despite more than 2 decades of neuroimaging investigations, there is currently insufficient evidence to fully understand the neurobiological substrate of auditory hallucinations (AH). However, some progress has been made with imaging studies in patients with AH consistently reporting altered structure and function in speech and language, sensory, and nonsensory regions. This report provides an update of neuroimaging studies of AH with a particular emphasis on more recent anatomical, physiological, and neurochemical imaging studies. Specifically, we provide (1) a review of findings in schizophrenia and nonschizophrenia voice hearers, (2) a discussion regarding key issues that have interfered with progress, and (3) practical recommendations for future studies.

177Lu-AMBA: Synthesis and characterization of a selective 177Lu-labeled GRP-R agonist for systemic radiotherapy of prostate cancer

Gastrin-releasing peptide receptors (GRP-R) are upregulated in many cancers, including prostate, breast, and lung. We describe a new radiolabeled bombesin (BBN) analog for imaging and systemic radiotherapy that has improved pharmacokinetics (PK) and better retention of radioactivity in the tumor. METHODS: DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2 (AMBA) was synthesized and radiolabeled. The human prostate cancer cell line PC-3 was used to determine the binding (Kd), retention, and efflux of 177Lu-AMBA. Receptor specificity was determined by in vitro autoradiography in human tissues. PK and radiotherapy studies were performed in PC-3 tumor-bearing male nude mice. RESULTS: 177Lu-AMBA has a high affinity for the GRP-R (Kd, 1.02 nmol/L), with a maximum binding capacity (Bmax) of 414 fmol/10(6) cells (2.5 x 10(5) GRP-R/cell). Internalization was similar for 177Lu-AMBA (76.8%), 177Lu-BBN8 (72.9%), and 125I-[Tyr4]-BBN (74.9%). Efflux was markedly lower for 177Lu-AMBA (2.9%) compared with 177Lu-BBN8 (15.9%) and 125I-[Tyr4]-BBN (46.1%). By receptor autoradiography, Lu-AMBA binds specifically to GRP-R (0.8 nmol/L) and to the neuromedin B receptor (NMB-R) (0.9 nmol/L), with no affinity for the bb3 receptor (>1,000 nmol/L). 177Lu-AMBA was renally excreted (55 %ID 1 h [percentage injected dose at 1 h]); tumor uptake at 1 and 24 h was 6.35 %ID/g and 3.39 %ID/g, respectively. One or 2 doses of 177Lu-AMBA (27.75 MBq/dose) significantly prolonged the life span of PC-3 tumor-bearing mice (P < 0.001 and P < 0.0001, respectively) and decreased PC-3 tumor growth rate over controls. When compared using World Health Organization criteria, mice receiving 2 doses versus 1 dose of 177Lu-AMBA demonstrated a shift away from stable/progressive disease toward complete/partial response; by RECIST (Response Evaluation Criteria in Solid Tumors), median survival increased by 36% and time to progression/progression-free survival increased by 65%. CONCLUSION: 177Lu-AMBA binds with nanomolar affinity to GRP-R and NMB-R, has low retention of radioactivity in kidney, demonstrates a very favorable risk-benefit profile, and is in phase I clinical trials.

Novel pressure-to-cornea index in glaucoma

BACKGROUND: Several conversion tables and formulas have been suggested to correct applanation intraocular pressure (IOP) for central corneal thickness (CCT). CCT is also thought to represent an independent glaucoma risk factor. In an attempt to integrate IOP and CCT into a unified risk factor and avoid uncertain correction for tonometric inaccuracy, a new pressure-to-cornea index (PCI) is proposed. METHODS: PCI (IOP/CCT(3)) was defined as the ratio between untreated IOP and CCT(3) in mm (ultrasound pachymetry). PCI distribution in 220 normal controls, 53 patients with normal-tension glaucoma (NTG), 76 with ocular hypertension (OHT), and 89 with primary open-angle glaucoma (POAG) was investigated. PCI's ability to discriminate between glaucoma (NTG+POAG) and non-glaucoma (controls+OHT) was compared with that of three published formulae for correcting IOP for CCT. Receiver operating characteristic (ROC) curves were built. RESULTS: Mean PCI values were: Controls 92.0 (SD 24.8), NTG 129.1 (SD 25.8), OHT 134.0 (SD 26.5), POAG 173.6 (SD 40.9). To minimise IOP bias, eyes within the same 2 mm Hg range between 16 and 29 mm Hg (16-17, 18-19, etc) were separately compared: control and NTG eyes as well as OHT and POAG eyes differed significantly. PCI demonstrated a larger area under the ROC curve (AUC) and significantly higher sensitivity at fixed 80% and 90% specificities compared with each of the correction formulas; optimum PCI cut-off value 133.8. CONCLUSIONS: A PCI range of 120-140 is proposed as the upper limit of "normality", 120 being the cut-off value for eyes with untreated pressures or=22 mm Hg. PCI may reflect individual susceptibility to a given IOP level, and thus represent a glaucoma risk factor. Longitudinal studies are needed to prove its prognostic value.

