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Hippocampal CA1 deformity is related to symptom severity and antipsychotic dosage in schizophrenia
Abnormalities of the hippocampus are intricately involved in the pathophysiology of schizophrenia. Hippocampal volume decrease is present at disease onset and has mainly been observed in the anterior and posterior part of the hippocampus. Nevertheless, an association between regionally specific hippocampal shape deformities putatively affecting a pathophysiologically crucial region, i.e. cornu ammonis field 1 (CA1), and symptomatology as well as required maintenance medication has not been observed. The aim of this study was to characterize the relationship between CA1-specific hippocampal surface deformations and symptom severity. Furthermore, we aimed to explore whether such specific morphological hippocampus abnormalities statistically predict the maintenance dosage of antipsychotic medication. Hippocampal shape and volume were determined by manual segmentation of high resolution, whole brain, three-dimensional structural magnetic resonance imaging scans. Associations between hippocampal volume, specific shape deformities in CA1, and positive and negative symptoms were assessed in 32 patients with schizophrenia and compared with 34 healthy control subjects. In addition to volume reductions of the left hippocampus, patients with schizophrenia displayed specific shape deformities in the left anterior and posterior CA1 subfield. Overall, the severity of positive symptoms was closely associated to these morphological deformities, specifically delusions and hallucinations. In addition, CA1 deformity was linked to the required antipsychotic dosage. Findings were replicated in a second, independent sample. Hippocampal CA1 deformity, possibly reflecting shrinkage, might result from a specific hyperactivity, leading to a circumscribed volume loss. Owing to its physiological function, deficits in CA1 may be directly involved in the pathogenesis of hallucinations and delusions, core symptoms in schizophrenia.
- chronic schizophrenia
- hippocampus shape
- positive symptoms
- antipsychotic medication of maintenance
In schizophrenia, alterations in the structure, function and physiology of the hippocampus have consistently been reported. Among those, hippocampal volume decreases are a robust finding in MRI studies using manual segmentation as well as in post-mortem studies (Bogerts, 1984, 1985, 1993a; DeLisi et al., 1988; Suddath et al., 1989; Breier et al., 1992; Heckers, 1997; Gur et al., 2000; Shenton et al., 2002).
Recent studies using computational image analysis methods investigated local and global differences in brain morphology that are potentially associated with neuropathological changes. In a series of studies, Csernansky et al. (1998) used high-dimensional deformation mapping showing hippocampal shape alterations in schizophrenia that were pronounced in anterior and lateral hippocampal regions (Haller et al., 1996; Csernansky et al., 1998, 2002; Wang et al., 2001). In contrast, using a shape representation technique, Shenton et al. (2002) failed to find overall differences in hippocampal shape between patients with schizophrenia and healthy control subjects. Szeszko et al. (2003) observed bilateral reductions of anterior hippocampal volumes in patients with first-episode schizophrenia. Accordingly, Narr et al. (2001, 2002) showed anterior and midbody structural hippocampus changes in schizophrenia. In these studies, volume deficits were particularly prominent in the left hemisphere of patients suffering from schizophrenia. Furthermore, Narr et al. (2004) reported volume reductions prominent in hippocampal regions that correspond to anterior and midbody cornu ammonis field 1 (CA1) and CA2 subfields in the left hemisphere of patients with first-episode schizophrenia.
The major efferent connections of the hippocampal formation to the cortex arise from the pyramidal cells of the CA1 and project either directly or via the subiculum to the cortex (Van Hoesen and Hyman, 1990). Pathology affecting the CA1 subfield results in a functional disconnection from its target areas. CA1 is specifically vulnerable to hypoxia (Duvernoy and Bourgouin, 1998; Harrison and Eastwood, 2001), a birth complication linked to schizophrenia. Furthermore, this hippocampal subregion appears sensitive to vascular cerebral insults or the hyperexcitation of glutamate receptors (Zola-Morgan et al., 1986; Duvernoy and Bourgouin, 1998). Dopamine hyperfunction, inhibiting glutamatergic (NMDA) N-methyl-D-aspartate input, dramatically reduces direct cortical input to CA1 via the perforant pathway. These effects of dopamine are blocked by typical antipsychotic drugs such as haloperidol, suggesting a link between dopaminergic activity and the CA1 field in schizophrenia-related pathophysiology (Otmakhova and Lisman, 2000; Lisman and Otmakhova, 2001).
Supporting the crucial role of hippocampal dysregulation, we recently showed that patients with schizophrenia exhibit a non-specific hyperactivity of the left hippocampus during a long-term memory task and that this hyperactivity is strongly related to positive symptom severity (Zierhut et al., 2010). Schobel et al. (2009) reported an increase in regional cerebral blood volume specifically in CA1. This abnormal cerebral blood volume increase is not only associated with positive symptoms but also predicts clinical progression from a prodromal state to psychosis.
To our knowledge, there is no study investigating the relationship between specific CA1 deformations—as a potential morphological marker—and symptom severity. We hypothesized that shape differences in terms of an inward deformation detectable in the CA1 region are closely associated to symptom severity. Furthermore, these shape differences in the CA subfield of patients with schizophrenia may statistically predict the required antipsychotic dosage, an indirect measure of symptom severity.
Therefore, we analysed hippocampal size and regional shape differences between patients with schizophrenia and healthy control subjects and related them to the patients' actual psychopathological state as well as the required antipsychotic dosage for maintenance treatment. The topographical distribution of the CA fields, dentate gyrus and subiculum is such that the CA1, CA2 and CA3 fields and subiculum are located at the surface of the hippocampal formation. Thus, we examined hippocampal surface deformations by using surface-based mesh modelling methods (Thompson et al., 1996a, b, 1997) to describe differences in hippocampal shape between diagnostic groups (Csernansky et al., 2002; Shenton et al., 2002). This mapping was then used to track regional differences in hippocampal surface parameters and local tissue distributions to characterize the regional specificity of hippocampal volume reductions in schizophrenia.
Materials and methods
A clinically well-characterized group of 32 patients with paranoid schizophrenia (11 female, medicated with atypical antipsychotic drugs, no benzodiazepines, Table 1) (ICD-10 F20, no neuropsychiatric comorbidities) and 34 healthy volunteers (14 female) participated in this study. According to the structured clinical interview of the positive and negative syndrome scale (PANSS), all patients were mildly to moderately impaired (Table 1), and all patients were in a remitted state. Patients had on average an illness duration of ∼10 years.
|Control subjects (n = 34, 14 females)
|Schizophrenia patients (n = 32, 11 females)
|Mean (SD)
|Mean (SD)
|30.71 (7.10)
|34.47 (8.63)
|Chlorpromazine equivalent of daily antipsychotic dose (mg/d)
|460.24 (389.35)
|Duration of illness (years)
|10.41 (8.73)
|13.18 (10.76)
|8.95 (7.34)
|Age of onset (years)
|25.03 (6.37)
|27.10 (7.98)
|23.95 (5.25)
|PANSS total score
|71.47 (21.61)
|PANSS positive subscale score
|16.75 (6.67)
|PANSS negative subscale score
|18.75 (8.72)
|PANSS general psychopathology subscale score
|36.03 (11.03)
Subjects were checked for MRI contraindications and gave written informed consent to participate. The study was approved by the institutional review board of the medical faculty, Otto-von-Guericke-University, Magdeburg. Control subjects underwent routine clinical interview for history of neurological and psychiatric illnesses. Subjects with present or past neurological or psychiatric disorders or reported use of any drugs were excluded. Clinical and demographic details are summarized in Table 1. The control group comprised healthy subjects comparable in age, gender and handedness with the patients group (Table 1).
Diagnosis of paranoid schizophrenia following ICD-10 criteria was established by psychiatric evaluation using the psychopathological diagnosis system established by the Association for Methodology and Documentation in Psychiatry (Bobon and Ansseau, 1986). Furthermore, the structured clinical interview of the PANSS was applied to specifically assess schizophrenia-related symptomatology (Kay et al., 1987; Kay and Opler, 1987). The interview was performed directly after the MRI scan.
To corroborate the findings in this initial sample, a second, independent sample of patients and control subjects was assessed. Detailed population characteristics, methods and results are provided in the Supplementary material.
Magnetic resonance imaging acquisition and data analyses
Three-dimensional, T1-weighted, high-resolution structural MRI scans of the brain were acquired on a 3 T Siemens MAGNETOM Trio scanner (Siemens) with an eight-channel phased-array head coil using a 3D-MPRAGE sequence (echo time = 4.77 ms, repetition time = 2500 ms, inversion time = 1100 ms, flip angle = 7°, bandwidth = 140 Hz/pixel, matrix = 256 × 256 × 192, isometric voxel size = 1.0 mm3). Images were reoriented along the anterior commissure posterior commissure line, and the spatial coordinate origin was manually set to the anterior commissure (Frisoni et al., 2008).
