Hebbian analysis of the transformation of medial entorhinal grid-cell inputs to hippocampal place fields.

The discovery of grid cells in the medial entorhinal cortex (MEC) permits the characterization of hippocampal computation in much greater detail than previously possible. The present study addresses how an integrate-and-fire unit driven by grid-cell spike trains may transform the multipeaked, spatial firing pattern of grid cells into the single-peaked activity that is typical of hippocampal place cells. Previous studies have shown that in the absence of network interactions, this transformation can succeed only if the place cell receives inputs from grids with overlapping vertices at the location of the place cell's firing field. In our simulations, the selection of these inputs was accomplished by fast Hebbian plasticity alone. The resulting nonlinear process was acutely sensitive to small input variations. Simulations differing only in the exact spike timing of grid cells produced different field locations for the same place cells. Place fields became concentrated in areas that correlated with the initial trajectory of the animal; the introduction of feedback inhibitory cells reduced this bias. These results suggest distinct roles for plasticity of the perforant path synapses and for competition via feedback inhibition in the formation of place fields in a novel environment. Furthermore, they imply that variability in MEC spiking patterns or in the rat's trajectory is sufficient for generating a distinct population code in a novel environment and suggest that recalling this code in a familiar environment involves additional inputs and/or a different mode of operation of the network.

A pharmacological investigation of noradrenergic receptor mechanisms in neophobia

The dorsal noradrenergic bundle (DB) is a major ascending pathway which originates in the locus coeruleus of the brainstem and projects to the forebrain. The behavioral role of the DB remains unclear, despite a great deal of effort. Selective attention and anxiety are two areas which have been the focus of recent research. Some studies of the DB utilize the neurotoxin 6-hydroxydopamine (6-OHDA), since 6-OHDA injection into this pathway results in greater than 90 percent depletion of cortical and hippocampal norepinephrine (NE). Neophobia, the fear of novelty, has been reported to be either increased or decreased by 6-OHDA lesions of the DB, depending on conditions. The selective attention hypothesis would be supported by increased neophobia after 6-OHDA lesions, while the anxiety hypothesis would be supported by decreased neophobia. We have examined the effects of 6-OHDA DB lesions on neophobia under conditions in which the test environment and/or the test food were novel. We found that the lesion attenuates neophobia, defined as an increased preference for novel food, when both the environment and food were novel. The lesion had no effect on neophobia when only the environment or food was novel.^ We examined the effects of chronic intraventricular NE infusions on behavior in our neophobia test, in sham and 6-OHDA DB lesioned animals. We found that chronic NE infusions into lesioned animals significantly reversed the lesion-induced attenuation of neophobia. Sham/NE infused animals demonstrated a 40 percent greater preference for familiar food compared to sham/saline infused animals. These data suggest that infusions of NE have an effect opposite to lesion-induced attenuation of neophobia. Chronic infusions of the alpha adrenoceptor agonists had no consistent effects on neophobia. The beta adrenoceptor agonist, isoproterenol reversed the lesion-induced attenuation of neophobia but not to a statistically significant degree. Isoproterenol increased neophobia in sham animals. Forskolin, an adenylate cyclase activator, mimicked the effects of NE infusion by significantly reversing the lesion-induced attenuation of neophobia, while increasing neophobia in sham animals. These results suggest that increased release of NE during stress increases neophobia in part by stimulating beta adrenoceptors which activate adenylate cyclase. ^

Optogenetic identification of a rapid eye movement sleep modulatory circuit in the hypothalamus.

Rapid-eye movement (REM) sleep correlates with neuronal activity in the brainstem, basal forebrain and lateral hypothalamus. Lateral hypothalamus melanin-concentrating hormone (MCH)-expressing neurons are active during sleep, but their effects on REM sleep remain unclear. Using optogenetic tools in newly generated Tg(Pmch-cre) mice, we found that acute activation of MCH neurons (ChETA, SSFO) at the onset of REM sleep extended the duration of REM, but not non-REM, sleep episodes. In contrast, their acute silencing (eNpHR3.0, archaerhodopsin) reduced the frequency and amplitude of hippocampal theta rhythm without affecting REM sleep duration. In vitro activation of MCH neuron terminals induced GABAA-mediated inhibitory postsynaptic currents in wake-promoting histaminergic neurons of the tuberomammillary nucleus (TMN), and in vivo activation of MCH neuron terminals in TMN or medial septum also prolonged REM sleep episodes. Collectively, these results suggest that activation of MCH neurons maintains REM sleep, possibly through inhibition of arousal circuits in the mammalian brain.

