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Introduction: Dorsal root ganglion pulsed radiofrequency (DRG-PRF) is frequently used for the treatment of chronic lumbar radicular pain with good outcomes in terms of pain management. Transforaminal epidural steroid injection (TFESI) is often administered immediately after DRG-PRF to increase the anti-inflammatory effects, but support for the synergic mechanism is lacking in the literature. The aim of this study was to investigate the potential role of TFESI immediately after DRG-PRF and its possible role on pain intensity and patient disability. Methods: A database of patients who underwent DRG-PRF with or without TFESI immediately after DRG-PRF was retrospectively analysed; propensity score matching was applied to the analysis to reduce possible bias. Pain intensity (numerical rating scale [NRS]) and Oswestry disability index (ODI) were recorded pre-operatively and at the 1- and 3-month follow-up in the two groups of patients. Results: A total of 252 patients were included in this retrospective analysis, 126 patients in the DRG-PRF + TFESI group and 126 patients in the DRG-PRF group after propensity score matching. Both groups displayed a significant reduction in pain intensity (NRS score reduction; p< 0.0001) and improvement in the ODI (p< 0.0001) from baseline at the 3-month follow-up. Interestingly, the use of TFESI after DRG-PRF was not associated with any clinical benefit as no difference in NRS and ODI was found between the two groups at the 1- and 3-month follow-ups. Conclusions: Our study revealed a significant pain reduction and disability improvement after DRG-PRF in patients with lumbar radicular pain. Interestingly, no positive role of TFESI immediately after DRG-PRF was observed. These findings suggest that DRG-PRF provides substantial pain relief, and no added benefit is obtained with subsequent steroid injection. Future prospective studies with expanded follow-up periods are needed to confirm these findings.

Neuroimaging research requires purpose-built analysis software, which is challenging to install and may produce different results across computing environments. The community-oriented, open-source Neurodesk platform (https://www.neurodesk.org/) harnesses a comprehensive and growing suite of neuroimaging software containers. Neurodesk includes a browser-accessible virtual desktop, command-line interface and computational notebook compatibility, allowing for accessible, flexible, portable and fully reproducible neuroimaging analysis on personal workstations, high-performance computers and the cloud.

Long-chain polyunsaturated fatty acids (LCPUFAs) are critical for fetal brain development. Infants born to preeclamptic mothers or those born growth restricted due to placental insufficiency have reduced LCPUFA and are at higher risk for developing neurodevelopmental disorders. Since plasma levels of testosterone (T) and fatty acid-binding protein 4 (FABP4) are elevated in preeclampsia, we hypothesized that elevated T induces the expression of FABP4 in the placenta leading to compromised transplacental transport of LCPUFAs. Increased maternal T in pregnant rats significantly decreased n-3 and n-6 LCPUFA levels in maternal and fetal circulation, but increased their placental accumulation. Dietary LCPUFAs supplementation in T dams increased LCPUFA levels in the maternal circulation and further augmented placental storage, while failing to increase fetal levels. The placenta in T dams exhibited increased FABP4 mRNA and protein levels. In vitro, T dose-dependently upregulated FABP4 transcription in trophoblasts. Testosterone stimulated androgen receptor (AR) recruitment to the androgen response element and trans-activated FABP4 promoter activity, both of which were abolished by AR antagonist. Testosterone in pregnant rats and cultured trophoblasts significantly reduced transplacental transport of C14-docosahexaenoic acid (DHA) and increased C14-DHA accumulation in the placenta. Importantly, FABP4 overexpression by itself in pregnant rats and trophoblasts increased transplacental transport of C14-DHA with no significant placental accumulation. Testosterone exposure, in contrast, inhibited this FABP4-mediated effect by promoting C14-DHA placental accumulation.In summary, our studies show that maternal hyperandrogenism increases placental FABP4 expression via transcriptional upregulation and preferentially routes LCPUFAs toward cellular storage in the placenta leading to offspring lipid deficiency.Graphical Abstract

At the time when prehistoric populations were uprooting and relocating themselves across much of the Southwest, an influx of thousands of immigrants possibly arrived onto the elevated and windswept terrain of Perry Mesa in central Arizona. During the Late Classic (A.D. 1280–1400), the expanded populations built large and imposing pueblos equally spaced along the mesa edge and overlooking 1000-foot cliffs. How so many people moved to Perry Mesa in late prehistory is a question we address with survey and ceramic analyses. We assess three migration scenarios: (1) a rapid deployment of a large population en masse for defense; (2) a prolonged migration stream, whereby newcomers steadily arrived to join founder groups, and (3) a scenario that truly was not a migration at all, but rather a local reorganization including the construction of the big pueblos. We also consider how the Perry Mesa case contributes to theory building for migration processes.