Finale Fixationen, sportmotorische Leistung und eine Inhibitionshypothese. Mechanismen des "Quiet Eye"

Vielfach konnte in den letzten Jahren die Bedeutung einer langen letzten Fixation vor Bewegungsbeginn – des sogenannten "Quiet Eye" – für die sportmotorische Leistung aufgezeigt werden. Obgleich dieses Phänomens breit untersucht wurde, mangelt es bislang an einer zufriedenstellenden Erklärung. In diesem Beitrag werden daher aktuelle Erklärungsversuche diskutiert. Es zeigt sich, dass vorliegende Beiträge aus der Kognitions- und der ökologischen Psychologie konzeptuelle oder methodische Mängel aufweisen. Aus diesen Gründen wird – zunächst für Aufgaben mit hohen Präzisionsanforderungen – ein Inhibitionsmechanismus zur Erklärung des Quiet-Eye-Phänomens vorgeschlagen mit der zentralen Aussage, dass die Verarbeitung leistungsrelevanter Hinweisreize durch ein "ruhiges Auge" von Störungen abgeschirmt wird. Abschließend kann gezeigt werden, dass sich der vorgeschlagene Mechanismus mit der bestehenden Befundlage als kompatibel erweist und er die Ableitung weitergehender Vorhersagen erlaubt.

The “Out of Africa Tribe” (II): Paleolithic warriors with big canoes and protective weapons

It is generally difficult to establish a timeline for the appearance of different technologies and tools during human cultural evolution. Here I use stochastic character mapping of discrete traits using human mtDNA phylogenies rooted to the Reconstructed Sapiens Reference Sequence (RSRS) as a model to address this question. The analysis reveals that the ancestral state of Homo sapiens was hunting, using material innovations that included bows and arrows, stone axes and spears. However, around 80,000 y before present, a transition occurred, from this ancestral hunting tradition, toward the invention of protective weapons such as shields, the appearance of ritual fighting as a socially accepted behavior and the construction of war canoes for the fast transport of large numbers of warriors. This model suggests a major cultural change, during the Palaeolithic, from hunters to warriors. Moreover, in the light of the recent Out of Africa Theory, it suggests that the “Out of Africa Tribe” was a tribe of warriors that had developed protective weapons such as shields and used big war canoes to travel the sea coast and big rivers in raiding expeditions.

Bacterial Meningitis After Sinus Surgery in Five Adult Horses.

OBJECTIVE To report meningoencephalitis as a complication after paranasal sinus surgery in 5 horses. STUDY DESIGN Case series. ANIMALS Adult horses (n = 5). METHODS Medical records (2005-2010) of 5 horses that developed neurologic signs after sinus surgery were reviewed to identify potential risk factors, cause(s), or common pathways for infection. RESULTS Underlying diseases were primary (n = 1) and secondary sinusitis (4) because of apical dental infection (1), sinus cyst (2), or masses in the ethmoturbinate region (2). Horses were treated by conventional surgical approaches and aftercare including repeated sinus lavage. Four horses had undulating pyrexia postoperatively despite antimicrobial therapy. All horses developed neurologic signs, eventually unresponsive to treatment. Suppurative meningoencephalitis was diagnosed macro- and/or microscopically on necropsy in all horses. CONCLUSION Meningitis is a rare but fatal complication after sinus surgery in horses.