Doppler sonography of the medial arterial blood supply to the coxofemoral joints of 36 medium to large breed dogs and its relationship with radiographic signs of joint disease.

The medial arterial supply to 68 of the 72 coxofemoral joints of 36 medium to large breed dogs was examined ultrasonographically. The medial circumflex femoral artery and three branches were identified; the artery and its transverse branch were identified in all 68 joints, and the deep branch was identified in 61 joints, and the ascending branch was identified in 63. However, the acetabular and obturator branches were not identified. The pulsatility index, the mean velocity and the peak systolic velocity of the medial circumflex femoral artery were determined and associated with a radiographic score of degenerative coxofemoral joint disease and a lath distraction index (LDI). In joints with a LDI greater than 0.35, the pulsatility index was significantly lower (P=0.023) and its mean velocity was higher (P=0.005). However, no significant associations were observed in individual dogs when the measurements in both joints were taken into account.

Comparison of theoretical fixation stability of three devices employed in medial opening wedge high tibial osteotomy: a finite element analysis.

BACKGROUND Medial open wedge high tibial osteotomy is a well-established procedure for the treatment of unicompartmental osteoarthritis and symptomatic varus malalignment. We hypothesized that different fixation devices generate different fixation stability profiles for the various wedge sizes in a finite element (FE) analysis. METHODS Four types of fixation were compared: 1) first and 2) second generation Puddu plates, and 3) TomoFix plate with and 4) without bone graft. Cortical and cancellous bone was modelled and five different opening wedge sizes were studied for each model. Outcome measures included: 1) stresses in bone, 2) relative displacement of the proximal and distal tibial fragments, 3) stresses in the plates, 4) stresses on the upper and lower screw surfaces in the screw channels. RESULTS The highest load for all fixation types occurred in the plate axis. For the vast majority of the wedge sizes and fixation types the shear stress (von Mises stress) was dominating in the bone independent of fixation type. The relative displacements of the tibial fragments were low (in μm range). With an increasing wedge size this displacement tended to increase for both Puddu plates and the TomoFix plate with bone graft. For the TomoFix plate without bone graft a rather opposite trend was observed.For all fixation types the occurring stresses at the screw-bone contact areas pulled at the screws and exceeded the allowable threshold of 1.2 MPa for at least one screw surface. Of the six screw surfaces that were studied, the TomoFix plate with bone graft showed a stress excess of one out of twelve and without bone graft, five out of twelve. With the Puddu plates, an excess stress occurred in the majority of screw surfaces. CONCLUSIONS The different fixation devices generate different fixation stability profiles for different opening wedge sizes. Based on the computational simulations, none of the studied osteosynthesis fixation types warranted an intransigent full weight bearing per se. The highest fixation stability was observed for the TomoFix plates and the lowest for the first generation Puddu plate. These findings were revealed in theoretical models and need to be validated in controlled clinical settings.

A Bundle of Services Increased Ascertainment of Tuberculosis among HIV-Infected Individuals Enrolled in a HIV Cohort in Rural Sub-Saharan Africa.