Assessment of hippocampal volume
To perform a consecutive shape analysis of the left and right hippocampus, 66 T1-weighted 3D-MPRAGEs were used for the manual hippocampus segmentation using the software package MRIcron (www.mricro.com). One rater (K.C.Z.) blind to group status made the volumetric assessment of the hippocampus for both hemispheres.
The hippocampus is symmetrically located in the medial temporal lobes and forms a bilaminar structure. The neuroanatomical criteria for hippocampal delineation were adapted from existing protocols (Jack et al., 1995; Pantel et al., 2000; Pruessner et al., 2000; Levitt et al., 2001; Narr et al., 2001, 2002) and based on the atlas of hippocampal anatomy (Duvernoy and Bourgouin, 1998; Duvernoy, 2005). For labelling, the coronal plane was used as default view. All voxels belonging to the hippocampus were labelled and stored as binary masks.
Reliability assessment of hippocampal volume
The same rater (K.C.Z.) repeatedly contoured the hippocampus from nine randomly chosen brains of both groups for intrarater reliability using intraclass correlation coefficients (ICC) for hippocampal volume (ICCIntra = 0.98). A different investigator outlined the hippocampus of the same nine brains to establish inter-rater reliability (ICCInter = 0.85). In accordance with Portney and Watkins (2000), those ICCs reflect an almost perfect agreement.
Assessment of hippocampus shape
On the basis of the manually segmented hippocampal volumes of both hemispheres, the contours of the hippocampus masks were traced in coronal slices using the software MultiTracer (Woods, 2003) and stored as contour files in the ucf file format. This program allows the user to make use of anatomical landmarks by viewing images in all three orthogonal planes simultaneously (Thompson et al., 2004a, b). The hippocampus contours were used for shape analysis by the freely available shape tools software as JavaScripts developed at the laboratory of NeuroImaging (LONI, UCLA School of Medicine, Los Angeles) (Thompson et al., 1996a; Narr et al., 2004).
Briefly, the spatial coordinates of points on the hippocampal surface were unitized using the script InterpolateContour to a mesh of 100 × 150 surface points resulting to 15 000 describing vertices. Based on these uniform surface data for the right and left hippocampi of all subjects, a statistical analysis of shape differences between patients and control subjects was performed. The radial distance of each vertex to the hippocampus midline was calculated with the MedialDistance script (LONI, UCLA School of Medicine, Los Angeles) and stored. The average hippocampi, including all right or all left hippocampi, were computed using the ShapeAverage script and stored in the unc file format. The radial distances of each vertex to the hippocampus midline were transformed in greyscale analyse images for each individual hippocampus. Distance values between 0 and 10 mm correspond to grey values between 0 and 1000. The analyse images were stored as single slice data in a 100 × 150 matrix with the origin in the centre of each image (Fig. 1 and Table 2). The statistical analyses of these distance maps in terms of a full factorial analysis were accomplished by SPM5 described later in the text. To illustrate group differences in a 3D-format of the hippocampus, the SPM(t) maps of the full factorial analysis were added as a additional column to the ucf contour files of the average hippocampi. This was realized with the script ShapeAttribute (LONI, UCLA School of Medicine, Los Angeles). By using the script ShapeViewer (LONI, UCLA School of Medicine, Los Angeles), the SPM(t) maps were superposed on a mean hippocampus shape of all subjects for both hemispheres, respectively. T-values were colour coded in spectrum colours (maximum positive t-value as white, maximum negative t-value as black).
|Control subjects > patients
|CA1, anterior
|CA1, posterior
PFDR-corrected < 0.05.
K = number of voxels within clusters; P-value = statistical significance after correction for multiple comparisons (voxel level).
Assessment of hippocampus length
To assess the possibility that shape differences between groups arise from a longitudinal displacement of surface areas owing to differences in hippocampus length between groups, the hippocampus length of both hemispheres was assessed and compared between groups using a one-way ANOVA. The individual hippocampus length of every hemisphere was calculated using the script MedialDistance (LONI, UCLA School of Medicine, Los Angeles) by summation of the distances between the centres of all neighbouring hippocampal slices.
Surface-based identification of hippocampal subregions
Based on the anatomical magnetic resonance atlas of the hippocampus (Duvernoy and Bourgouin, 1998; Duvernoy, 2005) and magnetic resonance-based 3D models of the hippocampus formation generated by Frisoni et al. (2006, 2008), we mapped neuropathological hippocampal areas onto the averaged hippocampus.
Statistical analyses
Analyses of covariance
Population characteristics were compared by one-way ANOVAs. Group and side differences in hippocampus volume were assessed by ANCOVAs (factors: group and hemisphere) with age and whole brain volume as covariates. Owing to a one-by-one gender matching procedure, gender was not included as covariate in the ANCOVA. The significance level was set to 0.05. All statistical analyses were conducted with SPSS, v15.0.
Group differences in the hippocampus shape were initially explored in SPM5 applying a full factorial model with age and total intracranial volume as covariates. Directional t-contrasts were defined between groups. The corresponding SPM(t) values were thresholded at a level of significance of P < 0.05 (corrected). Any clusters showing significant findings were reported if surviving false discovery rate (FDR) correction for multiple comparisons at the P < 0.05 level (corrected).
Regression and correlation analyses
In the patient group, we additionally conducted linear regression and correlation analyses (Pearson correlation coefficients for metric data, Spearman Rho correlation coefficients for ordinal data, partial correlation coefficients with chlorpromazine-equivalent or PANSS positive subscale score as covariates). For that analysis, we extracted the beta values from significant clusters in the hippocampus shape analysis using the MarsBar toolbox for SPM (Brett et al., 2002). The beta values were then entered in a regression and a correlation analysis with hippocampus volume, PANSS score (including positive, negative and general psychopathology subscale, as well as hypothesis driven single items from the positive scale: delusions, hallucinations), and chlorpromazine equivalent of daily antipsychotic dose as variables. Again, the significance level was set to 0.05.
Furthermore, an approximation of cumulative antipsychotic dose was estimated for every patient by multiplicating the chlorpromazine equivalent of the actual daily antipsychotic dose with years of disease duration. To assess whether the approximated cumulative antipsychotic dose was related to hippocampal volume loss and hippocampal shape alteration, a correlation analysis (Pearson correlation coefficient for metric data) was performed.
Hippocampus shape analysis
The component of the full-factorial model comparing the schizophrenia group with the control subjects revealed a significant group effect. Group differences of shape in terms of an inward deformity were evident in the left, but not the right anterior and posterior hippocampus of patients with schizophrenia (Table 2, Fig. 1). These neuropathological changes were located in a hippocampal region that is known to consist of the CA1 subfield (Figs. 2 and 3). Concomitantly, the volume of the left hippocampus was also significantly reduced in the patients with schizophrenia (Fig. 4, Table 4). Owing to close matching, gender effects were not detected (male > female: PFDR-corrected > 1.000; female > male: PFDR-corrected > 0.484). We additionally found a significant positive correlation between shape deformity in the left posterior CA1 subfield and the hippocampus volume of the left hemisphere (Table 3).
|CA1, posterior—hippocampus volume
|CA1, posterior—positive symptomatology
|CA1, posterior—hallucinatory behaviour
|CA1, posterior—delusions
|CA1, posterior—daily antipsychotic dose
|CA1, anterior—daily antipsychotic dose
|Hippocampus volume—daily antipsychotic dose
β = regression coefficient; R2 = proportion of the variance explained by the linear regression model; r = correlation coefficient.
Association between CA1 shape deformity and positive symptoms
For positive symptoms, the total subscale of the PANSS positive scale as well as the single items 'delusions' and 'hallucinations' were found to differentially correlate with the posterior CA1 subfield. Specifically, the hippocampal surface deformity in a region that consists of the CA1 subfield was negatively associated with the severity of positive symptoms (Table 3, scatter plot in Fig. 5). By controlling for the amount of daily antipsychotic treatment (partial correlation), that correlation remained significant (r = −0.386, P = 0.035). No significant association was found with the total score of the PANSS negative symptom scale and CA1 deformity.
Association between CA1 shape deformity and the prescribed antipsychotic treatment
Within the same regression model, anterior and posterior CA1 deformity was negatively associated with the amount of daily antipsychotic treatment in the patients with schizophrenia. Again, controlled for severity of positive symptoms (partial correlation), that association was significant too (CA1, anterior: r = −0.428, P = 0.018; CA1, posterior: r = −0.399, P = 0.029). Additionally, the lower left hippocampal volume was linked to a higher antipsychotic dosage (Table 3, scatter plots in Fig. 6).
