Demonstration of Muon-Beam Transverse Phase-Space Compression.

We demonstrate efficient transverse compression of a 12.5 MeV/c muon beam stopped in a helium gas target featuring a vertical density gradient and crossed electric and magnetic fields. The muon stop distribution extending vertically over 14 mm was reduced to a 0.25 mm size (rms) within 3.5 µs. The simulation including cross sections for low-energy µ^{+}-He elastic and charge exchange (µ^{+}↔ muonium) collisions describes the measurements well. By combining the transverse compression stage with a previously demonstrated longitudinal compression stage, we can improve the phase space density of a µ^{+} beam by a factor of 10^{10} with 10^{-3} efficiency.

Breast nodularity and ulceration: diffuse dermal angiomatosis a corticosteroid responsive disease.

Diffuse dermal angiomatosis of the breast (DDAB) is an uncommon ulcerative angiomatosis, which occurs in middle aged women with large pendulous breasts, a history of cigarette smoking, and risk factors for atherosclerosis. Based on its rarity, no well-defined therapeutic regimen has been elucidated. We report a case of DDAB in a woman with no history of smoking or radiographic evidence of occluded vasculature who presented with ulceration and pain-associated breast nodularity. She had a complete reproducible response to oral corticosteroids.

Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors.

Substantial evidence links alcohol drinking and serotonin (5-HT) functioning in animals. Lowered central 5-HT neurotransmission has been found in a subgroup of alcoholics, possibly those with more aggressive, assaultive tendencies. Several rodent studies have also suggested that intact 5-HT systems are important determinants of sensitivity and/or tolerance to ethanol-induced ataxia and hypothermia. Null mutant mice lacking the 5-HT1B receptor gene (5-HT1B-/-) have been developed that display enhanced aggression and altered 5-HT release in slice preparations from some, but not all, brain areas. We characterized these mice for sensitivity to several effects of ethanol. Mutant mice drank twice as much ethanol as wild-type mice, and voluntarily ingested solutions containing up to 20% ethanol in water. Their intake of food and water, and of sucrose, saccharin and quinine solutions, was normal. Mutants were less sensitive than wild-types on a test of ethanol-induced ataxia and, with repeated drug administration, tended to develop tolerance more slowly. In tests of ethanol withdrawal and metabolism, mutants and wild-type mice showed equivalent responses. Our results suggest that the 5-HT1B receptor participates in the regulation of ethanol drinking, and demonstrate that serotonergic manipulations lead to reduced responsiveness to certain ataxic effects of ethanol without affecting dependence.

Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2.

The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

An RCT to compare a bio-cellulose wound dressing with a non-adherent dressing in VLUs.

OBJECTIVE: To compare the efficacy of a bio-cellulose dressing (BWD) versus a non-adherent wound contact layer in venous leg ulcer (VLU) outpatients. METHOD: In a prospective, randomised, controlled multicentre study, 48 VLU patients were randomised to receive compression bandages and either standard care (non-adherent dressing; n=23) or a BWD (Suprasorb X; n=25). VLUs were evaluated for debridement efficacy, time to 75-100% granulation and ≥ 50% re-epithelialisation, reduction of ulcer size and patient-reported ulcer pain, comparing the status at day 0 and weekly, over a 12-week study treatment period. RESULTS: Thirty-three patients (n=18 BWD and n=15 control dressing) were included in the analysis. Autolytic debridement was significantly faster in the BWD group, with an 84% removal of yellow tissue compared with 26% in the control group, over the 12-week period (p < 0.0001). A median of 25 days were required to achieve 75-100% granulation in the BWD group vs 36 days for controls. A median of 36 days was taken to achieve ≥ 50% re-epithelialisation in the BWD group vs 50 days for controls. Patient-reported ulcer pain reduced significantly faster in the BWD group (p < 0.05), by week 7, 100% of patients reported no pain, compared with 63% of controls. CONCLUSION: Autolytic debridement was faster and more effective in the BWD group compared with standard care, as was pain reduction. Although the time to healing was shorter with the BWD vs standard care, the difference was not statistically significant. DECLARATION OF INTEREST: This study was supported by Xylos Corporation. The study product was called X-Cell at the time, and is now available as Suprasorb X (Lohmann & Rauscher). Each principal investigator (Alvarez, Phillips, Menzoian, Etris-Brown) and respective clinical centre received funding for the conduct of the study. Each site executed a clinical study agreement independently with the sponsor. The sponsors had no role in the design and conduct of the study, in the collection, analysis, or interpretation of data, or in the preparation of the manuscript, review, or approval of the manuscript. None of the authors received administrative, technical or material support for the conduct of this study. The authors have no relevant financial interest in this article.