Normal-weight women with polycystic ovary syndrome (PCOS) may have adipose tissue insulin resistance (adipose-IR).

During the early fourteenth century, perhaps thousands of migrants arrived atop the windswept landscape of Perry Mesa, in central Arizona. They built large massive room blocks strategically overlooking the access routes onto the mesa rim. A key to understanding the migration process is documenting the number of antecedent residents on the mesa and their settlement distribution. Different migration processes are implied if the mesa top was virtually vacant, moderately settled, or densely clustered immediately prior to the migrants’ arrival. Unfortunately, documenting the antecedent settlement pattern has been largely stymied by poor temporal control, which has left the antecedent remains largely invisible archaeologically. To fill the chronometric gap, Scott Wood (2014 Antecedents II: A Progress Report on the Origins of the Perry Mesa Settlement and Conflict Management System. Paper prepared for Fall 2012 Arizona Archaeological Council Conference; publication of proceedings pending) has recently described ceramic signatures for different time periods. In this paper, we test the validity and utility of Wood's Early Classic and Late Classic signatures. We then apply the dating refinements to better reconstruct the Perry Mesa migration process.

IMPORTANCE: The US Preventive Services Task Force recommends annual lung cancer screening (LCS) with low-dose computed tomography for current and former heavy smokers aged 55 to 80 years. There is little published experience regarding implementing this recommendation in clinical practice. OBJECTIVES: To describe organizational- and patient-level experiences with implementing an LCS program in selected Veterans Health Administration (VHA) hospitals and to estimate the number of VHA patients who may be candidates for LCS. DESIGN, SETTING, AND PARTICIPANTS: This clinical demonstration project was conducted at 8 academic VHA hospitals among 93 033 primary care patients who were assessed on screening criteria; 2106 patients underwent LCS between July 1, 2013, and June 30, 2015. INTERVENTIONS: Implementation Guide and support, full-time LCS coordinators, electronic tools, tracking database, patient education materials, and radiologic and nodule follow-up guidelines. MAIN OUTCOMES AND MEASURES: Description of implementation processes; percentages of patients who agreed to undergo LCS, had positive findings on results of low-dose computed tomographic scans (nodules to be tracked or suspicious findings), were found to have lung cancer, or had incidental findings; and estimated number of VHA patients who met the criteria for LCS. RESULTS: Of the 4246 patients who met the criteria for LCS, 2452 (57.7%) agreed to undergo screening and 2106 (2028 men and 78 women; mean [SD] age, 64.9 [5.1] years) underwent LCS. Wide variation in processes and patient experiences occurred among the 8 sites. Of the 2106 patients screened, 1257 (59.7%) had nodules; 1184 of these patients (56.2%) required tracking, 42 (2.0%) required further evaluation but the findings were not cancer, and 31 (1.5%) had lung cancer. A variety of incidental findings, such as emphysema, other pulmonary abnormalities, and coronary artery calcification, were noted on the scans of 857 patients (40.7%). CONCLUSIONS AND RELEVANCE: It is estimated that nearly 900 000 of a population of 6.7 million VHA patients met the criteria for LCS. Implementation of LCS in the VHA will likely lead to large numbers of patients eligible for LCS and will require substantial clinical effort for both patients and staff.

