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.

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.

External monitoring of kidney transplant function using Tc-99m(Sn)DTPA.

The purpose of this study was to evaluate the use of an external counting technique to provide daily monitoring of kidney transplant function by measuring the renal clearance of Tc-99m(Sn)DTPA. During the first few weeks following transplant, 15 patients had their renal clearance of Tc-99m DTPA measured daily over periods of 5-24 hr. Clearance rates were compared with daily plasma creatinine levels, and the effects of diurnal variation, drug treatment, and physical activity noted. The results show that any significant fall in clearance rate of chelate, indicating a rejection episode, preceded a rise in plasma creatinine levels by at least 24 hr. One episode of transplant failure presented as a sudden deterioration in clearance rate of chelate; in the others the change was more gradual but was still apparent within hours. It is considered that this noninvasive, low-dose, easy-to-perform technique is of considerable value in extended daily monitoring of renal function and is superior to standard daily or twice-weekly renography for the early detection of transplant rejection.

A method for assessing the significance of abnormalities in HMPO brain SPECT images.

METHODS: A normal atlas for HMPAO rCBF SPECT images was obtained from images of 53 normal controls. Following image registration and normalization, a mean image was extracted, while images representing correlated normal deviants were identified using principal component analysis. These images formed the "building blocks" of the atlas. For subsequent images, the atlas was used to create a "nearest normal equivalent" image, which was compared to a residual standard deviation image to determine the significance of deviations in the new image. RESULTS: Images from 30 patients (10 with Alzheimer's disease; 12 with single or multiple infarcts; and 8 normals) were analyzed. CONCLUSION: Using an optimal decision level, 10/10 patients with Alzheimer's disease and 11/12 patients with infarcts were correctly identified, with only one false-positive resulting. We utilized a database of images obtained from normal controls to create a normal atlas.

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.

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.

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.

An intercomparison of computer assisted data processing and display methods in radioisotope scintigraphy using mathematical tumours.

Several computer assisted processing and display methods are evaluated using a series of 100 normal brain scintigrams, 50 of which have had single 'mathematical tumours' superimposed. Using a standard rating system, or in some cases quantitative estimation, LROC curves are generated for each method and compared.

A perception experiment to assess the clinical accuracy of various methods of obtaining cardiac phase images.

Five methods of obtaining cardiac phase (and phase-like) images are compared. These are single-harmonic Fourier phase imaging; time-to-minimum using a two-harmonic fit to each dixel; time-to-minimum using four weighted harmonics; composite factorial phase imaging; and individual factorial phase imaging. Polaroid prints of phase images for both gated equilibrium studies (using all methods) and first-pass studies (first and last methods only) were shown to observers who were asked to rate the images according to their confidence of an abnormality presenting. A receiver operating characteristic (ROC) analysis was performed. For gated studies composite factorial phase imaging appears to be best, while all methods are significantly better than single-harmonic Fourier phase imaging. For first-pass studies individual factorial phase imaging appears to be superior to single-harmonic Fourier phase imaging.

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.

An estimation of noise levels in HMPAO RCBF SPECT images using simulation and phantom data; comparison with results obtained from repeated normal controls.

The purpose of this work was to determine noise levels in HMPAO RCBF SPECT images. Eight simulated images of a uniform sphere of activity were made at each of three different count levels. Three images of the Amersham brain phantom were obtained at each of three count levels, roughly corresponding to the simulation levels. Image reconstruction involved a modified Shepp-Logan filter with and without attenuation correction. The scaling constant in the Budinger equation was shown to vary little over the count range used with a mean value of 23 for uncorrected phantom data and 27 for corrected phantom data, corresponding to RMS noise levels of 7%-15%. The variance due to noise was calculated as a percentage of the variance obtained for 53 normal control studies following image registration and normalization. Values of 54% for uncorrected images and 67% for corrected images were obtained. For 10 normal controls a repeated study was performed. The ratio of within-subject to (single sample) between-subject variance was determined as 73% for uncorrected images and 78% for corrected images.

Processing of liver dynamic studies with technetium-labelled sulphur colloid.

The uptake of technetium-labelled sulphur colloid by the liver was investigated by monitoring 69 patients on a gamma camera/computer system. Following an intravenous injection 30 half-minute frames were collected and summed to give a composite view. Regions of interest were drawn round the liver and over the aorta and corresponding activity-time curves were formed. A simple physiological model has been assumed and two parameters, namely total uptake and rate of uptake, were shown to give fairly good separation between the classes of normal, cirrhosis, space occupying lesions, reticulosis and hepatitis. Furthermore the uptake rate-constant was also shown to be a useful indication of whether or not a reticulosis or hepatitis was in an acute phase. Principal components analysis was also applied to the liver curves producing two relevant components. However, a plot of the first against the second yielded no better separation of classes than that obtained by the model.

