Prolactin receptors in Rip-cre cells, but not in AgRP neurones, are involved in energy homeostasis.

Among its many functions, prolactin has been implicated in energy homeostasis, particularly during pregnancy and lactation. The arcuate nucleus is a key site in the regulation of energy balance. The present study aimed to examine whether arcuate nucleus neuronal populations involved in energy homeostasis are prolactin responsive and whether they can mediate the effects of prolactin on energy homeostasis. To determine whether Agrp neurones or Rip-Cre neurones are prolactin responsive, transgenic mice expressing the reporter td-tomato in Agrp neurones (td-tomato/Agrp-Cre) or Rip-Cre neurones (td-tomato/Rip-Cre) were treated with prolactin and perfused 45 minutes later. Brains were processed for double-labelled immunohistochemistry for pSTAT5, a marker of prolactin-induced intracellular signalling, and td-tomato. In addition, Agrp-Cre mice and Rip-Cre mice were crossed with mice in which the prolactin receptor gene (Prlr) was flanked with LoxP sites (Prlrlox/lox mice). The Prlrlox/lox construct was designed such that Cre-mediated recombination resulted in deletion of the Prlr and expression of green fluorescent protein (GFP) in its place. In td-tomato/Rip-Cre mice, prolactin-induced pSTAT5 was co-localised with td-tomato, indicating that there is a subpopulation of Rip-Cre neurones in the arcuate nucleus that respond to prolactin. Furthermore, mice with a specific deletion of Prlr in Rip-Cre neurones had lower body weights, increased oxygen consumption, increased running wheel activity and numerous cells in the arcuate nucleus had positive GFP staining indicating deletion of Prlr from Rip-Cre neurones. By contrast, no co-localisation of td-tomato and pSTAT5 was observed in td-tomato/Agrp-Cre mice after prolactin treatment. Moreover, Prlrlox/lox /Agrp-Cre mice had no positive GFP staining in the arcuate nucleus and did not differ in body weight compared to littermate controls. Overall, these results indicate that Rip-Cre neurones in the arcuate nucleus are responsive to prolactin and may play a role in the orexigenic effects of prolactin, whereas prolactin does not directly affect Agrp neurones.

Assessing finasteride-associated sexual dysfunction using the FAERS database.

BACKGROUND: Postmarketing reports suggest that finasteride causes sexual dysfunction despite a low incidence reported in clinical trials. Therefore, the extent of risk remains unknown. OBJECTIVE: To determine whether the risk of sexual dysfunction is higher among individuals treated with finasteride compared to a baseline risk for all other drugs using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: A case by non-case disproportionality approach was used whereby a reporting odds ratio (ROR) with 95% confidence interval (CI) was calculated. The National Ambulatory Medical Care Survey (NAMCS) was used to confirm results. RESULTS: A significant disproportionality in reporting of sexual dysfunction with the use of finasteride was observed whether finasteride was indicated for hair loss (ROR = 138.17, 95% CI: 133.13, 143.4), prostatic hyperplasia (ROR = 93.88, 95% CI: 84.62, 104.16) or any indication (ROR = 173.18, 95% CI: 171.08, 175.31). When these results were stratified by age, disproportionality was strongest at 31-45 years. CONCLUSION: Use of finasteride has led to an increase in reports of sexual dysfunction where it is believed to be the primary suspect.

Diagnosing variant Creutzfeldt-Jakob disease: a retrospective analysis of the first 150 cases in the UK.