Peri-adolescent exposure to (meth)amphetamine in animal models.

Experimentation with psychoactive drugs is often initiated in the peri-adolescent period, but knowledge of differences in the outcomes of peri-adolescent- vs adult-initiated exposure is incomplete. We consider the existing animal research in this area for (meth)amphetamines. Established for a number of phenotypes, is lower sensitivity of peri-adolescents than adults to acute effects of (meth)amphetamines, including neurotoxic effects of binge-level exposure. More variable are data for long-term consequences of peri-adolescent exposure on motivational and cognitive traits. Moreover, investigations often exclude an adult-initiated exposure group critical for answering questions about outcomes unique to peri-adolescent initiation. Despite this, it is clear from the animal research that (meth)amphetamine exposure during the peri-adolescent period, whether self- or other-administered, impacts brain motivational circuitry and cognitive function, and alters adult sensitivity to other drugs and natural rewards. Such consequences occurring in humans have the potential to predispose toward unfortunate and potentially disastrous family, social and livelihood outcomes.

Non-genetic factors that influence methamphetamine intake in a genetic model of differential methamphetamine consumption.

RATIONALE: Genetic and non-genetic factors influence substance use disorders. Our previous work in genetic mouse models focused on genetic factors that influence methamphetamine (MA) intake. The current research examined several non-genetic factors for their potential influence on this trait. OBJECTIVES: We examined the impact on MA intake of several non-genetic factors, including MA access schedule, prior forced MA exposure, concomitant ethanol (EtOH) access, and gamma-aminobutyric acid type B (GABAB) receptor activation. Selectively bred MA high drinking (MAHDR) and low drinking (MALDR) mice participated in this research. RESULTS: MAHDR, but not MALDR, mice increased MA intake when given intermittent access, compared with continuous access, with a water choice under both schedules. MA intake was not altered by previous exposure to forced MA consumption. Male MAHDR mice given simultaneous access to MA, EtOH, and an EtOH+MA mixture exhibited a strong preference for MA over EtOH and EtOH+MA; MA intake was not affected by EtOH in female MAHDR mice. When independent MAHDR groups were given access to MA, EtOH, or EtOH+MA vs. water in each case, MA intake was reduced in the water vs. EtOH+MA group, compared with the water vs. MA group. The GABAB receptor agonist R(+)-baclofen (BAC) not only reduced MA intake but also reduced water intake and locomotor activity in MAHDR mice. There was a residual effect of BAC, such that MA intake was increased after termination of BAC treatment. CONCLUSIONS: These findings demonstrate that voluntary MA intake in MAHDR mice is influenced by non-genetic factors related to MA access schedule and co-morbid EtOH exposure.

Chondromalacia of the cranial medial femoral condyle; its occurrence and association with clinical outcome in a population of adult horses with stifle lameness.

