1H-MRS at 4 tesla in minimally treated early schizophrenia.

We investigated glutamate-related neuronal dysfunction in the anterior cingulate (AC) early in schizophrenia before and after antipsychotic treatment. A total of 14 minimally treated schizophrenia patients and 10 healthy subjects were studied with single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) of the AC, frontal white matter and thalamus at 4 T. Concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln) and Gln/Glu ratios were determined and corrected for the partial tissue volume. Patients were treated with antipsychotic medication following a specific algorithm and (1)H-MRS was repeated after 1, 6 and 12 months. There were group x region interactions for baseline NAA (P=0.074) and Gln/Glu (P=0.028): schizophrenia subjects had lower NAA (P=0.045) and higher Gln/Glu (P=0.006) in the AC before treatment. In addition, AC Gln/Glu was inversely related to AC NAA in the schizophrenia (P=0.0009) but not in the control group (P=0.92). Following antipsychotic treatment, there were no further changes in NAA, Gln/Glu or any of the other metabolites in any of the regions studied. We conclude that early in the illness, schizophrenia patients already show abnormalities in glutamatergic metabolism and reductions in NAA consistent with glutamate-related excitotoxicity.

Changing the glucose cut-off values that define hypoglycaemia has a major effect on reported frequencies of hypoglycaemia.

AIMS/HYPOTHESIS: The aim of this analysis was to quantify the relationship between the frequency of hypoglycaemia and various glucose cut-off points for the definition of hypoglycaemia, within a range of HbA(1c) strata. METHODS: Data from two trials examining insulin glargine dose titration in 12,837 type 2 diabetic participants starting insulin therapy were combined. Curves for hypoglycaemia frequency plotted against endpoint HbA(1c) level were constructed, using a range of glucose cut-off points for hypoglycaemia. RESULTS: During the 12-week study period, 3,912 patients recorded 21,592 hypoglycaemic episodes, comprising 242 severe, 8,871 symptomatic and 12,479 asymptomatic events, corresponding to hypoglycaemia event rates of 0.10, 3.8 and 5.3 events per patient year. Increasing the hypoglycaemia cut-off point from, for instance, <3.1 to <3.9 mmol/l more than doubled the percentage of affected patients, e.g. from 17.7 to 43.3% at HbA(1c) 7.0-7.2%. At higher hypoglycaemia cut-off points the proportion of patients having only asymptomatic hypoglycaemia increased, e.g. from 30.7% at <3.1 mmol/l to 61.7% of patients at a cut-off point of <3.9 mmol/l. In sensitivity analysis, 121 of 1,756 patients with at least one self-monitored blood glucose value <3.1 mmol/l experienced severe hypoglycaemia, compared with 149 of 3,912 patients with a self-monitored blood glucose level of <3.9 mmol/l. Thus, to identify 28 more patients with severe hypoglycaemia, the number of patients experiencing only non-severe hypoglycaemia more than doubled. CONCLUSIONS/INTERPRETATION: The glucose cut-off point defining hypoglycaemia greatly affects the reported frequency of hypoglycaemia. When hypoglycaemia is to be defined by a predetermined glucose level, to have clinical relevance the cut-off should be set at a lower level than the threshold of 3.9 mmol/l proposed by the American Diabetes Association.

Quantitative spectroscopic imaging with in situ measurements of tissue water T1, T2, and density.

The use of tissue water as a concentration standard in proton magnetic resonance spectroscopy ((1)H-MRS) of the brain requires that the water proton signal be adjusted for relaxation and partial volume effects. While single voxel (1)H-MRS studies have often included measurements of water proton T(1), T(2), and density based on additional (1)H-MRS acquisitions (e.g., at multiple echo or repetition times), this approach is not practical for (1)H-MRS imaging ((1)H-MRSI). In this report we demonstrate a method for using in situ measurements of water T(1), T(2), and density to calculate metabolite concentrations from (1)H-MRSI data. The relaxation and density data are coregistered with the (1)H-MRSI data and provide detailed information on the water signal appropriate to the individual subject and tissue region. We present data from both healthy subjects and a subject with brain lesions, underscoring the importance of water parameter measurements on a subject-by-subject and voxel-by-voxel basis.

Posterior reversible encephalopathy syndrome (PRES) in pregnancy: a diagnostic challenge to obstetricians.