INTRODUCTION: Establishing an early clinical diagnosis in variant Creutzfeldt-Jakob disease (vCJD) can be difficult, resulting in extended periods of uncertainty for many families and sometimes a view that patients have been subjected to unnecessary investigations. This issue is accentuated by the progressive nature of vCJD and by the difficulty in achieving a confident clinical diagnosis before an advanced stage of illness. Although diagnostic delay may be a result of the non-specific early clinical features, a systematic analysis of the process of diagnosis was undertaken, with the aim of trying to achieve earlier diagnosis of vCJD. METHODS: Retrospective case file analysis was undertaken of the first 150 definite and clinically probable cases of vCJD identified by the UK surveillance system. RESULTS: There is a significant interval between illness onset and presentation to a primary care physician, which is influenced by the nature of the initial clinical features. Neurological review is invariably sought following the development of clinical signs and a diagnosis is then established relatively quickly. Despite the progressive clinical course, a confident clinical diagnosis is not usually achieved until a relatively advanced stage of illness (mean time to diagnosis 10.5 months) with a more rapid clinical progression accounting for those cases diagnosed earlier after symptom onset. CONCLUSIONS: Early clinical diagnosis in vCJD is not possible in the great majority of cases because of non-specific initial symptoms. Once neurological signs develop, a diagnosis is usually made promptly but this is often at a relatively advanced stage of illness. The inherent delays in the diagnosis of vCJD have implications for those involved in both public health and therapeutics.

Sensory features of variant Creutzfeldt-Jakob disease.

OBJECTIVE: Sensory symptoms are a prominent feature of variant Creutzfeldt-Jakob disease (vCJD), occurring at an early stage of the illness. They are persistent and can be troublesome. Here, they are described in detail and a possible anatomical basis is discussed. METHODS: The first 50 cases of vCJD confirmed by the National CJD Surveillance Unit (NCJDSU) were reviewed. Where possible the patients and their relatives were interviewed and case notes were examined. The presence and nature of sensory symptoms and signs were noted. Results of investigation and types of treatment offered were also reviewed. RESULTS: Of 50 definite cases, 64 % had persistent sensory symptoms, 16 % had no sensory symptoms and 18 % were uncertain. In 2 % there was insufficient information. Of the 32 with definite symptoms, 31 % were symptomatic from the onset of the illness. The symptoms were varied and some patients complained of more than one type of symptom. Limb pain was described in 63 % cases. This was the most common symptom and was often non-specific and poorly localised, usually occurring in the lower limbs. Other symptoms included cold feelings (25 % patients), dysaesthesia (28 % patients), paraesthesia (31 % patients) and numbness (25 % patients). The symptoms were lateralised in 31 % of patients. CONCLUSIONS: Sensory symptoms are a prominent feature of vCJD, occurring in nearly two thirds of cases. They may help distinguish variant from sporadic CJD. They are likely to be of thalamic origin but the recognised MRI changes in vCJD do not correlate with the presence or absence of sensory symptoms. Neuropathological changes in the thalamus, however, show marked astrocytosis and neuronal loss.

Use of 14-3-3 and other brain-specific proteins in CSF in the diagnosis of variant Creutzfeldt-Jakob disease.

OBJECTIVES: The detection of the protein 14-3-3 in the CSF has been shown to be a reliable and sensitive marker for sporadic Creutzfeldt-Jakob disease (CJD). Other brain-specific proteins such as neuron specific enolase (NSE), S-100b, and tau protein have also been reported to be increased in the CSF of patients with sporadic CJD. In 1996 a variant of CJD (vCJD) was described which is likely to be causally linked to the bovine spongiform encephalopathy agent. This study reports and compares the findings of CSF brain specific protein analysis in 45 patients with vCJD and in 34 control patients. METHODS: The CSF from 45 patients with vCJD and 34 controls were investigated for the presence of 14-3-3 by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting with chemiluminescent detection. Tau protein, S-100b, and NSE concentrations in CSF were measured using enzyme immunoassays. RESULTS: Protein 14-3-3 was detected in the CSF of 22/45 patients with vCJD and in 3/34 controls. The mean concentrations of NSE, S-100b, and tau protein in CSF were significantly raised in patients with vCJD compared with controls. The positive predictive value of CSF 14-3-3 was 86% and the negative predictive value was 63%. These values are lower than those reported for sporadic CJD. An increased CSF tau had a positive predictive value of 93% and a negative predictive value of 81%. The combination of CSF 14-3-3 and/or increased CSF tau had a positive predictive value of 91% and a negative predictive value of 84%. CONCLUSIONS: CSF protein 14-3-3 is not as useful a marker for vCJD as it is for sporadic CJD. Increased concentration of CSF tau was found to be a sensitive marker of vCJD but as concentrations may be increased in many forms of non-CJD dementia, this may limit its usefulness as a diagnostic test.