BACKGROUND: Chondromalacia of the cranial medial femoral condyle (CMFC) is a potential cause of stifle lameness in adult horses. However, there is scant published evidence of either its occurrence or its clinical significance. OBJECTIVES: To document the occurrence of CMFC seen during diagnostic arthroscopy in adult horses with stifle lameness and to investigate its prognostic significance. STUDY DESIGN: Retrospective cohort study. METHODS: The records were reviewed of all horses with unilateral or bilateral lameness localised to the stifle that underwent diagnostic arthroscopy of the cranial medial femorotibial joint at a UK equine hospital. The surgical findings were noted from each. Case outcomes were determined by unstructured telephone discussions with owners. A satisfactory outcome was defined as a horse that was in ridden work without ongoing anti-inflammatory medication. Multivariable logistic regression was used to create a model with an outcome time point at 12-month post-operatively. RESULTS: One hundred and four horses were included in the study. CMFC was found in 79. In 25 CMFC was the only finding, 54 horses had CMFC plus other pathology and 25 had other pathology, but no CMFC. At 12 months, horses with CMFC were 9.9 (95% CI 2.2-45.0, P<0.01) times more likely to have an unsatisfactory outcome than horses without CMFC. MAIN LIMITATIONS: The study relied on retrospective analysis of clinical notes and archived arthroscopy videos. Assessment of outcome was determined by unstructured telephone interview and therefore there is potential for reporting errors to exist. CONCLUSIONS: CMFC is a common arthroscopic finding in horses with stifle lameness and is significantly associated with an increased likelihood of the horse not being in ridden work at long-term follow-up.

Maternal antioxidant treatment prevents the adverse effects of prenatal stress on the offspring's brain and behavior.

Maternal exposure to stress during pregnancy is associated with an increased risk of psychiatric disorders in the offspring in later life. The mechanisms through which the effects of maternal stress are transmitted to the fetus are unclear, however the placenta, as the interface between mother and fetus, is likely to play a key role. Using a rat model, we investigated a role for placental oxidative stress in conveying the effects of maternal social stress to the fetus and the potential for treatment using a nanoparticle-bound antioxidant to prevent adverse outcomes in the offspring. Maternal psychosocial stress increased circulating corticosterone in the mother, but not in the fetuses. Maternal stress also induced oxidative stress in the placenta, but not in the fetal brain. Blocking oxidative stress using an antioxidant prevented the prenatal stress-induced anxiety phenotype in the male offspring, and prevented sex-specific neurobiological changes, specifically a reduction in dendrite lengths in the hippocampus, as well as reductions in the number of parvalbumin-positive neurons and GABA receptor subunits in the hippocampus and basolateral amygdala of the male offspring. Importantly, many of these effects were mimicked in neuronal cultures by application of placental-conditioned medium or fetal plasma from stressed pregnancies, indicating molecules released from the placenta may mediate the effects of prenatal stress on the fetal brain. Indeed, both placenta-conditioned medium and fetal plasma contained differentially abundant microRNAs following maternal stress, and their predicted targets were enriched for genes relevant to nervous system development and psychiatric disorders. The results highlight placental oxidative stress as a key mediator in transmitting the maternal social stress effects on the offspring's brain and behavior, and offer a potential intervention to prevent stress-induced fetal programming of affective disorders.

Image-guided, stereotactic perforator flap surgery: a prospective comparison of current techniques and review of the literature.

BACKGROUND: Image-guided stereotaxy is a recent advancement in imaging technology, allowing computer guidance to aid surgical planning and accuracy. Despite the use of multiple techniques for patient registration in several surgical specialities, only fiducial marker registration has been described for use in soft tissue reconstructive surgery. The current study comprises an evaluation of the current techniques available for this purpose. METHODS: A cohort of nine consecutive patients planned for elective free flaps were recruited, with the first five patients (four for the abdominal wall and one anterolateral thigh donor site) undergoing fiducial marker registration with a variable number of fiducial markers in order to determine the optimal number of fiducial markers to be used. Four subsequent patients undergoing perforator flap surgery underwent registration using three available registration modalities: fiducial marker registration, surface matching pointer/landmark and surface matching laser registration. RESULTS: For the abdominal wall, registration was not able to be achieved with five fiducial markers, and was successfully achieved in all cases with either six or seven fiducial markers. For the anterolateral thigh, registration was achieved with either nine or ten markers. The four patients who also underwent surface-landmark registration and 'Z-touch' laser surface matching registration all failed the registration process. CONCLUSION: Stereotactic navigation is a useful adjunct to the preoperative imaging of perforator flaps. Fiducial marker registration was able to be achieved in all cases, can be successfully achieved with a low and predictable number of fiducial markers, is highly accurate, and was the only reliable registration process in our experience.