Context:Normal weight polycystic ovary syndrome (PCOS) women may have altered adipose structure-function underlying metabolic dysfunction.Objective:This study examines whether adipose structure-functional changes exist in normal weight PCOS women and correlate with hyperandrogenism and/or hyperinsulinemia.Design:This is a prospective cohort study.Setting:The setting was an academic medical center.Patients:Six normal weight PCOS women and 14 age- and body mass index-matched normoandrogenic ovulatory (NL) women were included.Intervention(s):All women underwent circulating hormone and metabolic measurements; frequently sampled intravenous glucose tolerance testing; total body dual-energy x-ray absorptiometry; abdominal magnetic resonance imaging; and SC abdominal fat biopsy.Main Outcome Measure(s):Circulating hormones and metabolites, body fat and its distribution, and adipocyte size were compared between PCOS and NL women, and were correlated with each other in all women.Results:Circulating LH and androgen levels were significantly greater in PCOS than NL women, as were fasting insulin levels, pancreatic β-cell responsiveness to glucose, and total abdominal fat mass. Intra-abdominal fat mass also was significantly increased in PCOS women and was positively correlated with circulating androgen, fasting insulin, triglyceride, and non-high-density lipoprotein cholesterol levels in all women. SC abdominal fat mass was not significantly increased in PCOS women, but contained a greater proportion of small SC abdominal adipocytes that positively correlated with serum androgen levels in all women.Conclusion:Hyperandrogenism in normal weight PCOS women is associated with preferential intra-abdominal fat deposition and an increased population of small SC abdominal adipocytes that could constrain SC adipose storage and promote metabolic dysfunction.

In the Mississippian Southeast, little is known about the economy of how craft goods were produced. Archeologists do understand to a certain degree the organization of production of certain microlithic tools, saltpans, and stone palettes and pipes, but few craft production areas have been identified. Evidence from the floor of a structure on the summit of Mound D at the Carson site, in Coahoma County, Mississippi, suggests for the production of items made of wood and shell. Recovered lithic tools may potentially have been used to craft items like shell beads and gorgets and perhaps wooden and stone statuary. This study contributes significantly to the study of craft production and suggests elites at Carson may have played a strong role in controlling valued prestige items. In addition to standard analyses of artifacts, thin-section analysis and micromorphology are techniques with great potential for identifying activities that took place on surfaces uncovered through structure excavations. With continued research, it is possible that our study will play a significant role in elucidating the role of elites in the political economy of craft production.

This study arose in the context of having to estimate risk to the musical abilities of a trained singer (patient A.M.) recommended for right anterior temporal lobectomy (RATL) to ameliorate medically intractable seizures. To date there has been no systematic investigation of reorganisation of musical functions in the presence of epileptogenic lesions, although it is well established that RATL can impair pitch processing in nonmusicians.

The interactive nature of the 8th Annual Meeting of the Androgen Excess and PCOS Society Annual Meeting in Munich, Germany (AEPCOS 2010) and subsequent exchanges between speakers led to emerging concepts in PCOS regarding its genesis, metabolic dysfunction, and clinical treatment of inflammation, metabolic dysfunction, anovulation and hirsutism. Transition of care in congenital adrenal hyperplasia from pediatric to adult providers emerged as a potential model for care transition involving PCOS adolescents.The interactive nature of the 8th Annual Meeting of the Androgen Excess and PCOS Society Annual Meeting in Munich, Germany (AEPCOS 2010) and subsequent exchanges between speakers led to emerging concepts in PCOS regarding its genesis, metabolic dysfunction, and clinical treatment of inflammation, metabolic dysfunction, anovulation and hirsutism. Transition of care in congenital adrenal hyperplasia from pediatric to adult providers emerged as a potential model for care transition involving PCOS adolescents.

Previous studies of the Hohokam have suggested that obsidian procurement and distribution practices were conducted differently between two subsequent intervals, the Sedentary and Classic periods. In the Sedentary period, obsidian may have changed hands at events associated with the ballcourt ritual. By the Classic period, obsidian is argued to have moved either through an elite-sponsored or kinship-based economy. However, the Sedentary and Classic periods are long temporal intervals, which, when used to describe changes in time, can mask short-term but significant temporal variation. Our research employs a refined dating scheme, standard lithic analysis, and X-ray fluorescence spectrometry on a sample of obsidian from the Hohokam village of Las Colinas to determine: (1) when the change in obsidian exchange patterns actually began, (2) if the transition was an immediate shift or a gradual trend, and more generally (3) the behavioral changes related to the Sedentary to Classic transition. The results of our study suggest that there was not one decisive transition in the obsidian exchange system, but rather changes in the procurement patterns (i.e., frequency and sources) at two different points in time. These shifts in the movement of obsidian were felt at Las Colinas, and perhaps across much of the Hohokam region, and were seemingly related to the demise of the ballcourt network at the end of the middle Sedentary and the later rise of platform mounds during the early Classic period.