Post-partum clinical presentation with seizures and focal neurological deficit has a wide differential diagnosis. Two cases of the rare condition Posterior Reversible Encephalopathy Syndrome (PRES) associated with pregnancy are presented with complete recovery following multidisciplinary care. One of the cases was associated with Factor VII deficiency in pregnancy and the other with twin gestation and psoas abcess.

Alleviating anxiety in patients prior to MRI: A pilot single-centre single-blinded randomised controlled trial to compare video demonstration or telephone conversation with a radiographer versus routine intervention.

INTRODUCTION: Patients undergoing MRI often experience anxiety prior and during scanning. The aim of this study was to explore two simple, cost-effective and easily implemented interventions to reduce anxiety pre MRI scanning. METHODS: Seventy four patients attending first time for a MRI head, spine or cardiac scan were randomised into one of three interventions: video demonstration; telephone conversation with a radiographer; or routine MRI preparation (appointment letter). The State-Trait Anxiety Inventory (STAI) questionnaire was used to measure anxiety levels both pre and post intervention. Motion artefacts were visually assessed by 2 observers and a post scan survey was used to capture patient's satisfaction. RESULTS: ANCOVA revealed a significant reduction of anxiety in the video group (F = 13.664, p = 0.001), and also in the telephone group (F = 6.443, p = 0.015) compared to control patients. No significant difference was found between the two interventions (F = 0.665, p = 0.419). No difference was seen in motion artefacts between all three groups (Chi2 = 2.363 (p = 0.359) for observer 1 and Chi2 = 1.280 (p = 0.865) for observer 2). Fifty one percent (51.4%) of patients admitted to being anxious, with the possible outcome of the MRI results being the most common (18.9%) reason given for anxiety. CONCLUSION: This study has demonstrated that either of the interventions used can significantly reduce pre-MRI anxiety, with the video performing slightly better than the phone call intervention. Importantly, the routine appointment letter did not contain enough information to satisfy most patients, which argues strongly for a change in current practice.

Progesterone and estrogen receptors as prognostic variables in breast cancer.

Estrogen receptor (ER) and progesterone receptor (PR) levels have been measured in 374 tumors from patients with primary breast cancer and compared with axillary nodal status and other patient variables to determine their relationship to prognosis. Nodal status reliably predicted disease-free interval and overall survival, and both ER and PR status predicted overall survival both individually and within node-positive and node-negative subgroups. PR but not ER status was also able to predict disease-free survival both overall and in the node-positive subgroup. When the two receptor measurements were used in combination, a group of receptor-negative, (ER- and PR-negative), node-negative patients were identified with a significantly worse survival than that for an ER- and PR-positive group of node-positive patients. It is apparent that receptor status provides useful prognostic information in patients with early breast cancer and that ER and PR assays used in combination identify a subgroup of node-negative patients with poor prognosis who are likely to benefit from adjuvant therapy following mastectomy.

The use of neuroimaging in dementia by Irish general practitioners.

BACKGROUND: More than 48,000 people in Ireland are living with dementia, and the number is likely to rise to 130,000 by 2041. Dementia frequently remains undiagnosed, depriving many of early interventions and the opportunity to plan for the future. Neuroimaging is helpful in the diagnosis of dementia, yet it is often insufficiently utilised. General practitioners (GPs) often decide which patients should be referred on for specialist assessment and as such play a crucial role in dementia diagnosis. AIMS: To establish the accessibility of neuroimaging in dementia by GPs, current referral patterns, confidence in referral and opinions on radiology reports. METHODS: The research design was a postal survey among GPs in single and group practices in urban, rural and semi-rural areas in the east and southeast of Ireland. GPs were identified from the Irish Medical Directory and posted individual anonymous questionnaires. RESULTS: A third of participants reported that they had no direct access to neuroimaging. Access differed between public and private patients. GPs primarily referred to computed tomography and magnetic resonance imaging, but only 14.6 % based these referrals on published guidelines. A total of 47.8 % of participants were not very confident in their ability to choose the most appropriate modality. CONCLUSION: Access to neuroimaging investigations for suspected cases of dementia varies between locations and public and private systems. To improve diagnostic rates and ensure appropriate utilisation of imaging resources, GPs require access to clinical and referral guidelines to ensure appropriate use of neuroimaging and the best possible patient outcomes.

Abnormal cardiac pain perception in syndrome X.