Pathological margins and advanced cutaneous squamous cell carcinoma of the head and neck.

OBJECTIVE: The recommended treatment for cutaneous squamous cell cancer (CuSCC) of the head and neck is Mohs surgical excision or wide local excision. Excision is recommended to a gross surgical margin of 4-6 mm however this is based on limited evidence and specify a goal histologic margin. The objective of this study was therefore to examine the reported histological margin distance following WLE of advanced CuSCC and its association with recurrence and survival. STUDY DESIGN: Retrospective database review. SETTING: All patients included received treatment at UC Davis Department of Otolaryngology-Head and Neck Surgery and/or Radiation Oncology in Sacramento, California. SUBJECTS AND METHODS: The patients included were treated for advanced CuSCC with primary surgery with or without adjuvant therapy. Kaplan Meier survival curves with log rank analysis were then performed to compare 5-year recurrence free survival, and disease-specific survival for patients with different margin distances. RESULTS: Total number of subjects was 92. The overall 5-year DSS and RFS was 68.8 and 51.0% respectively. When the pathological margin distance was ≥5 mm, 5-year disease specific survival was improved when compared to margin distance less than 5 mm (94.7 vs 60.7 p = 0.034). CONCLUSION: The findings of this study suggest that a histologic margin of at least 5 mm may increase survival in advanced head and neck CuSCC patients.

Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors.

Although dopaminergic transmission has been strongly implicated in alcohol self-administration, the involvement of specific dopamine receptor subtypes has not been well established. We studied the ethanol preference and sensitivity of D2-receptor-deficient mice to directly evaluate whether dopamine D2 receptors contribute to alcohol (ethanol) consumption. We report a marked aversion to ethanol in these mice, relative to the high preference and consumption exhibited by wild-type littermates. Sensitivity to ethanol-induced locomotor impairment was also reduced in these mutant mice, although they showed a normal locomotor depressant response to the dopamine D1 antagonist SCH-23390. These data demonstrate that dopamine signaling via D2 receptors is an essential component of the molecular pathway determining ethanol self-administration and sensitivity.

Stereotactic image-guided navigation in the preoperative imaging of perforators for DIEP flap breast reconstruction.

Preoperative imaging is sought prior to DIEA (Deep Inferior Epigastric Artery) perforator flaps due to the potential for maximizing operative success and minimizing operative complications. Recent advances include the use of computed tomography (CT) angiography (CTA) and magnetic resonance angiography. Image-guided stereotactic surgery is a recent technique that has been used with success in several fields of surgery. The variability of perforator anatomy makes DIEA perforator flap surgery a suitable candidate for such technology, but as yet this has not been described. A study was undertaken to determine the feasibility of CT-guided stereotaxy technique in DIEA perforator flap surgery and to compare findings with both conventional CTA and operative findings. Five consecutive patients planned for an elective DIEA perforator flap were recruited. Each patient underwent preoperative imaging of the anterior abdominal wall vasculature with both conventional CTA and CT-guided stereotactic imaging. Imaging findings were compared to operative findings. In all cases, all the major perforators were accurately localized with stereotactic imaging and with conventional CTA. Stereotactic navigation demonstrated a slightly better (nonsignificant) correlation with perforator location than conventional CTA. As such, CT-guided stereotactic imaging is an accurate method for the preoperative planning of DIEA perforator flaps, providing additional and potentially more accurate data to conventional CTA. With no additional scanning required, the method described in this paper allows the combined use of both methods for preoperative planning.

Establishing the case for CT angiography in the preoperative imaging of abdominal wall perforators.