Geographical distribution of variant Creutzfeldt-Jakob disease in Great Britain, 1994-2000.

BACKGROUND: Geographical variation in the distribution of variant Creutzfeldt-Jakob disease (vCJD) might indicate the transmission route of the infectious agent to man. We investigated whether regional incidences of vCJD were correlated with regional dietary data. METHODS: The National CJD Surveillance Unit prospectively identified 84 people with vCJD up to Nov 10, 2000, in Great Britain. Their lifetime residential histories were obtained by interviews with a close relative. Cumulative incidences of vCJD by standard region were calculated. Grid references for places of residence in 1991 were identified and evidence of geographical clusters were sought. Data on diet in the 1980s were analysed for regional correlations with vCJD incidence. The socioeconomic status of the places of residence of people with vCJD was compared with that of the general population. FINDINGS: vCJD incidence was higher in the north of Great Britain than the south. The rate ratio (north vs south) was 1.94 (95% CI 1.27-2.98). The mean Carstairs' deprivation score for areas of residence of people with vCJD was -0.09 (-0.73 to 0.55), which is close to the national average of zero. Regional rates of vCJD were correlated with consumption of other meat or meat products as classified and recorded by the Household Food Consumption and Expenditure Survey (r=0.72), but not with data from the Dietary and Nutritional Survey of British Adults. Five people with vCJD in Leicestershire formed a cluster (p=0.004). INTERPRETATION: Regional differences in vCJD incidence are unlikely to be due to ascertainment bias. We had difficulty determining whether regional variations in diet might cause these differences, since the results of dietary analyses were inconsistent.

Diagnosis of new variant Creutzfeldt-Jakob disease.

As of December 31, 1998, 35 deaths had been attributed to new variant Creutzfeldt-Jakob disease (nvCJD) in the United Kingdom, of which 33 cases had been neuropathologically confirmed and 2 classified as probable nvCJD. Fifteen cases were male and 20 female. The median illness duration was 14 months (range, 8-38 months) and the median age at death was 29 years (range, 18-53 years). The dinical features were consistent with previous descriptions. In nearly all cases, there were early psychiatric symptoms after a median period of 6 months ataxia developed, followed by involuntary movements and cognitive impairment. Electroencephalograms did not show the "typical" appearances found in sporadic CJD, about half the cases tested had a positive 14-3-3 immunoassay, and over 70% of cases had bilateral pulvinar high signal on magnetic resonance brain scanning. Prion protein gene analysis showed that all cases were homozygous for methionine at codon 129. Diagnostic criteria for nvCJD have been formulated, which have a high sensitivity and specificity.

The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease.