Reduced hippocampal volume
Accompanying the hippocampal shape deformities in the left CA1 subfield, patients with schizophrenia showed significant hippocampal volume reductions in the left (main effect group) [F(1,62) = 5.659; P = 0.020] but not the right [F(1,62) = 2.792; P = 0.100] hemisphere (Table 4 and Fig. 4). There was no significant main effect regarding hemisphere and no significant interaction effect (group by hemisphere).
|Control subjects
|Schizophrenia patients
|(n = 34, 14 female)
|(n = 32, 11 female)
Note: l = left; r = right.
Estimated cumulative antipsychotic dose
In the patients with schizophrenia, the approximated cumulative antipsychotic dose did not correlate with hippocampal volume on either side (left: r = −0.08, P = 0.658; right: r = −0.201; P = 0.263). Furthermore, a correlation with the hippocampal surface inward deformation in the patients with schizophrenia was neither evident in the anterior (r = 0.101; P = 0.590) nor posterior CA1 subfield (r = −0.309, P = 0.091).
Hippocampus length
There were no significant group differences of hippocampus length between patients with schizophrenia and healthy control subjects [right: F(1,64) = 0.177, P = 0.676; left: F(1,64) = 2.554, P = 0.115].
Replication study
The main findings of this study were reproduced in a second, independent sample. Most importantly, the specific left hippocampal inward deformity attributable to CA1 in patients with schizophrenia was replicated. Moreover, the association of left hippocampal CA1 shrinkage with more pronounced positive symptoms was also evident in this sample. Finally, the link of CA1 shrinkage in patients with schizophrenia to the actually prescribed antipsychotic dosage was corroborated in the replication study. These results are provided in detail in the Supplementary material.
Schizophrenic patients showed an inward deformity of the left anterior and posterior CA1 subfield along with a left hippocampal volume reduction. These abnormalities in the left hippocampus are closely associated with the severity of positive symptoms and specifically of delusions and hallucinations. Thus, the smaller CA1, the more prominent are delusions and hallucinations in the patients.
CA1 and total hippocampal volume are also associated with the amount of prescribed antipsychotics. Smaller CA1 statistically predict higher dosage of daily antipsychotic treatment. Accordingly, low hippocampal volume is accompanied by a more intense neuropharmacological treatment.
To our knowledge, this is the first report to show that CA1 deformities statistically predict the severity of positive symptoms and the required antipsychotic dosage in patients with schizophrenia. Furthermore, these results have been replicated in a second, independent sample of 19 healthy control subjects and 13 patients with schizophrenia (Supplementary material).
Shape deformities in left anterior and posterior CA1
The pattern of hippocampal deformity in the present sample of patients with schizophrenia suggests a unilateral deformity of the anterior and posterior CA1 subfield of the left hippocampus. In chronically ill patients with schizophrenia, such a deformation pattern has not explicitly been attributed to the CA1 partition before, even though this observation is supported by a pattern of hippocampal deformity in first-episode schizophrenia that has been described by previous studies (Bilder et al., 1995; Csernansky et al., 1998; Narr et al., 2001, 2002, 2004; Szeszko et al., 2003).
Inspecting the location of the posterior cluster in Fig. 3, it is evident that it is located in the proximity of the border of CA1 and CA2/3 and might possibly be misattributed to CA1 due to hippocampus length differences between groups. Though, a surface misallocation of the observed shape differences that might arise from such a longitudinal displacement of hippocampal surface areas due to, for example, a shortening of the hippocampus in schizophrenia, appears unlikely as there was no significant group difference of hippocampus length detectable in either hemisphere.
Role of CA1 in schizophrenia
The functional importance of the hippocampal CA1 subfield arises from its specific neuronal connectivity. Major efferences from the CA1 project to the cortex (Van Hoesen and Hyman, 1990) while neighbouring CA3 neurons interconnect with CA1 through the Shaffer collaterals.
Because hippocampal subregions are interconnected to form a circuit, a 'lesion' in one subregion might cause secondary dysfunction in other subregions. CA1 receives its main input via the Shaffer collaterals from CA3 and from the entorhinal cortex (Small et al., 2011). The loss of CA3 GABAergic interneurons in patients with schizophrenia may lead to an overstimulation of glutamatergic AMPA- (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. In conjunction with increased synaptic glutamate release, this—in turn—might cause hyperactivity in the CA1 subfield (Benes, 1999). Supporting evidence arises from several functional MRI studies that have reported a hyperactive state in CA1 in patients with schizophrenia (Kawasaki et al., 1992; Gur et al., 1995; Heckers et al., 1998). Furthermore, dopamine hyperfunction, which inhibits glutamatergic NMDA input, is shown to dramatically reduce direct cortical input to CA1. Thus, such a hyperglutamatergic state in the CA1 subfield, caused by a deficient inhibition of CA3 and a dopaminergic hyperfunction, might not only cause neuronal hyperactivity but also—because of the neurotoxicity of glutamate—neuronal damage resulting in volume loss in CA1. Such pathology affecting CA1, as evident in the present data, may lead to a functional disconnection of the hippocampus from its target areas. It thus provides support for the hypothesis that schizophrenia involves a disturbance of the connections between the hippocampus and other downstream brain regions (Weinberger et al., 1992), which might impair functionality of the latter.
CA1 inward deformities are closely related to positive symptoms
CA1 shrinkage was also found to be associated with measures of delusions and hallucinations. Our data show for the first time, that morphological deformities in CA1 statistically predict severity of hallucinations and delusions. Previous studies failed to find an association between hippocampal shape deformities and symptom severity in patients with schizophrenia (Csernansky et al., 1998, 2002). Csernansky et al. (1998, 2002) used general pattern matching and a template of hippocampal neuroanatomy to represent hippocampus shape using eigenvectors. With this technique, the eigenvectors obtained from each individual warp do not directly reflect stereotaxic information but rather provide an aggregate measure of general hippocampal shape differences between groups. Possibly, this approach is not suitable to detect correlations between subfield deformities and symptom severity that appear to be highly regionally specific.
To date, symptomatology in patients with schizophrenia was linked to CA1 alterations only on a functional level. Schobel et al. (2009) reported an association between a functional hyperactivation of CA1 and increased positive symptoms. This raises the intriguing possibility that hyperactivity in CA1 may—because of disturbed information processing for example—actually drive the psychotic symptoms of hallucinations and delusions; core symptoms of schizophrenia. This putatively crucial role of hippocampal hyperactivity is supported by the observation that schizophrenia-like psychotic symptoms in patients with temporal lobe epilepsy are associated with such hyperactive hippocampal states (Elliott et al., 2009a, b). Such hippocampal hyperactivity has been postulated by a number of PET (Friston et al., 1992) and functional MRI studies (Gur et al., 1995; Kawasaki et al., 1992; Medoff et al., 2001; Malaspina et al., 2004) observing increased cerebral blood flow in mediotemporal and hippocampal regions. Several studies applying memory tasks have observed decreased hippocampal activation in these tasks (Heckers et al., 1998, 1999; Ragland et al., 1998; Weiss and Heckers, 2001). But in fact, this finding from functional MRI and PET studies applying between-task comparisons does not directly contradict the concept of a basally increased neuronal activity of the hippocampus. If there is a basally increased hippocampal activity, it might well be that such a pre-existing activity only increases to a lesser degree in a hippocampus-dependent task compared with states with a lower basal hippocampus activity (Heckers et al., 1998; Weiss and Heckers, 2001).
In the study by Schobel et al. (2009), the hippocampal hyperactivity was specifically restricted to CA1, and not present in CA3 or dentate gyrus, underscoring the special importance of the hippocampal CA1 subfield in schizophrenia. This finding strikingly reflects computational and neurobiological models of the pathogenesis of psychosis that have highlighted the critical role of CA1 in the development of core psychotic symptoms in schizophrenia (Krieckhaus et al., 1992; Benes, 1999; Otmakhova and Lisman, 2000; Lisman and Otmakhova, 2001; Lisman et al., 2010; Zhang et al., 2012). This again relates to the finding of Schobel et al. (2009) that CA1 hyperactivity is specifically predictive of the development of full-blown psychosis in a subgroup of prodromal subjects and is specifically related to the total positive symptoms subscore of the PANSS and to delusions, both in schizophrenic and prodromal patients.
It is conceivable that the structural CA1 alteration observed in the present study is a consequence of a hyperactive state of the hippocampus CA1 subfield as described by Schobel et al. (2009). In this context, it fits well with the fact that CA1 inward deformity is directly correlated with positive symptoms, especially delusions and hallucinations in the present study.
Anterior and posterior CA1 deformities statistically predict psychopharmacological treatment
Deformities of CA1 are not only associated to symptomatology but also statistically predict the amount of antipsychotics applied to alleviate those symptoms. Our data show that the smaller the CA1, the higher the ordinated daily antipsychotic dose. The alternative explanation of this relation, i.e. a hippocampal volume reduction and shape alteration due to long-term effects of antipsychotic medication (for a detailed overview, see Moncrieff and Leo, 2010) appears unlikely, considering the finding that approximated cumulative antipsychotic dose is not related to volume and shape alterations in the present sample of patients with schizophrenia.