Prenatal testosterone excess in sheep leads to reproductive and metabolic disruptions that mimic those seen in women with polycystic ovary syndrome. Comparison of prenatal testosterone-treated sheep with prenatal dihydrotestosterone-treated sheep suggests facilitation of defects by androgenic as well as androgen-independent effects of testosterone. We hypothesized that the disruptive impact of prenatal testosterone on adult pathology may partially depend on its conversion to estrogen and consequent changes in maternal and fetal endocrine environments. Pregnant Suffolk sheep were administered either cottonseed oil (control) or testosterone propionate in cottonseed oil (100 mg, i.m. twice weekly), from Day 30 to Day 90 of gestation (term is ∼147 d). Maternal (uterine) and fetal (umbilical) arterial samples were collected at Days 64–66, 87–90, and 139–140 (range; referred to as D65, D90, and D140, respectively) of gestation. Concentrations of gonadal and metabolic hormones, as well as differentiation factors, were measured using liquid chromatography/mass spectrometer, radioimmunoassay, or ELISA. Findings indicate that testosterone treatment produced maternal and fetal testosterone levels comparable to adult males and D65 control male fetuses, respectively. Testosterone treatment increased fetal estradiol and estrone levels during the treatment period in both sexes, supportive of placental aromatization of testosterone. These steroidal changes were followed by a reduction in maternal estradiol levels at term, a reduction in activin A availability, and induction of intrauterine growth restriction in D140 female fetuses. Overall, our findings provide the first direct evidence in support of the potential for both androgenic as well as estrogenic contribution in the development of adult reproductive and metabolic pathology in prenatal testosterone-treated sheep.

Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)–driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets.

Constitutive expression of the chimeric NPM/ALK fusion protein encoded by the t(2;5)(p32;q35) is a key oncogenic event in the pathogenesis of most anaplastic large cell lymphomas (ALCLs). The proteomic network alterations produced by this aberration remain largely uncharacterized. Using a mass spectrometry (MS)–driven approach to identify changes in protein expression caused by the NPM/ALK fusion, we identified diverse NPM/ALK-induced changes affecting cell proliferation, ribosome synthesis, survival, apoptosis evasion, angiogenesis, and cytoarchitectural organization. MS-based findings were confirmed using Western blotting and/or immunostaining of NPM/ALK-transfected cells and ALK-deregulated lymphomas. A subset of the proteins distinguished NPM/ALK-positive ALCLs from NPM/ALK-negative ALCLs and Hodgkin lymphoma. The multiple NPM/ALK-deregulated pathways identified by MS analysis also predicted novel biologic effects of NPM/ALK expression. In this regard, we showed loss of cell adhesion as a consequence of NPM/ALK expression in a kinase-dependent manner, and sensitivity of NPM/ALK-positive ALCLs to inhibition of the RAS, p42/44ERK, and FRAP/mTOR signaling pathways. These findings reveal that the NPM/ALK alteration affects diverse cellular pathways, and provide novel insights into NPM/ALK-positive ALCL pathobiology. Our studies carry important implications for the use of MS-driven approaches for the elucidation of neoplastic pathobiology, the identification of novel diagnostic biomarkers, and pathogenetically relevant therapeutic targets.

Abstract: Overexpression of Bcl-2 protein occurs via both t(14;18)-dependent and independent mechanisms and contributes to the survival and chemoresistance of non-Hodgkin lymphomas. HA14–1 is a nonpeptidic organic small molecule, which has been shown to inhibit the interaction of Bcl-2 with Bax, thereby interfering with the antiapoptotic function of Bcl-2. In this study, we sought to determine the in vitro efficacy of HA14–1 as a therapeutic agent for non-Hodgkin lymphomas expressing Bcl-2. Assessment of cell viability demonstrated that HA14–1 induced a dose- (IC50 = 10 μM) and time-dependent growth inhibition of a cell line (SudHL-4) derived from a t(14;18)-positive, Bcl-2-positive, non-Hodgkin lymphoma. HA14–1 effectively induced apoptosis via a caspase 3-mediated pathway but did not affect either the p38 MAPK or p44/42 MAPK pathways. Western blot analyses of Bcl-2 family proteins and other cell cycle-associated proteins were performed to determine the molecular sequelae of HA14–1-induced apoptosis. The results show down-regulation of Mcl-1 but up-regulation of p27kip1, Bad, Bcl-xL, and Bcl-2 proteins, without change in Bax levels during HA14–1-mediated apoptosis. Our findings further elucidate the cellular mechanisms accompanying Bcl-2 inhibition and demonstrate the potential of Bcl-2 inhibitors as therapeutic agents for the treatment of non-Hodgkin lymphomas.