BACKGROUND: There is a need for an accurate non-invasive diagnostic test for variant Creutzfeldt-Jakob disease (vCJD). We investigated the sensitivity and specificity of bilateral pulvinar high signal on magnetic resonance imaging (MRI) for the diagnosis of vCJD. METHODS: MRI from patients with vCJD and controls (patients with suspected CJD) were analysed. Scans were reviewed on two separate occasions by two neuroradiologists and scored for the distribution of changes, and likely final diagnosis. Scans from vCJD cases were reassessed to reach a consensus on all abnormalities. FINDINGS: We analysed 36 patients and 57 controls. vCJD patients were correctly identified based on bilateral pulvinar high signal in 29 of 36 and 32 of 36 cases on the first assessment by the two radiologists, and 32 of 36 and 31 of 36 on their second assessment. Bilateral increased pulvinar signal was identified in one of 57 and one of 57 controls on the first assessment and two of 57 and three of 57 controls on the second assessment. These reported changes in controls were graded as minimal/equivocal in six of seven patients and moderate in one (<0.5% of all control assessments). 80% of the assessments in vCJD cases were graded as moderate or substantial. On consensus review, 28 of 36 cases and none of 57 controls had prominent bilateral pulvinar signal-sensitivity 78% (95% CI 60-90%) and specificity 100% (95% CI 94-100%). Other common MRI features of vCJD were medial thalamic and periaqueductal grey matter high signal, and the notable absence of cerebral atrophy. Pulvinar high signal correlated with histological gliosis. INTERPRETATION: In the appropriate clinical context the MRI identification of bilaterally increased pulvinar signal is a useful non-invasive test for the diagnosis of vCJD.

[111Indium-DTPA-D-phe] octreotide scintigraphy in the diagnostic assessment of palpable breast lumps.

It has been suggested that [111Indium-DTPA-D-Phe] octreotide scintigraphy may be useful in the staging of breast cancer. We evaluated its role in the diagnostic assessment of 40 female patients with palpable breast lumps. All were clinically assessed and imaged by ultrasound or mammography. Thirty patients had adequate FNA cytology performed. Histological examination following core or excision biopsy showed 31 lumps to be benign and 9 to be malignant. All patients with invasive cancer proceeded to wide local excision or mastectomy with an axillary clearance. The mean diameter of malignant lesions was 2.4 cm (SEM 0.3 cm). The sensitivity (22%), specificity (81%) and positive predictive value (25%) of octreotide scintigraphy in the detection of breast cancer was inferior to that of clinical assessment (56%, 90% and 71%), radiological imaging(77%, 96% and 100%) and FNA cytology (88%, 95% and 88%). No axillary uptake of isotope was seen in 4 patients with nodal metastases. Four scans showed uptake of isotope at one or more sites remote from the clinically or radiologically significant lesion. [111Indium-DTPA-D-Phe] octreotide scintigraphy provided no additional diagnostic information to that given by triple assessment and does not appear to have a role in the evaluation of breast lumps.

Use of significance image to determine patterns of cortical blood flow abnormality in pathological and at-risk groups.

UNLABELLED: The purpose of this work was to determine whether certain pathological groups and other groups at risk for neurological damage exhibited distinctive patterns of regional cerebral blood flow (rCBF) abnormality. METHODS: HMPAO SPECT images obtained from six groups of subjects were compared with a normal cortical rCBF atlas, based on multivariate, voxel-by-voxel methods. In each case, a significance image was outputted, highlighting voxels with deficits of > or =3 s.d. of normal. Abnormal patterns were examined for the six groups, which comprised a further 40 normal volunteers, 18 diver controls, 50 divers with decompression illness (DCI), 34 boxers, 23 schizophrenics and 21 subjects with Alzheimer's disease. RESULTS: The percentages of abnormal cortical voxels for each group were 0.41%, 0.53%, 1.38%, 1.05%, 0.56% and 2.24%, respectively. The percentages of images in each group with at least one lesion of 10 or more connected abnormal voxels and at least 10 lesions of two or more connected voxels, respectively, were 8% and 8% (normal volunteers), 17% and 11% (diver controls), 38% and 38% (divers with DCI), 41% and 29% (boxers), 26% and 13% (schizophrenics) and 90% and 48% (subjects with Alzheimer's disease). This suggests that multiple small lesions are as common as single large lesions for divers with DCI but not for patients with Alzheimer's disease or schizophrenia. Large lesions are located predominantly in the parietal and inferior temporal regions for Alzheimer's disease, in the parietal and occipital regions for divers with DCI and boxers and in the inferior frontal region for schizophrenia. CONCLUSION: It appears that the groups considered here do have different rCBF patterns and that the significance image is a useful way of demonstrating this fact.