To date, only two studies have been published addressing the relationship between antipsychotic treatment and hippocampal volume, but not the exact location via shape analyses (Bogerts et al., 1993b; Pegues et al., 2003). Pegues et al. (2003) reported no significant correlations between hippocampal volumes and medication level. Bogerts et al. (1993b) similarly reported a non-significant correlation between temporolimbic tissue volumes with maximum doses of antipsychotic drug treatment. Our data show a significant correlation between hippocampal volume and psychopharmacological treatment contradicting both studies. These discrepancies might be the result of different methodologies applied. Bogerts et al. (1993b) used a 1.0 T magnetic resonance system with a whole head image resolution of 1.0 × 0.6 × 3.1 mm. Pegues et al. (2003) performed all MRI studies with a 1.5 T Magnetom using a 1.0 m × 1.4 × 3 mm resolution. In the present study, we used a 3 T Magnetom with a much higher resolution of 1 mm3 and a higher structural precision. Thus, the discrepancies between our results and the two mentioned studies (Bogerts, 1993a; Pegues et al., 2003) may arise from the lower image resolution and as consequence a reduced precision in the manual segmentation of small brain structures with irregular shapes, like the hippocampus.
No previous study has investigated the relationship between the deformation of a distinct hippocampal subregion and antipsychotic treatment in patients with schizophrenia. Thus, to our knowledge, this is the first demonstration of a direct causal relationship between morphological abnormalities and the necessary pharmacological treatment in schizophrenia. As CA1 is additionally predicting symptom severity, it appears that the smaller the CA1, the more severe the symptomatology and, hypothetically, the higher the antipsychotic dosage that is required to reduce symptomatology.
These clear-cut findings notwithstanding, it appears necessary to point out that other important aspects such as genetic, social and psychological factors, the assessment of whose influence is beyond the scope of this study, also play a crucial role in determining the individual dosage of antipsychotic medication.
Reduced left hippocampal volume
The schizophrenic patients in our study showed reduced left hippocampal volume. This finding is consistent with several recent studies that have documented larger right, compared with left hippocampal volumes in both schizophrenic patients and control subjects (Pearlson et al., 1997; Marsh et al., 1999; Velakoulis et al., 1999; Niemann et al., 2000; Wang et al., 2001).
Accordingly, previous studies provide further evidence that limbic structure volumes are more prominently reduced in the left hemisphere and additionally show that a left hemispheric volume reduction was evident in patients with first-episode schizophrenia, whereas in chronically ill patients, the hippocampi of both hemispheres are affected. A probable explanation for these different laterality findings in the two patient samples is that pre-existing bilateral hippocampal pathology occurs in more severe forms of the illness and predisposes to poorer treatment response and a worse outcome.
Our data indeed show significant volume reduction of left hippocampus even though our sample mainly consisted of chronically ill patients with schizophrenia. An explanation based on the argumentation of Bogerts et al. (1993b) could be that our patient sample consisted of patients with a less severe course of the disease and thus only a lateralized volume reduction of the hippocampus, promising better treatment response and outcome. Clearly, only longitudinal studies may establish with certainty whether grey matter volume is lost or simply never fully developed.
Nevertheless, some caveats regarding the interpretation of our findings should be highlighted. First, the use of hippocampal surface models relies on manual tracing, and systematic bias owing to changes in the anatomy of the hippocampus of patients might adversely affect its reliability. The reliability of the method has been shown to be high (Thompson et al., 2004a); however, it is possible that there is a systematic bias in these tracings that is correlated with diagnosis. Although the tracings are made by raters blind to diagnosis, any difference in image contrast between patients with schizophrenia and healthy subjects could also alter the boundaries. Finally, the localization of neuroanatomical regions of the hippocampal formation is far from perfect owing to interindividual variations of neuroanatomy and variability of image quality and resolution.
A further shortcoming may be the fact that none of the patients were drug-naïve at the time of study. However, all patients had received second generation antipsychotics, and the non-significant correlation between illness duration and hippocampal volume (r = 0.235; P = 0.211) argues against a strong influence of antipsychotic medication on the dependent variables. This is also consistent with the majority of hippocampal voluming studies in patients with schizophrenia (Bogerts et al., 1993b; Kawasaki et al., 1993; Marsh et al., 1994; Zipursky et al., 1994; Csernansky et al., 1998; Whitworth et al., 1998; Stefanis et al., 1999; Altshuler et al., 2000; Gur et al., 2000).
This is the first evidence of a link between the severity of positive symptoms in patients with schizophrenia and a morphological alteration of a distinct hippocampal subregion, namely CA1. This deformation might be the consequence of a disease-specific hyperactive hippocampal state presumably leading to atrophic changes, possibly reflecting neuronal or glial loss in the course of the disease. As deficits in CA1 may further cause deficits in connected processing circuits, this abnormality might be critical for the development of schizophrenia and its symptomatology. Furthermore, CA1 shrinkage is statistically related to the dosage of antipsychotic maintenance treatment. Thus, CA1 apparently plays an important role in the pathophysiology of schizophrenia and might represent a biological marker of the clinical severity in this disease.
This study was supported by a grant from the Deutsche Forschungsgemeinschaft to KS and BB (KFG 163, TP 6).
Supplementary material
Supplementary material is available at Brain online.
The authors thank Denise Scheermann and Gertje Wank for proficient assistance in MRI scanning and Cindy Eckart for helpful assistance during data analysis. We thank H. G. Bernstein for important anatomical counselling. They also acknowledge all patients who have participated in the present study.
- Abbreviations
- cornu ammonis field 1
- positive and negative syndrome scale
- © The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: firstname.lastname@example.com


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Vanessa Carlton Cancels Shows Due To Lost Pregnancy
Singer Vanessa Carlton shared some sad news with fans yesterday while explaining why she had to cancel four tour dates in November.
In a lengthy post on her Facebook page, Carlton revealed she lost her pregnancy due to fallopian pregnancy. She writes, "I announced that I was pregnant during the first week of tour. The day after our NYC show on Oct 15th, I was diagnosed with an ectopic pregnancy, or in my case it was a fallopian pregnancy (the embryo settled in my tube, which is the width of a straw.) This is not considered a viable pregnancy because the fetus cannot develop and it is a high risk situation for the mother because of the potential for tubal rupture and internal bleeding."
Instead of extensive surgery, Carlton opted for a shot and chemotherapy. However, her fallopian tube began to rupture and she suffered internal bleeding, forcing her doctor to perform surgery.
Carlton still hoped to perform in November, but she explains, "...a week to the day from my emergency surgery I started getting intense nerve pain in one of my incisions. I was all set to fly to Vancouver on Wednesday but, alas, I am not ready yet. So, sadly, I will need to cancel the first four dates of my November tour - this includes Vancouver, Bellingham, Portland and Seattle. I need to stay close to my doctors and the hospital in case this initial pain turns into something more serious. I'm ready to get back out there mentally though and if all goes even remotely as planned I will be ready for San Francisco."

subset: commoncrawl


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Rumors, rumors and more rumors. 'Tis the season for NFL rumors to abound. From the NFL draft to possible trades to free agency to, well, every little detail of the Jimmy Graham situation, there are no shortage of rumors at the moment.
Below, we'll take a look at a few of the latest rumors to make the rounds. Believe them at your own risk; ignore them at your own peril. Or, um, something like that.
New Orleans Saints
All eyes remained affixed on the Graham situation, but Adam Schefter of ESPN stirred the waves a bit on Wednesday when he tweeted the following:
Saints shopping RB Pierre Thomas and WR Lance Moore to other teams, per sources, and even could be open to trading RB Darren Sproles also.— Adam Schefter (@AdamSchefter) March 6, 2014
Of course, all roads in New Orleans seem to lead to Graham, and moving these players for a pick could clear some much-needed cap space. Plus, in a deep draft, the Saints could replace all three. And especially at running back, New Orleans is pretty loaded, with Mark Ingram and Khiry Robinson still on the roster.
Of course, no matter what happens, it remains likely Graham will return to the team. Saints general manager Mickey Loomis recently told Rich Gannon and Bruce Murray of SiriusXM NFL Radio (via Mike Florio of Pro Football Talk) the following:
These negotiations are always a process, and Jimmy's been a great player for us for the last four years. Look, I had hoped and I'm sure he had hoped we'd come to some conclusion on a longer-term deal before this. But we haven't yet, and hopefully we will. ... We'll just let it play out, and I'm sure we'll get something resolved.