Experimentally induced fetal androgen excess induces polycystic ovary syndrome-like traits in adult female rhesus monkeys (Macaca mulatta). Developmental changes leading to this endocrinopathy are not known. We therefore studied 15 time-mated, gravid female rhesus monkeys with known female fetuses. Nine dams received daily s.c. injections of 15 mg of testosterone propionate (TP), and six received injections of oil vehicle (control) from 40 through 80 days of gestation (term, 165 days; range, ±10 days). All fetuses were delivered by cesarean section using established methods at term. Ultrasound-guided fetal blood sample collection and peripheral venous sample collection of dams and subsequent infants enabled determination of circulating levels of steroid hormones, LH and FSH. The TP injections elevated serum testosterone and androstenedione levels in the dams and prenatally androgenized (PA) fetuses. After cessation of TP injections, testosterone levels returned to values within the reference range for animals in these age groups, whereas serum androstenedione levels in PA infants were elevated. The TP injections did not increase estrogen levels in the dams or the PA fetuses or infants, yet conjugated estrogen levels were elevated in the TP-injected dams. Serum levels of LH and FSH were elevated in late-gestation PA fetuses, and LH levels were elevated in PA infants. These studies suggest that experimentally induced fetal androgen excess increases gonadotropin secretion in PA female fetuses and infants and elevates endogenous androgen levels in PA infants. Thus, in this nonhuman primate model, differential programming of the fetal hypothalamo-pituitary unit with concomitant hyperandrogenism provides evidence to suggest developmental origins of LH and androgen excess in adulthood.

Folliculogenesis is a complex process, in which multiple endocrine and intraovarian paracrine interactions create a changing intrafollicular microenvironment for appropriate oocyte development. Within this microenvironment, bidirectional cumulus cell-oocyte signaling governs the gradual acquisition of developmental competence by the oocyte, defined as the ability of the oocyte to complete meiosis and undergo fertilization, embryogenesis, and term development. These regulatory mechanisms of follicle growth, controlled in part by the oocyte itself, are susceptible to derangement in polycystic ovary syndrome (PCOS), a heterogeneous syndrome characterized by ovarian hyperandrogenism, insulin resistance, and paracrine dysregulation of follicle development. Consequently, only a subset of PCOS patients experience reduced pregnancy outcome after ovarian stimulation for in vitro fertilization. Recent data implicate functional associations between endocrine/paracrine abnormalities, metabolic dysfunction, and altered oocyte gene expression with impaired oocyte developmental competence in women with PCOS. Therefore, an understanding of how developmentally relevant endocrine/paracrine factors interact to promote optimal oocyte developmental is crucial to identify those PCOS patients who might benefit from long-term correction of follicle growth to improve fertility, optimize follicular responsiveness to gonadotropin therapy, and enhance pregnancy outcome by in vitro fertilization.

Recent advancements in determining the production sources of prehistoric Hohokam pottery from the Phoenix basin, Arizona, have shown that ceramic manufacture was highly concentrated during the Sedentary period (ca. AD 950-1100). For example, nearly all of the bowls and small jars consumed in the lower Salt River valley were decorated red-on-buff pots imported from the middle Gila River valley to the south. An analysis of the sand temper in the buff wares showed that many, if not most, of these red-painted vessels were made in one locality along the Gila River, thereby supporting the idea that a reliable and efficient mechanism for commodity exchange was extant at that time, possibly in the form of periodic marketplaces associated with ritual ballgames. The pottery results imply a level of dependence on ballgame-related transactions that had not been recognized before, indicating their central importance to the Hohokam Sedentary period economy.