OBJECTIVES To report on trends of tuberculosis ascertainment among HIV patients in a rural HIV cohort in Tanzania, and assessing the impact of a bundle of services implemented in December 2012, consisting of three components:(i)integration of HIV and tuberculosis services; (ii)GeneXpert for tuberculosis diagnosis; and (iii)electronic data collection. DESIGN Retrospective cohort study of patients enrolled in the Kilombero Ulanga Antiretroviral Cohort (KIULARCO), Tanzania.). METHODS HIV patients without prior history of tuberculosis enrolled in the KIULARCO cohort between 2005 and 2013 were included.Cox proportional hazard models were used to estimate rates and predictors of tuberculosis ascertainment. RESULTS Of 7114 HIV positive patients enrolled, 5123(72%) had no history of tuberculosis. Of these, 66% were female, median age was 38 years, median baseline CD4+ cell count was 243 cells/µl, and 43% had WHO clinical stage 3 or 4. During follow-up, 421 incident tuberculosis cases were notified with an estimated incidence of 3.6 per 100 person-years(p-y)[95% confidence interval(CI)3.26-3.97]. The incidence rate varied over time and increased significantly from 2.96 to 43.98 cases per 100 p-y after the introduction of the bundle of services in December 2012. Four independent predictors of tuberculosis ascertainment were identified:poor clinical condition at baseline (Hazard Ratio (HR) 3.89, 95% CI 2.87-5.28), WHO clinical stage 3 or 4 (HR 2.48, 95% CI 1.88-3.26), being antiretroviralnaïve (HR 2.97, 95% CI 2.25-3.94), and registration in 2013(HR 6.07, 95% CI 4.39-8.38). CONCLUSION The integration of tuberculosis and HIV services together with comprehensive electronic data collection and use of GeneXpert increased dramatically the ascertainment of tuberculosis in this rural African HIV cohort.

Suprasellar chordoid neoplasm with expression of thyroid transcription factor 1: evidence that chordoid glioma of the third ventricle and pituicytoma may form part of a spectrum of lineage-related tumors of the basal forebrain.

Chordoid glioma of the third ventricle is a rare neuroepithelial tumor characterized by a unique histomorphology and exclusive association with the suprasellar/third ventricular compartment. Variously interpreted as either astrocytic- or ependymal-like, and speculatively ascribed to the lamina terminalis/subcommissural organ, its histogenesis remains, nevertheless, unsettled. Here, we report on a suprasellar chordoid glioma occurring in a 52-year-old man. Although displaying otherwise typical morphological features, the tumor was notable for expression of thyroid transcription factor 1, a marker of tumors of pituicytic origin in the context of the sellar region. We furthermore found overlapping immunoprofiles of this example of chordoid glioma and pituicytic tumors (pituicytoma and spindle cell oncocytoma), respectively. Specifically, phosphorylated ribosomal protein S6, a marker of mTOR pathway activation, was expressed in both groups. Based on these findings, we suggest that chordoid glioma and pituicytic tumors may form part of a spectrum of lineage-related neoplasms of the basal forebrain.

Consistent nuclear expression of thyroid transcription factor 1 in subependymal giant cell astrocytomas suggests lineage-restricted histogenesis.

Thyroid transcription factor 1 (TTF-1) is encoded by the NKX2-1 homeobox gene. Besides specifying thyroid and pulmonary organogenesis, it is also temporarily expressed during embryonic development of the ventral forebrain. We recently observed widespread immunoreactivity for TTF-1 in a case of subependymal giant cell astrocytoma (SEGA, WHO grade I) – a defining lesion of the tuberous sclerosis complex (TSC). This prompted us to investigate additional SEGAs in this regard. We found tumor cells in all 7 specimens analyzed to be TTF-1 positive. In contrast, we did not find TTF-1 immunoreactivity in a cortical tuber or two renal angiomyolipomas resected from TSC patients. We propose our finding of consistent TTF-1 expression in SEGAs to indicate lineage-committed derivation of these tumors from a regionally specified cell of origin. The medial ganglionic eminence, ventral septal region, and preoptic area of the developing brain may represent candidates for the origin of SEGAs. Such lineagerestricted histogenesis may also explain the stereotypic distribution of SEGAs along the caudate nucleus in the lateral ventricles.

Methylation of NR3C1 is related to maternal PTSD, parenting stress and maternal medial prefrontal cortical activity in response to child separation among mothers with histories of violence exposure.