One thing is for certain—it's probably unlikely any team will pay Graham a huge contract and give up two first-round picks in the process. Consider the following, from Bleacher Report's Mike Freeman:
Packers source when asked notion of them giving up 2 No.1s for Jimmy Graham: "Beyond dumb." Ten-Point Stance: http://t.co/ixpCkfFOK5— mike freeman (@mikefreemanNFL) March 5, 2014
Those picks are extremely valuable, and as good as Graham is, his injury concerns probably make him too risky to give up two firsts. Expect him to be a Saint next season.
Minnesota Vikings
At first, it seemed only Adrian Peterson was interested in adding quarterback Michael Vick to the Minnesota Vikings.
@MikeVick would intently make the vikings a playoff team!— Adrian Peterson (@AdrianPeterson) March 6, 2014
But now, it seems the team could potentially grant the star running back his wish. From Florio:
Per a source with knowledge of the situation, the Vikings could become very interested in Vick if Matt Cassel chooses to sign elsewhere.
Cassel, who signed a two-year deal in 2013, has opted out of the second season. On Thursday, coach Mike Zimmer said that he wants Cassel to stay, if Cassel wants to stay. He'd been due to earn $3.7 million in 2014.
Vick doesn't necessarily fit with offensive coordinator Norv Turner's system, but that may not matter. Peterson publicly has made his preference known. Privately, he could be lobbying even more strongly. The Vikings have committed to Peterson as the current and future face of the franchise; will they give him what he apparently wants?
Vick would certainly add some more excitement to this Vikings offense. Bringing him aboard would put less pressure on the team to select a quarterback in the first round, as the top three options will likely be off the board by the time they select.
This rumor could have some legs, folks.
Houston Texans
While free agency will soon be the dominant story around the NFL, the Texans are going to control the storylines once the NFL draft gets closer. Such are the perks when you hold the first overall pick.
In the coming weeks, expect the team to be linked with a number of players, all likely a part of an elaborate misinformation campaign to keep other teams guessing or enticing them to offer a package to trade for that top overall pick.
At the moment, rumors linking the Houston Texans to Jadeveon Clowney are starting to heat up. From Lance Zierlein of Sports Talk 790 in Houston:
Looking more and more like Texans go with best player on their board (likely Clowney) and a QB later in the draft. Traits usually win out.— Lance Zierlein (@LanceZierlein) March 6, 2014
Clowney is considered by many to be the top overall talent in this draft, so it wouldn't be a shocker if the Texans drafted him. But the team is also in dire need of a quarterback, so floating their interest for Clowney in the hopes that other potential suitors will try to strike up a deal for the top overall pick makes sense.


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He might look like a seventh-grade science teacher, but Ed Boon is an industry legend, and is responsible for creating the violently iconic fighting franchise Mortal Kombat. Boon and his team at Warner Bros. Interactive are hard at work on the next installment in the storied series, aptly titled Mortal Kombat. Longtime MK fans will find plenty of old-school flavor here (oh, and lots and lots of gruesome fatalities and rivers of blood).
Check out our interview with Boon below to find out more about the "love letter to fans" that is Mortal Kombat.


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The IRS is reminding taxpayers that it has unveiled a "simpler option" to figure the business use of a home.
IRS Highlights Simplified Home Office Deduction
washington, D.C. (July 29, 2013)
Get access to this article and thousands more...
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Shaping Water and Soil at Inspiration Farm
"If you grow good soil, everything else falls into place. You grow good plants, you grow good animals, you grow good people." Permaculturist Brian Kerkvliet shows how he gently shapes soil to form ponds which overflow into connected swales (ditches on contour). They slow and retain water while distributing nutrients through the whole landscape. On the mound of soft earth dug out from one swale, he planted mostly edible cover crops, berry bushes and 25 fruit tree species in only three days. "We don't till [the soil]," he says. "The worms till. The moles till. We find the niche where each element works the best." Episode 267. [inspirationfarm.com]
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Owner | President
Yes I am a proud owner of the Z10. I would. Say it was a smooth transition for me from my 9800, to my Z10. The only problem I had was my missing blackberry protect which stores my task etc: I found....
Liked On: 04-08-2013, 03:25 PM
Okay, finally have my Z10, it fabulous. Can't wait to get familiarized. With it. Oh! It's Black.
Liked On: 02-17-2013, 03:30 AM
I am so excited of the launching of Blackberry Z10 tonight. also appointing Alicia Keys as the Global Ambassador. I cant wait to see all the new and exciting things Blackberry will continue to bring...
Liked On: 01-30-2013, 09:58 PM
Liked On: 01-30-2013, 09:53 PM
Good. Point
Liked On: 12-06-2012, 05:03 PM
Black is great. How about a navy blue
Liked On: 10-28-2012, 08:47 PM


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A.M. Roundup: 'Wizard Of Oz' Munchkin Margaret Pellegrini Dies, 'Big Brother' Recap, Percy Jackson Saves NOLA
Previously on Big Brother: Howard and Candice tried to get Amanda out of the house, but logic was too much for the fragile brains of the houseguests. Howard was evicted during Racist #1's HoH and Racist #2 was immediately made HoH. One guess who she targeted? Jessie stood up for herself and all the viewers who were sick of Amanda. (recap)
The production of new action adventure movie Percy Jackson: Sea Of Monsters served as a major clean-up operation for one of New Orleans, Louisiana's most beloved amusement parks after director Thor Freudenthal chose to turn The Six Flags Jazzland attraction into his Circeland on the island of Polyphemus. In order to film there, the moviemaker and his crew had to clear the theme park of alligators, snakes and debris which had been dumped there by Hurricane Katrina in 2005 - and they did such a good job, locals thought the old place had re-opened. (story)
Jennifer Aniston and Justin Theroux will reportedly marry this weekend. The 'We're the Millers' actress and her fiance are so determined to keep their nuptials secret, friends and family invited to their Los Angeles home on Saturday have been told it is for Justin's 42nd birthday party. (story)
Margaret Pellegrini, one of the last living Munchkins from The Wizard Of Oz, died on Wednesday at the age of 89. Pellegrini, who played the Flowerpot Munchkin in the 1939 film, passed away near her Glendale, Arizona home from complications from a recent stroke. (story)
NFL stars Eli and Peyton Manning star in a new rap video for DirecTV's NFL Sunday Ticket, which gives subscribers the opportunity to watch "Football on Your Phone." (story)
Jay Z is the type of boss many people would love to have. The rapper recently gave each of his employees a $50,000 bonus. His reason? He got a huge tax rebate so he generously rewarded 80 staff members - totaling a whopping $6.4 million. (story)
Lea Michele is diving into her work following the accidental overdose of her boyfriend and co-star Cory Monteith last month. The actress tweeted a photo of herself on the set of "Glee" with the caption: "Feels so good to be home…#GleeSeason5." (story)
Robin Thicke's new album "Blurred Lines" has topped the charts in its first week, knocking Selena Gomez's "Stars Dance" from the top spot. The album debuted at number one after selling 177,000 copies following its July 30 release, becoming the first chart-topper for the singer. (story)
Robert Pattinson has started new rumors he has reconciled with Twilight co-star Kristen Stewart after he was spotted outside her home in Los Angeles. (story)
Check out pics of 14 more sexy celebs with the best looking, most kissable lips on the planet. (story)


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Rx only
Indomethacin Capsules, USP for oral administration are provided in two dosage strengths which contain either 25 mg or 50 mg of indomethacin. Indomethacin is a non-steroidal anti-inflammatory indole derivative designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid.
The structural formula is:
Indomethacin, USP is practically insoluble in water and sparingly soluble in alcohol. It has a pKa of 4.5 and is stable in neutral or slightly acidic media and decomposes in strong alkali.
Each capsule for oral administration contains 25 mg or 50 mg of indomethacin and the following inactive ingredients: colloidal silicon dioxide, gelatin, FD&C Green #3, magnesium stearate, microcrystalline cellulose, powdered cellulose, sodium lauryl sulfate, sodium starch glycolate, titanium dioxide and D&C Yellow #10.
Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antipyretic and analgesic properties. Its mode of action, like that of other anti-inflammatory drugs, is not known. However, its therapeutic action is not due to pituitary-adrenal stimulation.
Indomethacin is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached during therapy which have been demonstrated to have an effect in vivo as well. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Moreover, prostaglandins are known to be among the mediators of inflammation. Since indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
Indomethacin has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis.
Indomethacin affords relief of symptoms; it does not alter the progressive course of the underlying disease.
Indomethacin suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with indomethacin for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. Indomethacin may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects.
Indomethacin has been reported to diminish basal and CO2 stimulated cerebral blood flow in healthy volunteers following acute oral and intravenous administration. In one study, after one week of treatment with orally administered indomethacin, this effect on basal cerebral blood flow had disappeared. The clinical significance of this effect has not been established.
Indomethacin capsules have been found effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis (see INDICATIONS AND USAGE).