Cerebral perfusion and psychometric testing after exposure to high altitude in the mountains.

Exposure to hypobaric hypoxia is known to cause reductions in mental performance and decision-making and it has been reported that these effects are not fully reversed following descent from altitude. Eight climbers had cerebral perfusion scans performed and undertook a battery of psychometric tests prior to, and upon return from, an expedition to climb the eleventh highest mountain in the world, Gasherbrum 1. No decrements were found in either their performance on the psychometric tests nor to their cerebral perfusion following the expedition. Two subjects had significant cerebral perfusion abnormalities prior to the expedition, which had improved immediately following their return from the expedition. Repeat scans four months later showed the lesion of one of the subjects had returned and there were indications that the lesion in the other subject was beginning to return. These findings are in contrast to previous studies which have suggested that altitude exposure leads to permanent reductions in brain function, this could be because in those studies factors other than hypobaric hypoxia per se lead to the reductions in brain function.

An assessment of two methods for generating automatic regions of interest.

Two fully automatic methods for generating regions of interest (ROIs) for nuclear medicine images are described and assessed. One of these, involving registration of a previously defined ROI onto a new image, uses spatial information and is appropriate for two- and three-dimensional images which may be static or dynamic. The other method is based on artificial neural networks and uses temporal information. It is appropriate for dynamic images only. The registration method has been tested using 10 pairs of stress and redistribution images obtained from cardiac perfusion SPET. Regions of interest of the left ventricular muscle, defined on the stress images, were registered onto the redistribution images, where they were compared with reproducibility of manually drawn ROIs. Both methods were tested on 17 99Tcm-MAG3 kidney dynamic studies, where the original ROIs corresponding to both kidneys and the bladder were defined using the COST B2 hybrid phantom. Our results indicate that neither method is as reliable as having ROIs redrawn by the operator, although there are indications that an artificial neural network which combines the use of the spatial and temporal information could prove useful for dynamic studies.

Functional bone imaging in the detection of ischemic osteopathies.

The efficiency and accuracy of a functional imaging technique in the detection of ischemic osteopathy is reviewed over a 10-year period. The study includes 161 patients who had trauma, 101 patients who had suspected Perthes disease, 43 patients who had dysbarism, and 22 patients who had renal transplants on steroid immunosuppressive therapy. After intravenous injection of 7.7 MBq kg-1 Tc-99m HDP data were collected on all patients during the first 20 minutes, accretion rate functional images were produced, and static bone scans performed after 3 hours. All patients were followed up until a definitive diagnosis (clinical and radiologic) of avascular necrosis or osteochondritis was confirmed or denied. Of the 327 patients studied, 114 had positive accretion rate images and 213 negative accretion rate images. There were 8 false-positive scan results and 2 false-negative scan results. The overall predictive accuracy was 97% (disease prevalence 33%) with a sensitivity rate of 98% and a specificity rate of 96%. The authors conclude that the technique is a valuable predictive diagnostic indicator for ischemic osteopathies.

CA549 and TPS patterns in the diagnosis and staging of patients with breast carcinoma.

This study compares the clinical value of the breast cancer tumour makers CA549 and TPS, and their tandem use when one or both markers indicate abnormality. For 144 patients presenting with active disease, 33 were classified as Stage I, 37 as Stage II, 40 as Stage III and 34 as Stage IV. For these patients the sensitivity of CA549 using a cut-off of 10 U/ml was 27%, 32%, 42% and 79%, respectively. The sensitivity of TPS for each stage using a cut-off of 100 U/l was 12%, 22%, 28% and 73%, respectively. At these cut-off levels, 36%, 46%, 63% and 91% of patients, respectively, have either CA549 or TPS or both markers raised. For 161 patients with diagnosed benign breast disease, the specificity of marker levels was 96% for CA549, 88% for TPS and 84% for tandem use. CA549 is shown to be superior to TPS and this was confirmed by Receiver Operating Characteristic (ROC) analysis using variable threshold levels, with the areas under the curves for all stages combined being 0.74 +/- 0.03 (ISD) and 0.66 +/- 0.03, respectively. The corresponding area under the curve for tandem use (0.75 +/- 0.03) is marginally greater than for either individual marker, although the difference with respect to CA549 is statistically insignificant.