Prior research has shown that mothers with Interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) report greater difficulty in parenting their toddlers. Relative to their frequent early exposure to violence and maltreatment, these mothers display dysregulation of their hypothalamic pituitary adrenal axis (HPA-axis), characterized by hypocortisolism. Considering methylation of the promoter region of the glucocorticoid receptor gene NR3C1 as a marker for HPA-axis functioning, with less methylation likely being associated with less circulating cortisol, the present study tested the hypothesis that the degree of methylation of this gene would be negatively correlated with maternal IPV-PTSD severity and parenting stress, and positively correlated with medial prefrontal cortical (mPFC) activity in response to video-stimuli of stressful versus non-stressful mother-child interactions. Following a mental health assessment, 45 mothers and their children (ages 12-42 months) participated in a behavioral protocol involving free-play and laboratory stressors such as mother-child separation. Maternal DNA was extracted from saliva. Interactive behavior was rated on the CARE-Index. During subsequent fMRI scanning, mothers were shown films of free-play and separation drawn from this protocol. Maternal PTSD severity and parenting stress were negatively correlated with the mean percentage of methylation of NR3C1. Maternal mPFC activity in response to video-stimuli of mother-child separation versus play correlated positively to NR3C1 methylation, and negatively to maternal IPV-PTSD and parenting stress. Among interactive behavior variables, child cooperativeness in play was positively correlated with NR3C1 methylation. Thus, the present study is the first published report to our knowledge, suggesting convergence of behavioral, epigenetic, and neuroimaging data that form a psychobiological signature of parenting-risk in the context of early life stress and PTSD.

The cost effective management of Central Line-Associated Bloodstream Infections (CLABSIs) comparing the central line bundle to antimicrobialcoated central venous catheters: A systematic review

Central Line-Associated Bloodstream Infections (CLABSIs) are one of the most costly and preventable cases of morbidity and mortality among intensive care units (ICUs) in health care today. In 2008, the Centers for Medicare and Medicaid Services Medicare Program, under the Deficit Reduction Act, announced it will no longer reimburse hospitals for such adverse events among those related to CLABSIs. This reveals the financial burden shift onto the hospital rather than the health care payer who can now withhold reimbursements. With this weighing more heavily on hospital management, decision makers will need to find a way to completely prevent cases of CLABSI or simply pay for the financial consequences. ^ To reduce the risk of CLABSIs, several clinical, preventive interventions have been studied and even instituted including the Central Line (CL) Bundle and Antimicrobial Coated Central Venous Catheters (AM-CVCs). I carried out a formal systematic review on the topic to compare the cost-effectiveness of the Central Line (CL) Bundle to the commercially available antimicrobial coated central venous catheters (AM-CVCs) in preventing CLABSIs among critically and chronically ill patients in the U.S. Evidence was assessed for inclusion against predefined criteria. I, myself, conducted the data extraction. Ten studies were included in the review. Efficacy in reducing the mean incidence rate of CLABSI by the CL Bundle and AM-CVC interventions were compared with one another including costs. ^ The AM-CVC impregnated with antibiotics, rifampin-minocycline (AI-RM) is more clinically effective than the CL Bundle in reducing the mean rate of CLABSI per 1,000 catheter days. The lowest mean incidence rate of CLABSI per 1,000 catheter days among the AM-CVC studies was as low as zero in favor of the AI-RM. Moreover, the review revealed that the AI-RM appears to be more cost-effective than the CL Bundle. Results showed the adjusted incremental cost of the CL Bundle per ICU patient requiring a CVC to be approximately $196 while the AI-RM at only an additional cost of $48 per ICU patient requiring a CVC. ^ Limited data regarding the cost of the CL Bundle made it difficult to make a true comparison to the direct cost of the AM-CVCs. However, using the result I did have from this review, I concluded that the AM-CVCs do appear to be more cost-effective in decreasing the mean rate of CLABSI while also minimizing incremental costs per CVC than the CL Bundle. This review calls for further research addressing the cost of the CL Bundle and compliance and more effective study designs such as randomized control trials comparing the efficacy and cost of the CL Bundle to the AM-CVCs. Barriers that may face health care managers when implementing the CL Bundle or AM-CVCs include additional costs associated with the intervention, educational training and ongoing reinforcement as well as creating a new culture of understanding.^