Preoperative imaging of the donor site vasculature for deep inferior epigastric artery (DIEA) perforator flaps and other abdominal wall reconstructive flaps has become more commonplace. Abdominal wall computed tomography angiography (CTA) has been described as the most accurate and reproducible modality available for demonstrating the location, size, and course of individual perforators. We drew on our experience of 75 consecutive patients planned for DIEA-based flap surgery undertaking CTA at a single institution. Seven of these cases have been reported to highlight the utility of CTA for preoperative planning, emphasizing the unique information supplied by CTA that may influence operative outcome. Among all cases that underwent preoperative imaging with CTA, there was 100% flap survival, with no partial or complete flap necrosis. We found that in three of the cases described, the choice of operation was necessarily selected based on CTA findings (DIEA perforator flap, transverse rectus abdominis myocutaneous flap, and superficial superior epigastric artery flap). In addition, three cases demonstrate that CTA findings may dictate the decision to operate at all, and one case demonstrates the utility of CTA for evaluating the entire abdominal contents for comorbid conditions. Our experience with CTA for abdominal wall perforator mapping has been highly beneficial. CTA may guide operative technique and improve perforator selection in uncomplicated cases, and in difficult cases it can guide the most appropriate operation or indeed if an operation is appropriate at all. This is particularly the case in the setting of comorbidities or previous abdominal surgery.

Developments in perforator imaging for the anterolateral thigh flap: CT angiography and CT-guided stereotaxy.

INTRODUCTION: The anterolateral thigh flap is an increasingly popular reconstructive option despite uncertainty in its perforator anatomy. Perforators are not always present, vary in size and intramuscular course, and have variable cutaneous courses and supply. As such, preoperative imaging has become favored. METHODS: The current study describes the preliminary use of two new modalities for preoperative imaging: computed tomography (CT) Angiography and CT-guided stereotaxy. These have been utilized in the preoperative imaging of two patients undergoing ALT flap reconstruction. Each patient underwent each of these techniques combined with Doppler ultrasound, the previous standard modality. The size, location, and course of perforators were explored and compared with operative findings. RESULTS: Both techniques are technically feasible, highly accurate, and provide more information to the surgeon than ultrasound. CONCLUSION: CT Angiography and CT-guided stereotaxy are useful adjuncts to Doppler ultrasound for imaging perforators prior to ALT flaps. A larger study is suggested to quantify the accuracy of these techniques.

Treatment of medial condylar fractures of the third metatarsus in three horses with fibreglass casts under standing neuroleptanalgesia.

Minimally displaced condylar fractures propagating into the third metatarsal diaphysis were treated conservatively in one thoroughbred and two Arabian racehorses. In each case a neuroleptanalgesic protocol provided adequate pain relief for a rigid fibreglass cast to be applied in a weight-bearing position. The fractures healed completely and the three horses recovered uneventfully. Two of them returned successfully to racing and the third was used for breeding.

Electrosurgery as the sole means of haemostasis during the laparoscopic removal of pathologically enlarged ovaries in mares: a report of 55 cases.

REASONS FOR PERFORMING STUDY: There is little published clinical evidence on the use of a laparoscopic approach for the removal of pathologically enlarged ovaries in standing mares. OBJECTIVES: To show the orders of success and complication rates that can be expected if pathologically enlarged ovaries are removed from standing, sedated mares under laparoscopic guidance using only electrosurgical means of haemostasis. METHODS: A retrospective analysis was made of 55 mares in which the removal of an enlarged ovary was attempted by applying a standard laparoscopic procedure for routine ovariectomy in standing mares including a reliance solely on one of 2 types of electrosurgical bipolar forceps with an integrated guillotine for haemostasis and transection of the ovarian pedicle. The outcomes and complications encountered were recorded. Logistic regression analysis was performed to identify the risk of any complications associated with the size of the ovary removed and the instrument used. RESULTS: In 54 of the 55 mares, the surgery was successfully accomplished by the planned approach. In one mare there was significant intraoperative haemorrhage and this necessitated the additional use of a prosthetic haemostatic device. The only other complications encountered were post operative abdominal discomfort (n = 9), delayed incisional wound healing (n = 6) and iatrogenic uterine puncture (n = 2). One mare developed a rectal tear, but not as a direct complication of the surgical procedure. None of these prevented a long-term successful outcome. CONCLUSIONS: The removal of pathologically enlarged ovaries (up to 30 cm diameter) from mares under standing sedation can be accomplished predictably and safely by applying the standard laparoscopic approach that is established for routine laparoscopic ovariectomy, including a reliance solely on endoscopic electrosurgery instruments for haemostasis of the ovarian pedicle. POTENTIAL RELEVANCE: This study shows that the simple standing laparoscopic technique now favoured for routine ovariectomy can be used safely and reliably for the removal of pathologically enlarged ovaries. This promises to be of significant clinical advantage to mares so affected.

Sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone: a quantitative trait locus study of common genetic influence.

Previous studies have suggested that common genetic mechanisms influence sensitivity to the locomotor-stimulant effects of ethanol and allopregnanolone. We conducted two quantitative trait locus (QTL) studies to identify chromosomal regions that harbor genes that influence locomotor response to ethanol (2 g/kg) and allopregnanolone (17 mg/kg) using F2 crosses between C57BL/6J and DBA/2J mice. Because our previous data from the BXD recombinant inbred strains had indicated that chromosome 2 contained QTL for sensitivity to the locomotor-stimulant effects of both ethanol and allopregnanolone, we also tested reciprocal chromosome 2 congenic strains for sensitivity to the locomotor-stimulant effects of both drugs. The F2 analysis for ethanol sensitivity identified significant QTL on chromosomes 1 and 2 and suggestive QTL on chromosomes 5 and 9. The analysis of the allopregnanolone F2 study identified suggestive QTL on chromosomes 3, 5 and 12. Suggestive evidence for a female-specific QTL on chromosome 2 was also found. The studies of congenic mouse strains indicated that both the congenic strains captured one or more QTL for sensitivity to the locomotor-stimulant effects of both ethanol (2 g/kg) and allopregnanolone (17 mg/kg). When Fisher's method was used to combine the P values for the RI, F2 and congenic studies of the chromosome 2 QTL, cumulative probability scores of 9.6 x 10(-15) for ethanol and 7.7 x 10(-7) for allopregnanolone were obtained. These results confirm the presence of QTL for ethanol and allopregnanolone sensitivity in a common region of chromosome 2 and suggest possible pleiotropic genetic influence on sensitivity to these drugs.

Corticotropin-releasing factor receptor type 2-deficient mice display impaired coping behaviors during stress.

Two cognate receptors (CRF(1) and CRF(2)) mediate the actions of the stress-regulatory corticotropin-releasing factor (CRF) family of peptides. Defining the respective roles of these receptors in the central nervous system is critical in understanding stress neural circuitry and the development of psychiatric disorders. Here, we examined the role of CRF(2) in several paradigms that assess coping responses to stress. We report that CRF(2) knockout mice responded to a novel setting with increased aggressive behavior toward a bulbectomized conspecific male and show increased immobility during acute swim stress compared with wild-type mice. In addition, CRF(2)-deficient mice exhibited impaired adaptation to isolation stress as evinced by prolonged hypophagia and associated weight loss. Collectively, these results point toward a role for CRF(2) pathways in neural circuits that subserve stress-coping behaviors.

Identifying genes for alcohol and drug sensitivity: recent progress and future directions.

New methods for identifying chromosomal regions containing genes that affect murine responses to alcohol and drugs have been used to identify many provisional quantitative trait loci (QTLs) since 1991. By 1998, 24 QTLs had been definitively mapped (P<5x10(-5)) to specific murine chromosomes, which indicates the presence of a relevant gene or genes at each location. The syntenic (homologous) region of the human genome for these genes is often known. For many mapped QTLs, candidate genes with relevant neurobiological function lie within the mapped region. Data that implicate candidate genes for specific responses include studies of knockout animals. Current strategies for gene identification include the use of congenic strains containing QTL regions introduced from another strain. There is increasing emphasis on gene-gene and gene-environment interactions in such studies.