A voxel-by-voxel multivariate analysis of cerebral perfusion defects in divers with 'bends'.

Past analysis of dysbaric-induced cerebral perfusion defects, demonstrated by 99Tcm-hexamethylpropylene amine oxime (99Tcm-HMPAO) single photon emission tomography in divers using quantitative and/or univariate techniques, has resulted i considerable controversy regarding the significance of these lesions compared to those seen in control subjects, correlations with clinical findings and the role of 99Tcm-HMPAO as a prognostic indicator in decompression sickness. We tried to address these problems by using a multivariate approach to a voxel-by-voxel analysis, involving the use of principal components, to determine ranges of normality in 50 reference controls. In subsequent images, abnormality was defined as 10 spatially connected voxels at an appropriate significance level of three standard deviations. The images of 50 divers with clinically diagnosed 'bends' were compared with those of a further 40 normal population controls with no previous history of loss of consciousness, head injury or dysbarism. The results showed that 19 of 50 divers with 'bends' and 3 of 40 population controls had significant perfusion defects, representing a significant difference between divers with dysbarism and population controls at the level P < 0.002. It is concluded that dysbarism causes significant cerebral cortical perfusion defects in affected divers both in 'silent' and symptomatic (clinically correlated) areas.

Optimization of factors affecting the state of normality of a medical image.

The purpose of this paper is to examine the first stage of the diagnostic process in medical imaging, namely determination of the state of normality, and to attempt to optimize factors contributing to this stage. An image of a given type is defined as abnormal if it does not belong to the appropriate class of normal images. All images must be pre-processed involving image registration and normalization to align and scale the images with respect to each other. Normal ranges may be determined for each voxel (or other appropriate region) from a representative normal sample using univariate analysis, obtaining mean and standard deviation images, or multivariate analysis, which accounts also for normal patterns of variation (represented as principal components). For a new image, the variation from normality (in SDs) for each region may be determined. Since the spatial distribution of this parameter is thought to be relevant, connectivity of abnormal voxels was considered as a possible factor. For the purposes of this study, SPECT images indicating regional cerebral blood flow were used. Images from 50 normal subjects formed the normal sample. A further 40 normal subjects and 200 patients referred with suspected dementia were then analyzed using the normal ranges. ROC analysis, using number of SDs as a variable threshold, was used to optimize the factors. Normalization to global values followed by multivariate analysis using four or five principal components provided optimal discrimination. Connectivity of voxels emerged as an important factor, around 10 connected voxels being optimal for this study.

Cerebral perfusion and psychometric testing in military amateur boxers and controls.

The objective was to compare two neurophysiological variables in active amateur boxers with non-boxing sportsmen. 41 boxers and 27 controls were given psychometric tests: 34 boxers and 34 controls underwent technetium-99m hexamethylpropyleneamineoxime single photon emission computerised tomography (Tc-99m HMPAO SPECT) cerebral perfusion scans. The controls performed better at most aspects of the psychometric tests. Boxers who had fought fewer bouts had a tendency to perform better at psychometric tests than those boxers who had fought more bouts. Tc-99m HMPAO SPECT cerebral perfusion scanning showed that controls had less aberrations in cerebral perfusion than the boxers. In conclusion, significant differences were shown in two neurophysiological variables between young amateur sportsmen who box and those who do not. The long term effects of these findings remain unknown.