OBJECTIVES: The purpose of this study was to determine whether a diminished cardiac pain threshold contributes to chest pain in patients with syndrome X. BACKGROUND: There have been some reports of an altered pain perception in syndrome X. METHODS: Intracardiac catheter manipulation was performed in four groups of patients (syndrome X [group 1, 36 patients]; mitral valve disease and normal coronary arteries [group 2, 36 patients]; mitral valve disease and coronary artery disease [group 3, 36 patients]; and heart transplant recipients with normal coronary arteries [group 4, 36 patients]). Coronary flow velocity was measured in patients with syndrome X and in transplant recipients by use of an intracoronary Doppler catheter positioned in the left anterior descending coronary artery at intracardiac catheter manipulation. Coronary flow reserve in response to papaverine was also measured in patients with syndrome X and in transplant recipients. RESULTS: Intracardiac stimulation produced typical anginal chest pain in 34 group 1 (syndrome X) patients (94%). However, chest pain was produced only in five patients (14%) in group 2, seven patients (19%) in group 3 and no patients in group 4. There were no significant changes in coronary blood flow velocity associated with chest pain in group 1 patients. Coronary flow reserve in response to a hyperemic dose of intracoronary papaverine was significantly lower in the syndrome X group. There was no significant difference in the prevalence with which the stimulation tests produced chest pain in patients with syndrome X with an impaired coronary flow reserve or a positive radionuclide scan. CONCLUSIONS: The results of our study suggest that abnormal cardiac pain perception is a fundamental abnormality in syndrome X.

Aging-associated endothelial dysfunction in humans is reversed by L-arginine.

OBJECTIVES: This study investigated the hypothesis that aging selectively impairs endothelium-dependent function, which may be reversible by administration of L-arginine. BACKGROUND: An impaired response to acetylcholine with aging has been demonstrated in humans. However, the mechanisms underlying this impaired response of the coronary microvasculature remain to be determined. METHODS: We infused the endothelium-independent vasodilators papaverine and glyceryl trinitrate (GTN) and the endothelium-dependent vasodilator acetylcholine (1,3,10 and 30 micrograms/min) into the left coronary artery of 34 patients (27 to 73 years old) with atypical chest pain, negative exercise test results, completely normal findings on coronary angiography and no coronary risk factors. Coronary blood flow was measured with an intracoronary Doppler catheter. The papaverine and acetylcholine infusions were repeated in 14 patients (27 to 73 years old) after an intracoronary infusion of L-arginine (160 mumol/min for 20 min). RESULTS: There was a significant negative correlation between aging and the peak coronary blood flow response evoked by acetylcholine (r = -0.73, p < 0.0001). However, there was no correlation to papaverine (r = -0.04, p = 0.82) and GTN (r = -0.24, p = 0.17). The peak coronary blood flow response evoked by acetylcholine correlated significantly with aging before L-arginine infusion (r = -0.87, p < 0.0001), but this negative correlation was lost after L-arginine infusion (r = -0.37, p = 0.19). CONCLUSIONS: The results suggest that aging selectively impairs endothelium-dependent coronary microvascular function and that this impairment can be restored by administration of L-arginine, a precursor of nitric oxide.

Cardioesophageal reflex: a mechanism for "linked angina" in patients with angiographically proven coronary artery disease.

OBJECTIVES: The purpose of this study was to investigate the presence of a cardioesophageal reflex in patients with coronary artery disease that may explain the mechanism of "linked angina." BACKGROUND: It has been previously shown that esophageal acid stimulation can reduce coronary blood flow in patients with syndrome X, suggesting the presence of a cardioesophageal reflex in humans. METHODS: We studied the effect of esophageal acid stimulation on coronary blood flow in 14 patients with angiographically documented significant coronary artery disease and in 18 heart transplant recipients. Hydrochloric acid (0.1 mol/liter) and 0.9% saline solution were infused in random, double-blind manner (60 ml over 5 min) through a fine-bore tube positioned in the patient's distal esophagus, and coronary blood flow measurements were obtained after each infusion by use of a 3.6F intracoronary Doppler catheter positioned in the proximal left anterior descending coronary artery. RESULTS: Coronary blood flow was reduced significantly by esophageal acid stimulation in the coronary artery disease group (before acid 70.4 +/- 14.3 ml/min, after acid stimulation 46.4 +/- 19.1 ml/min [mean +/- SD], p < 0.01). However, there was no significant difference in coronary blood flow during saline infusion (73.5 +/- 15.3 vs. 72.5 +/- 14 ml/min). Coronary blood flow in the heart transplant group was not affected by acid or saline infusion. CONCLUSIONS: Esophageal acid stimulation can cause animal attacks and significantly reduce coronary blood flow in patients with coronary artery disease. The lack of any significant effect in heart transplant recipients with heart denervation suggests a neural reflex.