Following single oral doses of indomethacin capsules 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered indomethacin capsules are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of indomethacin oral suspension was found to be bioequivalent to a 50 mg indomethacin capsule when each was administered with food.
Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be about 4.5 hours. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose.
Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyl-desbenzoyl metabolites, all in the unconjugated form. About 60 % of an oral dosage is recovered in urine as drug and metabolites (26 % as indomethacin and its glucuronide), and 33 % is recovered in feces (1.5 % as indomethacin).
About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta.
Carefully consider the potential benefits and risks of indomethacin capsules and other treatment options before deciding to use indomethacin. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
Indomethacin has been found effective in active stages of the following:
Indomethacin is contraindicated in patients with known hypersensitivity to indomethacin or the excipients (see DESCRIPTION).
Indomethacin should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/anaphylactoid reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactic/Anaphylactoid Reactions, and PRECAUTIONS: General: Preexisting Asthma).
Indomethacin is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).
Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate over renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients with volume depletion, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of indomethacin, even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state (see PRECAUTIONS: Drug Interactions).
As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to indomethacin. Indomethacin should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS: General: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactic/anaphylactoid reaction occurs.
NSAIDs, including indomethacin, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
In late pregnancy, as with other NSAIDs, indomethacin should be avoided because it may cause premature closure of the ductus arteriosus.
Corneal deposits and retinal disturbances, including those of the macula, have been observed in some patients who had received prolonged therapy with indomethacin. The prescribing physician should be alert to the possible association between the changes noted and indomethacin. It is advisable to discontinue therapy if such changes are observed. Blurred vision may be a significant symptom and warrants a thorough ophthalmological examination. Since these changes may be asymptomatic, ophthalmologic examination at periodic intervals is desirable in patients where therapy is prolonged.
Indomethacin may aggravate depression or other psychiatric disturbances, epilepsy, and parkinsonism, and should be used with considerable caution in patients with these conditions. If severe CNS adverse reactions develop, indomethacin should be discontinued.
Indomethacin may cause drowsiness; therefore, patients should be cautioned about engaging in activities requiring mental alertness and motor coordination, such as driving a car. Indomethacin may also cause headache. Headache which persists despite dosage reduction requires cessation of therapy with indomethacin.
Indomethacin cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of indomethacin in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, indomethacin should be discontinued.
In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of indomethacin on labor and delivery in pregnant women are unknown.
Indomethacin is excreted in the milk of lactating mothers. Indomethacin is not recommended for use in nursing mothers.
Safety and effectiveness in pediatric patients 14 years of age and younger have not been established.
Indomethacin should not be prescribed for pediatric patients 14 years of age and younger unless toxicity or lack of efficacy associated with other drugs warrants the risk.
In experience with more than 900 pediatric patients reported in the literature or to the manufacturer who were treated with Capsules indomethacin, side effects in pediatric patients were comparable to those reported in adults. Experience in pediatric patients has been confined to the use of Capsules indomethacin.
If a decision is made to use indomethacin for pediatric patients 2 years of age or older, such patients should be monitored closely and periodic assessment of liver function is recommended. There have been cases of hepatotoxicity reported in pediatric patients with juvenile rheumatoid arthritis, including fatalities. If indomethacin treatment is instituted, a suggested starting dose is 1 mg/kg/day given in divided doses. Maximum daily dosage should not exceed 4 mg/kg/day or 150 to 200 mg/day, whichever is less. As symptoms subside, the total daily dosage should be reduced to the lowest level required to control symptoms, or the drug should be discontinued.
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions (see WARNINGS, Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation and DOSAGE AND ADMINISTRATION). Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
Indomethacin may cause confusion or, rarely, psychosis (see ADVERSE REACTIONS); physicians should remain alert to the possibility of such adverse effects in the elderly.
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see WARNINGS: Renal Effects).
The adverse reactions for indomethacin capsules uled in the following table have been arranged into two groups: (1) incidence greater than 1%; and (2) incidence less than 1%. The incidence for group (1) was obtained from 33 double-blind controlled clinical trials reported in the literature (1,092 patients). The incidence for group (2) was based on reports in clinical trials, in the literature, and on voluntary reports since marketing. The probability of a causal relationship exists between indomethacin and these adverse reactions, some of which have been reported only rarely.
|Incidence greater than 1%
abdominal distress or pain
headache (11.7%)
depression and fatigue (including malaise and ullessness)
|Incidence less than 1%
bloating (includes distention)
peptic ulcer
rectal bleeding
single or multiple ulcerations, including perforation and hemorrhage of the esophagus, stomach, duodenum or small and large intestines
intestinal ulceration associated with stenosis and obstruction
gastrointestinal bleeding without obvious ulcer formation and perforation of preexisting sigmoid lesions (diverticulum, carcinoma, etc.) development of ulcerative colitis and regional ileitis
ulcerative stomatitis
toxic hepatitis and jaundice (some fatal cases have been reported)
intestinal strictures (diaphragms)
anxiety (includes nervousness)
muscle weakness
involuntary muscle movements
psychic disturbances including psychotic episodes
mental confusion
aggravation of epilepsy and parkinsonism
peripheral neuropathy
ocular-corneal deposits and retinal disturbances, including those of the macula, have been reported in some patients on prolonged therapy with indomethacin
blurred vision
hearing disturbances, deafness
congestive heart failure
chest pain
arrhythmia; palpitations
weight gain
fluid retention
flushing or sweating
rash; urticaria
petechiae or ecchymosis
exfoliative dermatitis
erythema nodosum
loss of hair
Stevens-Johnson Syndrome
erythema multiforme
toxic epidermal necrolysis
bone marrow depression
anemia secondary to obvious or occult gastrointestinal bleeding
aplastic anemia
hemolytic anemia
thrombocytopenic purpura
disseminated intravascular coagulation
acute anaphylaxis
acute respiratory distress
rapid fall in blood pressure resembling a shock-like state
pulmonary edema
vaginal bleeding
proteinuria, nephrotic syndrome, interstitial nephritis
BUN elevation
renal insufficiency, including renal failure
breast changes, including enlargement and tenderness, or gynecomastia
Other reactions have been reported but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, the possibility cannot be excluded. Therefore, these observations are being uled to serve as alerting information to physicians:
Cardiovascular: thrombophlebitis
Hematologic: Although there have been several reports of leukemia, the supporting information is weak.
Genitourinary: urinary frequency
A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, including indomethacin, sometimes with fatal outcome (see also PRECAUTIONS: General).
The following symptoms may be observed following overdosage: nausea, vomiting, intense headache, dizziness, mental confusion, disorientation, or lethargy. There have been reports of paresthesias, numbness and convulsions.
Treatment is symptomatic and supportive. The stomach should be emptied as quickly as possible if the ingestion is recent. If vomiting has not occurred spontaneously, the patient should be induced to vomit with syrup of ipecac. If the patient is unable to vomit, gastric lavage should be performed. Once the stomach has been emptied, 25 or 50 g of activated charcoal may be given. Depending on the condition of the patient, close medical observation and nursing care may be required. The patient should be followed for several days because gastrointestinal ulceration and hemorrhage have been reported as adverse reactions of indomethacin. Use of antacids may be helpful.
The oral LD50 of indomethacin in mice and rats (based on 14 day mortality response) was 50 and 12 mg/kg, respectively.
Carefully consider the potential benefits and risks of indomethacin and other treatment options before deciding to use indomethacin. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).
After observing the response to initial therapy with indomethacin, the dose and frequency should be adjusted to suit an individual patient's needs.
Indomethacin is available as 25 mg and 50 mg capsules.
Adverse reactions appear to correlate with the size of the dose of indomethacin in most patients but not all. Therefore, every effort should be made to determine the smallest effective dosage for the individual patient.
Indomethacin ordinarily should not be prescribed for pediatric patients 14 years of age and under (see WARNINGS).
Dosage Recommendations for Active Stages of the Following:
In patients who have persistent night pain and/or morning stiffness, the giving of a large portion, up to a maximum of 100 mg, of the total daily dose at bedtime may be helpful in affording relief. The total daily dose should not exceed 200 mg. In acute flares of chronic rheumatoid arthritis, it may be necessary to increase the dosage by 25 mg or, if required, by 50 mg daily.
If minor adverse effects develop as the dosage is increased, reduce the dosage rapidly to a tolerated dose and OBSERVE THE PATIENT CLOSELY.
If severe adverse reactions occur, STOP THE DRUG. After the acute phase of the disease is under control, an attempt to reduce the daily dose should be made repeatedly until the patient is receiving the smallest effective dose or the drug is discontinued.
Careful instructions to, and observations of, the individual patient are essential to the prevention of serious, irreversible, including fatal, adverse reactions.
As advancing years appear to increase the possibility of adverse reactions, indomethacin should be used with greater care in the elderly (see PRECAUTIONS: Geriatric Use).