Objective. To characterize the evolution of brain activation in stroke patients with variable motor recovery and quantify changes relative to healthy controls. Methods. Serial PET activation studies, using a simple finger-tapping task, and quantitative measures of motor performance were obtained in 9 patients (2-7 weeks poststroke and 6 months later) and compared with serial healthy volunteer data. Results. Patients with moderate impairment and good recovery (n= 5) activated the primary sensorimotor cortex (SM1) contralateral to the paretic hand moved, bilateral supplementary motor area (SMA), contralateral cingulate gyrus, and ipsilateral lateral premotor cortex. Activation in the bilateral SMA was greater at the initial study but reduced over time compared to healthy controls and poor recoverers. Patients with severe impairment and poor recovery (n=4) showed limited activation of contralateral SM1 and SMA at both studies and no significant change over time. A posterior shift in SM1 activation was evident in good and poor recoverers. Conclusions.Activation of typical motor regions and recruitment of additional sites occur subacutely poststroke, with evolution to normal patterns in moderately impaired patients who recover well. In comparison, severely impaired, poor-recovery patients show persistent, reduced activation. Dynamic changes in SMA, differentially observed in good recoverers over 6 months, highlight its importance in recovery.

Background:Within dentistry, a limited body of literature exists regarding the referral relationships between general practitioners (GPs) and specialists. The purpose of this study was to investigate the referral relationship between GPs and periodontists within the state of Virginia. Methods:A survey was developed that focused on the demographic variables in the referral relationship between GPs and periodontists. The survey was mailed to 800 dentists throughout the state of Virginia. Descriptive statistics were completed along with multivariate logistic regression analysis comparing the responses with the number of patients referred per month to periodontists. Results:Female respondents were more likely to refer three or more patients per month to a periodontist than a male respondent (P<0.02). Those dentists who practiced with one other dentist were twice as likely to refer more frequently when compared to solo practitioners or larger group practices (P<0.03). Dentists employing two hygienists were more likely to refer patients than those with fewer hygienists (P<0.02). Those whose practices were >5 miles from the nearest periodontist were more likely to refer patients compared to dentists geographically closer to a periodontist (P<0.02). No other variables had a significant effect on the referral of more patients per month to a periodontist. Conclusions:This study indicates that four demographic variables have a statistical influence on the number of referrals per month from a GP to a periodontist. These variables are as follows: female gender, practicing with one other dentist, employing two or more hygienists, and being >5 miles away from the nearest periodontist.

Functional connectivity maps the distributed network of brain regions fluctuating synchronously during a continuous brain state. This study sought to investigate whether patients with left temporal lobe epilepsy (TLE) differ from controls in their resting‐state functional connectivity between typical language regions. We studied 17 patients with left TLE, together with eight healthy controls, using seeded functional connectivity. Seed regions were defined using the regions of maximal activation and deactivation during a language functional magnetic resonance imaging (fMRI) task in a separate cohort of 30 controls. Language fMRI produced the expected activation pattern, which was not different between patients and controls. However, functional connectivity between language areas during rest was markedly different; whereas controls showed connectivity between each of the seed areas and the majority of the language areas, patients showed connectivity only with a few areas, particularly the seed area itself. This difference was significant in the direct comparison of patients and control connectivity maps. We suggest that this reduced connectivity in left temporal lobe epilepsy may reflect a disturbance of the language network during resting state in patients and may be related to subtle language difficulties in this patient population. Ann Neurol 2006

The mechanisms underlying the transition from interictal to ictal states are poorly understood. Non-linear mathematical analysis of EEG frequency components has confirmed the presence of a pre-ictal state in focal epilepsy. We report on functional MRI (fMRI) analysis of the pre-ictal state in three patients with intractable focal epilepsy. Each subject had a typical partial seizure in the scanner while continuous blood oxygen level dependent (BOLD) fMRI images were acquired. The pre-ictal BOLD changes were first analysed by statistically comparing BOLD signals of two one-minute blocks. Further examination of the full time course was then performed. Each patient showed highly significant, focal BOLD signal changes. In Patient 1, a striking pre-ictal BOLD signal increase was seen over the region of the seizure focus identified on complementary epilepsy investigations. No significant BOLD signal decreases were observed. Patient 2 showed widespread pre-ictal BOLD increase contralateral to the presumed seizure focus, as well as a focal BOLD decrease near the presumed seizure focus. In Patient 3, pre-ictal BOLD increase was co-localized with the site of hyperperfusion seen on ictal single photon emission computed tomography (SPECT). However, this was contralateral to the seizure focus localization based on seizure symptomatology. No significant BOLD decreases were seen. The time course data in each patient studied showed change of the BOLD signal several minutes before the onset of the seizure. Highly significant BOLD fMRI signal changes occur before the onset of seizures, supporting the presence of a pre-ictal state. These changes can be localized to the site of the presumed seizure focus, as well as to other brain regions, suggesting that the pre-ictal BOLD signal changes and their underlying mechanisms are complex.