Risk factor analysis for the major hazards following heart transplantation--rejection, infection, and coronary occlusive disease.

This study demonstrates the importance of analyzing survival by cause of death in order to achieve a better understanding of the prognostic indicators involved. It further emphasizes the need for analysis of risk factors in both univariate and multivariate models, and the danger of making judgements based on premature analysis of data on follow-up after heart transplantation. Survival following transplantation is characterized by the major hazards of early death due to infection and rejection and late graft loss due to coronary occlusive disease (COD). This study summarizes the first-graft survival experience for 323 transplant patients at Papworth Hospital, and assesses a number of potential risk factors for (1) early mortality, (2) late mortality from COD, and (3) development of COD. The potential risk factors considered for all hazards are donor and recipient age, sex, blood group, and matching of these factors; donor cause of death and recipient immunosuppression; inotropic support; waiting time; preoperative diagnosis and previous cardiac surgery; ischemic time; and extubation time. In addition, for development of, and graft loss from, COD, perioperative rejection and cytomegalovirus infection; hypertension at discharge; and cholesterol, triglycerides, and lipids at two years were assessed as risk factors. Advances in immunosuppression were observed to have increased overall survival rates and decreased mortality from infection, rejection, and COD, as well as decreasing morbidity from COD. Fatal rejection was found to be more likely in female recipients, recipients over 40 years, recipients of grafts from donors over 30 years old, patients who were transplanted for valvular heart disease, and patients who waited less than three months for their transplant. Male recipients of female donor organs were more likely to lose their grafts as a result of COD. Patients older than 50 and hearts from donors older than 40 conferred a high risk of development of and loss from COD. Patients transplanted for ischemic heart disease were more likely to develop COD. High cholesterol, low HDL, high LDL, and high triglycerides at two years after transplant showed some evidence of high risk for the subsequent development of COD, although these relationships are not statistically significant at this stage. Contrary to other recent studies, cytomegalovirus infection was not found to be a risk factor for the development of COD.

Closed-head minimal traumatic brain injury produces long-term cognitive deficits in mice.

Victims of minimal traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study we adopted a non-invasive closed-head weight-drop mouse model to produce mTBI. We examined the effects of 20, 25, or 30 g weight drop 7, 30, 60 and 90 days following injury on mice's ability to perform the Morris water maze. The mice suffered profound long-lasting learning and memory deficits that were force- and time-dependent. Although the injured mice could acquire the task, they could not improve their initial escape latency by more than 50%, while normal mice improved by up to 450% (P<0.001). In order to directly compare the learning ability of individual mice following our mTBI we have devised a new measure which we term learning rate. We define learning rate as the rate the mouse improved its own performance in consecutive trials in a given experimental day. The learning rate of control mice increased linearly throughout the testing period with a slope of approximately 0.9. Injured mice that sustained 20 and 25 g weight drop could also improve their learning rate linearly but with a slope of only 0.2. Mice who sustained 30 g weight drop could not improve their learning rate linearly and reached a plateau after the third experimental learning day. These results indicate that the severity of injury may correlate with the degree of integration of the learning task. These cognitive deficits occurred without any other clear neurological damage, no evident brain edema, no notable damage to the blood-brain barrier and no early anatomical changes to the brain (observed by magnetic resonance imaging imaging). These results demonstrate that persistent deficits of cognitive learning abilities in mice, similar to those observed in human post-concussive syndrome, can follow mTBI without any anatomical damage to the brain and its surrounding tissue.

Anomalous effect of serum on the antimicrobial activity of cefoperazone.

This study investigated the effect of added serum on cefoperazone activity in vitro. Due to protein-binding, an 8-fold difference would be expected between minimum inhibitory concentrations in broth and in broth plus 90% serum. Using supplemented Mueller-Hinton broth (sMH) and sMH plus 90% heat-inactivated human serum there were differences of 3.36 +/- 0.92 for Staphylococcus aureus strain ATCC1 25923, 1.39 +/- 0.47 for Escherichia coli strain ATCC 25922 and 1.43 +/- 0.39 for Pseudomonas aeruginosa strain ATCC 27853. Serum-related modal increases in minimum inhibitory concentrations of cefoperazone for clinical isolates were 4-fold versus Staphylococcus aureus (5 strains), Klebsiella species (5 strains) and Pseudomonas aeruginosa (8 strains), and 2-fold versus Escherichia coli (4 strains). On the addition of serum to 2 strains of Serratia marcescens, divergent effects were seen. Minimum lethal concentrations of cefoperazone were generally identical to, or a low multiple of, corresponding minimum inhibitory concentrations. Variables other than protein binding may account for the anomalous activity of antibiotics against organisms in serum. These factors favour the activity of cefoperazone against several clinically important species.