Indomethacin Capsules, USP are available containing either 25 mg or 50 mg of Indomethacin, USP.
The 25 mg capsule is a hard-shell gelatin capsule with a light green opaque cap and a light green opaque body axially printed with MYLAN over 143 in black ink on both the cap and body. The capsule is filled with a white powder blend. They are available as follows:
bottles of 100 capsules
bottles of 1000 capsules
The 50 mg capsule is a hard-shell gelatin capsule with a light green opaque cap and a light green opaque body axially printed with MYLAN over 147 in black ink on both the cap and body. The capsule is filled with a white powder blend. They are available as follows:
bottles of 100 capsules
bottles of 500 capsules
Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]
Protect from light.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
Mylan Pharmaceuticals Inc.
Morgantown, WV 2650
(See the end of this Medication Guide for a ul of prescription NSAID medicines.)
What is the most important information I should know about medicines called Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
What are Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
NSAID medicines are used to treat pain and redness, swelling, and heat (inflammation) from medical conditions such as:
Who should not take a Non-Steroidal Anti-Inflammatory Drug (NSAID)?
Do not take an NSAID medicine:
Tell your healthcare provider:
What are the possible side effects of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)?
|Serious side effects include:
|Other side effects include:
Get emergency help right away if you have any of the following symptoms:
Stop your NSAID medicine and call your healthcare provider right away if you have any of the following symptoms:
These are not all the side effects with NSAID medicines. Talk to your healthcare provider or pharmacist for more information about NSAID medicines.
Other information about Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Aspirin is an NSAID medicine but it does not increase the chance of a heart attack. Aspirin can cause bleeding in the brain, stomach, and intestines. Aspirin can also cause ulcers in the stomach and intestines. Some of these NSAID medicines are sold in lower doses without a prescription (over-the-counter). Talk to your healthcare provider before using over-the-counter NSAIDs for more than 10 days.
NSAID medicines that need a prescription
|Generic Name
|Cataflam, Voltaren, Arthrotec (combined with misoprostol)
|Lodine, Lodine XL
|Nalfon, Nalfon 200
|Motrin, Tab-Profen, Vicoprofen (combined with hydrocodone), Combunox (combined with oxycodone)
|Indocin, Indocin SR, Indo-Lemmon, Indomethagan
|Mefenamic Acid
|Naprosyn, Anaprox, Anaprox DS, EC-Naprosyn, Naprelan, Naprapac (copackaged with lansoprazole)
|Tolectin, Tolectin DS, Tolectin 600
This Medication Guide has been approved by the U.S. Food and Drug Administration.


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|The 27th Alaska State Legislature, 2011 - 2012
Insurance: Health Care & Other
|Signed Into Law! Chapter 23 SLA 11
Sponsored by the House Labor & Commerce Committee
"An Act relating to health care insurance, exemption of certain insurers, reporting, notice, and record-keeping requirements for insurers, biographical affidavits, qualifications of alien insurers assuming ceded insurance, risk-based capital for insurers, insurance holding companies, licensing, federal requirements for nonadmitted insurers, surplus lines insurance, insurance fraud, life insurance policies and annuity contracts, rate filings by health care insurers, long-term care insurance, automobile service corporations, guaranty fund deposits of a title insurer, joint title plants, fraternal benefit societies, multiple employer welfare arrangements, hospital and medical service corporations, health maintenance organizations, and alternate forms of payment to policyholders; and providing for an effective date."
Posted: March 7, 2011 : v27-LS0444-A
House Bill 164 is a compilation of various provisions to make changes to the Insurance Code to enhance, update and provide uniformity with national standards to improve the regulation of the insurance industry.
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This is my first time reviewing Missha. Can't believe it, I only have some of Missha brand and this is one of it. This is sponsored by Cosmetic Love. One of my favorite online shop selling Korean cosmetics with free shipping worldwide. Anyway, heard how famous this BB Cream is, and when I got the chance I just picked that up, especially since it has a smaller size. I prefer smaller size BB Cream because it's compact and I can try others too without feeling guilty. ^_^
It is a multi function BB Cream with effect of UV blocking, whitening and wrinkle care, creating perfect cover makeup.
- Dermatologist test for skin safety -
This M Perfect Cover BB Cream makes your skin tone clean and natural by concealing blemishes with exellent skin coverage. It is a multi functional makeup cream with blocking UV rays, whitening and wrinkle care effects and simplifies makeup formalities. Its moisturized application with W/S texture makes sleek skin tone while supplying moisture and nutrition at the same time.
It provides excellently concealing any types of pigmentation or discoloration area on face including acne, couperose, vitiligo, age spots, sun spots and dark circles.
- For all skin type even for acne skin type
- It can be used as a makeup base or foundation.
- Containing substances for Soothing the skin (Na-complex)
MISSHA M Perfect BB Cream Contains natural ingredients that do not damage or irritate the skin. With Continuous use, your sensitive skin will be calm, protected from redness and keep its health.
MISSHA M BB Cream is a natural care cream for sensitive skin, naturally covering the irregularities on the skin as well as improving skin texture. Botanical ingredients, such as mugwort and pumpkin, and the nutritional ingredients keep skin moist and silky. MISSHA M BB Cream is a multifunctional product that can be used instead of makeup base and foundation.
INTRODUCTION to BB cream
- Blemish Balm, also call BB Cream, is known to have been formulated as an after-treatment cream to help patients who have gone through laser skin surgery to soothe and regenerate the skin.
- Helps to soften skin texture
- Prolonged used of product may help to improve overall texture of skin & fade acne scars
- Act as a makeup base & foundation
- Helps to cover the irregularities on the skin, even out skin tone, camouflage under eye circles, scars & add radiance to face.
[How to Use]
1. After using B.B Boomer, apply an appropriate amount along the skin texture and finish with powder
2. Do not need to apply sun cream in addition
1. For external use only
2. Do not swallow
3. Keep out of reach of children
4. Avoid contact with eyes
SPF (Sun Protection Factor): SPF of the product is measured by test methods of KDFA (Korea Food & Drug Administration)
Water (Aqua), Cyclomethicone, Ethylhexyl Methoxycinnate, Zinc Oxide, Caprylic/Capric Triglyceride, Mineral Oil, Phenyl Trimethicone, Talc, Arbutin, Hydrolyzed Collagen, Dimethicone, Macadamia Terifolia Seed Oil, Squalane, Adenosine, Cetyl PEG/PPG-10/1 Dimethicone, PEG-10 Dimethicone, Polyethylene, Beeswax (Cera Alba), Glycerin, Propylene Glycol, Caviar Extract, Algae Extract, Ceramide 3, Rosamarinus Officinalis (Rosemary) Leaf Extract, Chamomilla Recuitita (Matricaria) FLower Extract, Sodium Hyaluronate, Sodium Chloride, Fragrance (Parfum), Methylparaben, Propylparaben, Disodium EDTA, Hydroxisohexyl 3-Cyclohexene Carboxaldehyde, Butylphenyl Methylpropional, Benzyl Salicylate, Hydroxycitronellal, Alpha-Isomethyl lonone, Hexyl Cinnamal, Linalool, Citronellol MAY CONTAIN [+/-; Titanium Dioxide (CI 77891), Iron Oxides (CI 77491, CI 77492, CI 77499)]
The BB Cream comes in a glossy maroon tube and silver cap. Love the box too, it is glossy with gold, brown and dots. Cute combination. The downside is the cap is easily get dirty because of its material. Good thing the description is in English and printed on the front side.
The backside is all in Korean. That's why product details from the website is very important. ^_^
The liquid consistency is medium, between light and thick. It's a bit too thick for my liking, I prefer something with more moisturizing formula. But it is still easy to blend and it matches my skintone well. It makes my skin whiten but not fake and it evens out my yellowish skin. The finish is between dewy and matte.
The coverage is medium but it's buildable. I only use one layer and it covers up my blemishes pretty well. So glad that it works good on my dark circle too.
+ Comes in 2 size 50ml and 20ml
+ Good coverage
+ Moisturizing but for dry skin still need to prep your skin well
+ Good oil control
+ Affordable
+ High SPF
- Melting in hot weather
- Not suitable for dark skin
I like the coverage, it covers my blemishes pretty well. It is the smallest BB Cream I have in real size, travel friendly. The consistency is medium but a bit thick for my liking, sticky a bit after applying. My skin is normal dry and it is a bit drying for me but it has good oil control from what I've heard, so don't forget to prep the skin well before applying. It is good in AC room but for very hot weather, it's a bit melting but good thing it has high SPF. Overall, I love it! It is similar with foundation but lighter. This is my BB Cream choice when I go to a party or so.