Malformations of cortical development have characteristic interictal discharges, yet the mechanisms of generation of these discharges are not known in humans. Interictal discharges in malformations of cortical development were studied with EEG-fMRI.

The prenatally androgenised female rhesus monkey has become a model for polycystic ovary syndrome (PCOS) in women, with early prenatal androgenisation entraining a permanent PCOS-like phenotype characterised by luteinising hormone (LH) hypersecretion due to reduced hypothalamic sensitivity to steroid negative feedback and relative insulin excess associated with increased abdominal adiposity. These combined reproductive and metabolic abnormalities occur in combination with ovarian hyperandrogenism and follicular arrest in adulthood, and with premature follicle differentiation and impaired embryo development during gonadotrophin therapy for in vitro fertilization (IVF). The ability of prenatal androgen excess in fetal rhesus monkeys to entrain multiple organ systems in utero provides evidence that the hormonal environment of intrauterine life programmes target tissue differentiation, raising the possibility that hyperandrogenism in human fetal development promotes PCOS in adulthood. This hypothesis developed in prenatally androgenised female rhesus monkeys, however, also must include data from clinical studies of PCOS to clarify the homology between human and non-human primates in intrafollicular steroidogenesis and its impact on oocyte developmental competency. By doing so, future studies promise to develop new clinical strategies that will lead to improved pregnancy outcome and reduced pregnancy loss in women with disorders of insulin action, including PCOS, obesity and diabetes mellitus.

Presents directions in doing a coin illusion magic trick.

Shortly after being introduced in the nineteen eighties, magnetic resonance imaging (MRI) became a key tool for the investigation of patients with epilepsy, due to its ability to acquire high quality images. The strength of the magnetic field of a scanner is measured in tesla (T). This review addresses the clinical and research potential in epilepsy of MR imaging at 1.5 T and 3 T. A typical clinical scanning protocol at 1.5 T for a patient with refractory epilepsy may include T1‐ and T2‐weighted imaging, fluid‐attenuated inversion recovery (FLAIR) imaging, and a 3D volume acquisition sequence. A research protocol may add quantification of structural imaging, such as volumetric assessment and T2‐relaxometry, together with functional measures, such as MR‐spectroscopy, functional MRI and diffusion weighted sequences. MR‐spectroscopy assesses the metabolites of the seizure focus and other brain areas. Functional MRI allows localisation of cognitive and sensori‐motor function and the ability to assess the spatial relationship of these functions to the seizure focus. Whereas these techniques can be performed at 1.5 T, particularly MR‐spectroscopy and functional MRI benefit from increased magnetic field‐strength. Higher magnetic field‐strength is associated with a higher signal‐to‐noise ratio (SNR). The increased SNR can allow shorter imaging times for a given resolution, higher resolution for a given imaging time, or combination of both. The use of higher magnetic field‐strengths is therefore indicated for the (fast) imaging of ill subjects, for long protocols, including structural, metabolic and functional imaging, and for novel applications, such as continuous EEG recording and functional MRI for the detection of the seizure focus. Disadvantages of MR imaging in epilepsy at a high field‐strength of 3 T and above are, apart from engineering and technical challenges, the greater energy deposition into tissue and increased susceptibility to artefacts. So far, magnets of 3 T and above have been used mainly for research applications, however the benefits of high field‐strength for MR spectroscopy and functional MRI, and the usefulness of these techniques for the investigation of epilepsy patients are obvious incentives for the use of 3 T systems in routine clinical investigations. [Published with neuroimaging sequences.]