Functional imaging in the early diagnosis of dysbaric osteonecrosis.

Eight divers who developed permanent scintigraphic bone changes following dives to various depths took part in a study to determine the nature of these lesions. Only one of these divers had radiologically evident bone changes in his scintigraphic lesion. Dynamic scintigrams of the bones containing the lesions were obtained from all eight divers and functional images generated of both amplitude (osteoblastic activity) and accretion (microvasculature) rate constants. All had increased amplitude in the area of the scintigraphic lesion indicating continuing osteoblastic activity. Three divers showed a decreased accretion rate in the lesions, indicating impairment or absence of local microcirculation; one of these was the diver who showed radiological changes prior to the study and the other two subsequently developed radiologically evident osteonecrosis. It is concluded that functional images, generated from dynamic bone scintigrams, can successfully predict dysbaric osteonecrosis.

99Tcm-HMPAO single photon emission tomography in the diagnosis of cerebral barotrauma.

Cerebral barotrauma, or the neurological manifestation of the "bends", is a relatively common disease of divers and aviators. To date, however, no-one has succeeded in demonstrating a cerebral or spinal cord lesion in vivo following a decompression incident, despite the presence of definitive clinical signs and symptoms of central nervous system involvement. This paper describes the use of 99Tcm-labelled hexamethylpropyleneamine oxime (99Tcm-HMPAO) with single photon emission tomography in a study of three individuals involved in driving accidents. All three suffered cerebral barotrauma during decompression and all exhibited clinical signs and symptoms of dysbarism to a varying degree. Imaging was performed at time intervals ranging from 2 h to several days following the incidents. The results showed well defined cerebral ischaemic lesions in all three subjects. We conclude that 99Tcm-HMPAO imaging provides a significant advance in locating and demonstrating cerebral lesions following barotrauma and will contribute greatly to our understanding of the pathophysiological processes involved.

The use of induction in the design of an expert system for thyroid function studies.

In this study, the role of induction in the design of an expert system for diagnosing thyroid disorders is evaluated. An expert system was first designed conventionally, based on interaction between a knowledge engineer and a thyroid specialist. This involved weighting three tests (T3, free T4 and TSH) according to the reliability of the test and the presence or otherwise of influencing factors. Compatibility was then tested with known ranges for the parameter values, and a diagnosis made of one of three possible outcomes (euthyroid; hypothyroid; hyperthyroid). Two expert systems were then induced using, firstly, a set of rules and, secondly, a sample set chosen from a database. These systems were then tested against the expert designed system. Both induced systems produced results which were superior to the expert designed system and, in addition, provided insight into the decision-making process. It is concluded that induction is very useful in the design of expert systems of this nature.

The evaluation of a gastric bile probe.

The purpose of this study was to validate a new technique for measuring duodenogastric bile reflux in the human subject. A custom built cadmium telluride gamma detector (Radiation Monitoring Devices, Mass), small enough to be passed into the oesophagus and stomach, was developed and tested for sensitivity to 99Tcm and 75Se radioisotopes. When immersed in radiolabelled water, the detector was capable of measuring gamma radiation in quantities as low as 0.1 microCi (0.0037 MBq) per ml. Two patients (A and B) with endoscopically proven bile reflux, and three normal volunteers (C, D and E) underwent oesophageal manometry to map the position of the lower oesophageal sphincter (LOS). The gamma probe was passed via the nose, to a position in the gastric fundus, 5 cm below the LOS. Each subject was placed supine under a gamma camera (Siemens LFOV 37 ZLC head), centred on the epigastrium. A 4 mCi (148 MBq) dose of radiolabelled 99Tcm-HIDA was administered intravenously, and simultaneous internal/external scanning was performed for between 45 and 90 min. Internal gamma probe data was transferred by a screened cable to a Memolog 600 portable recorder, using a 5 s counting interval, and from the gamma camera to a Nodecrest Micas III computer, using a 15 s counting interval. Gamma camera counts from a region of interest over the fundus of the stomach were then correlated with counts from the internal probe using a linear regression analysis program on the Nodecrest. The internal gamma probe functioned well at body temperature in the acidic gastric environment. Radiolabelled bile refluxed into the stomach during HIDA scanning in three out of the five subjects (one patient and two normal volunteers). There was a strong correlation between internal and external gamma counts (A, r = +0.79; C, r = +0.53; E, r = +0.54; P greater than 0.01). In the other two cases, there was no bile reflux, but still a significant correlation between internal and external gamma counts (B, r = +0.89; D, r = +0.75; P greater than 0.01). The mean correlation coefficient for the series of five cases was +0.70. We conclude firstly that the newly developed internal gamma detector is capable of measuring the reflux of radiolabelled bile into the human stomach and, secondly, that bile reflux may occur in normal subjects as well as those with upper gastrointestinal pathology.

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.

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.