This product is sponsored by
Product link: [MiSSHA] M Perfect Cover BB Cream 20ml SPF42 PA+++
Price: $8.94
Free Worldwide Shipping


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With great wine being produced in some of the least likely places around the world—take Tannat from Uruguay, for example—it should come as no surprise that producers from all areas of the United States are getting in on the action, too. And while the rise of quality bottlings from off-the-beaten-path wine regions is unlikely to challenge the supremacy of the country's most famous appellations, it is, nonetheless, having a very real impact on restaurants.California, Washington and Oregon ...
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PLEASANTON, Calif. — "Get Out & Grill" is the name of a private-label-themed contest at Safeway. Shoppers who buy two packages of Rancher's Reserve beef in a single transaction through June 10 are automatically entered into a sweepstakes to win a grand prize of a backyard entertainment center, complete with outdoor kitchen that includes a refrigerator and pizza oven; and a movie theatre that includes a screen and projector. Other prizes include a Weber grill with a Rancher's reserve ...
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This custom drawstring bag with reinforced corners are not only very popular but also inexpensive and comes in 16 colors!
Get noticed easily with this compact sized custom drawstring backpack featuring dual reflective stripes.
Make your logo a force to be reckoned with by putting it on this smart custom briefcase.
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Made of vinyl, this clear custom drawstring backpack is perfect for fans packing their stadium and event day items safely.
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Tag Archives: book London hotels
10 Must-See Things inside Buckingham Palace
Buckingham Palace, the official residence of the Monarch of England, is top of the list of the must-see places in London of any visitor who comes to the city. No visit can be complete without a visit to this iconic Royal residence where the Queen and family are staying today. … Continue reading
Top London Attractions for Families
London is a great place to take children, as well as the experience of being able to visit the capital city, which they will no doubt have heard much about at school, there is also a great deal for them to see and do. Here are three of our favourite … Continue reading
The Benefits of a Business Base In London
Thanks to the digital age, we live in a world that literally never sleeps, and this is never truer than in the world of business. London is a major player in the world economy and its trade and tourism provide a major source of income helping to stabilise Britain's position … Continue reading
Enjoy London on a Budget
When people think about trips to London, they usually associate it with the need to have lots of money to pay for hotel rooms and tube tickets and so on. However, it is actually possible to visit London and not need to take out a second mortgage on your home! … Continue reading
Posted in London Hotel Tagged best hotel in london, best hotels travel, best London hotels, book London hotels, Cheap Hotel London, easy accommodation london, hotel conference facilities, last minute top secret hotels, london accommodation guide, London hotels, London hotels deals, London Last Minute Hotels, London Piccadilly Hotels Leave a comment
London hotel discounts- Make your stay even more exciting!
If you have visited London in the past, you must be surely aware that living or vacationing in London is quite an expensive affair. The hotels here are expensive and you need to be quite flexible with your budget if you look forward to a memorable vacation in London. However, … Continue reading
Posted in London Hotel Tagged best London hotels, book London hotels, Cheap Hotel London, cheap London hotels, easy accommodation london, easy london accommodation, last minute top secret hotels, london accommodation guide, London hotels discount, London Hotels Special Offers, luxury hotels london deals, Oxford Street, Shaftesbury suites Leave a comment
Cost-effective and Amazing London Budget Hotels from Shaftesbury Group
Being one of the most expensive cities of the world, London surely requires a fortune to visit. However, with the amazing number of tourist destination and official hubs, it continues to rule of the hearts of the travellers. People love to spend their holidays in London and thousands of them … Continue reading
Christmas Parties in London
London is a great city if you are looking for a vibrant and exciting place to hold your work's Christmas Party. Not only is there a huge choice of venues and locations to choose from, you also have the city itself to explore the following day and some of the … Continue reading
Reasons to Lodge in UK London Hotels
Behave like a Roman if you are in Rome – so goes a saying that advices you and me to lodge in UK London Hotels for the good while in London for a business or otherwise. What's special about UK London Hotels? While deciding on your vacation plan or business … Continue reading


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Arkansas loses senior starting middle linebacker Weston Dacus, and the coaching staff has come across Scranton (Pa.) Lackawanna College's Mike Balogun as a potential replacement.
Hogs target JUCO linebacker
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Cut the Rope
Your original file link
u son of a . wat d fck is ds
hi friend.....whn i open this game it disply "memory full close some application"...but thr is no app is run in tasks... plz..help me
i think it's because the RAM of your phone is not enough.
cuesta mucho que los juegos sirban
when i downloaded it the name was changed into sexmaal!Fake
Why i cant download this on my phone Sony Ericsson Vivaz U8A? It says if i download this something will happen wrong with my computer? Sorry for my bad english I'm from Philippines
Try scanning the file with a software to check for virus or harmful files
it says it may harm my computer so I did not download it


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Lean-To conservatories (or Sunrooms) are probably the simplest in design and originally the most popular conservatory option. With its clean lines and timeless appearance the Lean-To conservatory style is still a very popular choice today.
Lean-To conservatories classically have a low pitched roof which makes them ideally suited to bungalows or houses restricted by height.
Whether you opt for a dwarf wall or glass from floor to ceiling this design is ideal for blending home and garden and offers a traditional structure for years of enjoyment


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1300 flights canceled in Dallas/Fort Worth
Snow and Ice Storm slow down Dallas Airport and delay flights
< Bus Crash Survivors Near Pendleton
Jan 02, 2013 07:55
Category: General News
Category: General News
Suspect Jumped into Spokane River
A suspected car thief on the run from Spokane police yesterday made a bad choice. After police chased him to the Spokane River, the suspect jumped into the river to escape. After a few minutes in the icy cold water, he climbed out and was taken away by the police—not to jail, to the hospital, so they could treat him for hypothermia. Then jail.


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Hank Moody
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Roosevelt Franklin
|This article includes a list of references, related reading or external links, but its sources remain unclear because it lacks inline citations. (November 2015) (Learn how and when to remove this template message)
Roosevelt Franklin was a Muppet featured on the children's television series Sesame Street during the early 1970s. He is purple with shaggy black hair that stands on end. His name is a word play on the name of US President Franklin Roosevelt. Sesame Street cast member Matt Robinson, who also played Gordon, provided Roosevelt Franklin's voice.
Franklin is an intelligent boy who often speaks in rhyme or scat. Franklin began to appear less frequently in episodes created after the mid-1970s until he no longer was on the series.
Roosevelt Franklin usually appears in scenes with his mother, voiced by Loretta Long, who plays Susan on the series, and Roosevelt frequently recited poetry. Later scenes are set in a classroom, in which Roosevelt appears to fill in for an absent teacher.
Franklin is featured on a 1971 record album called The Year Of Roosevelt Franklin, which was reissued in 1974 as My Name Is Roosevelt Franklin.
External links[edit]
- Roosevelt Franklin on Muppet Wiki, an external wiki
- Roosevelt Franklin as classroom teacher
- Roosevelt Franklin chosen as the Most Underrated Muppet
- 9 Muppets Kicked Off Sesame Street
|This article about a fictional television character is a stub. You can help Wikipedia by expanding it.


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With the help of the cycling team I'll be putting on this great training series this year. Come out and Cyclocross!
This year we will be running five weeks of training series races every Wednesday night at Kingman Farm. Everyone is encourage to participate in the event. Mountain bikes are absolutely welcome at the races!
Also, in past years we have had some great feedback from riders/racers about improvements. Please keep in the suggestions coming, we want to make this as good as possible for you!
The Schedule:
"B" Race goes off promptly at 5:00 and lasts 30 minutes
"A" Race goes off promptly at 5:35 and lasts 45 minutes
The first race will be Wednesday September 14th, and follow for five weeks (that means races fall on September 14th, 21st, 28th, October 5th, 12th)
Map is viewable here:
Entry Fees:
ENTRY FEES ARE ONLY $5! Adding the extra race is only $3 dollars. We also offer the complete series package, all 5 races for just $20! It's a buy 4 get 1 free sort of deal! That's a lot of 'cross for not a lot of money. All proceeds from the race benefit the UNH Cycling Team (a worthwhile cause).
Rules and Other Things to Know:
- We are NOT a USAC sanctioned event. All normal rules of cyclocross still apply.
- All riders must sign waivers before competing.
From the North/South:
From I 95 take the Spaulding Turnpike North to Exit 8W (Madbury/Route 155). Follow Rt 155 for three miles. There will be signs indicating a right turn on to an access road off of a small dirt parking lot.
From Durham:
Take Madbury Road to the intersection of Rt 4. At the set of lights, go straight through, crossing Rt 4. This will intersect with Rt 155. Take a right onto 155, and about a mile later take a left turn into Kingman Farm.
From the East and West
Take Rt 4 to the intersection with Madbury Road. (from the East, take a right and from the West take a left) and then follow the directions from Durham.
For more information about the event, please contact me via facebook or at email@example.com
Thank You to: La Festa Brick and Brew