Five early-treated and four late-treated prenatally androgenized and five normal female rhesus monkeys were studied to determine whether prenatal testosterone propionate exposure beginning Gestational Days 40–44 (early-treated) or 100–115 (late-treated) affects follicular steroidogenesis during recombinant human FSH (rhFSH) treatment. All monkeys underwent rhFSH injections, without human chorionic gonadotropin administration, followed by oocyte retrieval. Serum FSH, LH, estradiol (E2), progesterone (P), 17α-hydroxyprogesterone (17 OHP), androstenedione (A4), testosterone, and dihydrotestosterone were measured basally during rhFSH therapy and at oocyte retrieval. Follicle fluid (FF) sex steroids, oocyte fertilization, and embryo development were analyzed. Circulating FSH, E2, 17 OHP, A4, and dihydrotestosterone levels increased similarly in all females. Serum LH levels decreased from basal levels in normal and late-treated prenatally androgenized females but were unchanged in early-treated prenatally androgenized females. Serum P levels at oocyte retrieval were comparable with those before FSH treatment in all females. All prenatally androgenized females showed reduced FF levels of A4and E2but not P or dihydrotestosterone. Intrafollicular T concentrations also were significantly lower in late-treated compared with early-treated prenatally androgenized females or normal females. In early-treated prenatally androgenized females, but not the other female groups, intrafollicular A4and E2levels were reduced in follicles containing oocytes that failed fertilization or produced zygotes with cleavage arrest before or at the five- to eight-cell embryo stage. Therefore, in monkeys receiving rhFSH therapy alone without human chorionic gonadotropin administration, early prenatal androgenization reduced FF concentrations of E2and A4in association with abnormal oocyte development, without having an effect on P, testosterone, or dihydrotestosterone concentrations.

During the ovarian or menstrual cycle, prior to ovulation, many female primates exhibit a relatively prolonged follicular phase and terminate the postovulatory luteal phase with menstrual bleeding. The prolonged follicular phase is a trait that distinguishes primate from nonprimate species. It enables extended estrogen‐induced proliferation and growth of the uterine endometrium prior to progesterone‐induced maturation during the luteal phase to accommodate a potential pregnancy with a rapidly invading placenta. Progressive development of both an extended duration of estrogen‐induced, preimplantation endometrial proliferation and a rapidly invading placenta across the Primate order may well have been necessary to accommodate differentiation and growth of an increasingly large fetal brain. Prolongation of the follicular phase in primates has also led to the isolation of the final stages of follicle selection (growth deviation of the dominant follicle from its contemporaries) solely within the follicular phase and thus outside the protection of luteal phase progesterone inhibition of pituitary luteinizing hormone (LH) secretion. Such primate reproductive characteristics put the latter stages of ovarian follicle selection at risk of exposure to excessive pituitary secretion of LH. Excessive secretion of LH during follicle selection could result not only in impaired follicle development, excessive ovarian androgen secretion, and ovulation failure, but also in excessive estrogenic stimulation of the uterine endometrium without intervening menstrual periods. Such reproductive abnormalities are all found in a single, prevalent infertility syndrome afflicting women in their reproductive years: polycystic ovary syndrome (PCOS). We propose that successful female reproductive adaptations to accommodate the growth demands of large‐brained primate fetuses have facilitated a particular vulnerability of higher primates to hypergonadotropic disruption of ovulatory function, as found in PCOS. Am. J. Hum. Biol. 15:296–319, 2003. © 2003 Wiley‐Liss.

Objective: The aim of this study was to investigate the effects of early‐gestational androgen excess on adult body fat distribution in female rhesus monkeys. Research Methods and Procedures: Six midreproductive‐aged, adult female rhesus monkeys that were exposed to androgen excess started during the first one‐third of gestation were pair‐matched to control females by age, body weight, and body mass index. Body composition was determined using somatometrics, DXA, and computed tomography. Results: Total abdominal and intra‐abdominal fat depots are increased in adult female rhesus monkeys exposed to prenatal androgen excess. Discussion: Early gestational androgen excess in female rhesus monkeys causes a preferential accumulation of total abdominal and intra‐abdominal fat during adulthood. Fat accumulation in these regions is independent of total body adiposity, occurring throughout the spectrum of body mass index in these animals. This study establishes alterations in abdominal adiposity as another consequence of prenatal androgen excess in female rhesus monkeys that may contribute to the impaired insulin secretion observed in these animals during adulthood.

AbstractSending a disabled child to a specialist residential school may mean that they live for much of the year at a school a long way from home. New research examines the role of social services departments in helping families think about this important decision. This article explores the views of social services staff on residential schools and the issues they face around how best to work with families who are thinking about a residential school for their child.