Small shifts in craniotomy position in the lateral fluid percussion injury model are associated with differential lesion development.

Previous studies have shown that location and direction of injury may affect outcome in experimental models of traumatic brain injury. Significant variability in outcome data has also been noted in studies using the lateral fluid percussion brain injury model (FPI) in rats. In recent studies from our laboratory, we observed considerable variability in localization and severity of tissue damage as a function of small changes in craniotomy position. To further address this issue, we examined the relationship between craniotomy position and brain lesion size/location in rats subjected to moderate FPI (2.28 +/- 0.18 atmospheres). With placement of a 5-mm craniotomy adjacent to the sagittal suture, there was both ipsilateral and contralateral damage as detected at 3 weeks posttrauma using T2-weighted magnetic resonance imaging (MRI). The MRI lesions were generally restricted to the hippocampus and subcortical layers. Shifting of the craniotomy site laterally was associated with increased ipsilateral tissue damage and a greater cortical component that correlated with distance from the sagittal suture. In contrast, the contralateral MRI lesion did not change significantly in size or location unless the center of the craniotomy was placed more than 3.5 mm from the sagittal suture, under which condition contralateral damage could no longer be detected. Ipsilateral tissue damage as determined from the MRI scans was linearly correlated to motor outcome but not with cognitive outcome as assessed by the Morris Water Maze. We conclude that craniotomy position is critical in determining extent and location of tissue injury produced during the lateral FPI model in rats. Addressing such potential variability is essential for studies that address either injury mechanisms or therapeutic treatments.

Heart transplantation in patients over 54 years of age with triple-drug therapy immunosuppression.

Between April 1, 1986, and December 31, 1989, 206 patients received orthotopic heart transplants with triple-drug therapy immunosuppression (cyclosporine, azathioprine, prednisone). Forty-six patients were aged 55 years or more at the time of transplantation and 160 patients were less than 55 years of age; these two groups were compared. Selection criteria and treatment regimen were the same in both groups. In our experience, although both groups had good postoperative survival, older patients had higher mortality rates early after transplantation, particularly from rejection and infection. Patients over 55 years of age had similar nonfatal rejection rates and were no more likely to have infectious episodes than younger patients. As demand for heart transplantation increases and waiting lists lengthen, the age of potential recipients should be an important factor in deciding how to allocate scarce donated organs, although age should not be exclusive.

A method of analyzing the onset and progression of coronary occlusive disease after transplantation and its effect on patient survival.

The development of transplant-acquired coronary occlusive disease is monitored with serial angiography and is graded on a three-point scale as normal, mild (< 50% stenosis), or severe (> or = 50% stenosis). Previous studies have provided information about the time to the first sign of disease on angiography or empirical descriptions of progression. The number of observed transitions between grades of disease has been recorded, and a Markov model based on these transitions is used to estimate the rate of progression through angiographically defined disease grades and the mortality rates from each grade. Five hundred thirty-six angiograms from 240 patients were analyzed. Fifty-three graft failures occurred. The annual transition rate per patient year from normal to mild disease was low, 0.120 (95% credible interval, 0.096 to 0.154), although the transition from mild to severe disease was relatively high, 0.482 (95% credible interval, 0.325 to 0.671). Annual death rates from normal, mild, and severe grades were 0.032 (95% credible interval, 0.016 to 0.052), 0.076 (95% credible interval, 0.007 to 0.187) and 0.415 (95% credible interval, 0.244 to 0.640), respectively. Before onset of disease patients have a hazard-free course, and mild disease displayed on angiography is relatively non-life-threatening. However, once mild disease has been detected by angiography, progression to severe disease is rapid, and severe disease carries a very poor prognosis.

Lack of association between endomyocardial evidence of rejection in the first six months and the later development of transplant-related coronary artery disease.

The development of transplant-related coronary artery disease (TCAD) is the major determinant of long-term heart transplant survival. To test the hypothesis that TCAD might be related to cellular myocardial rejection, the grades of rejection seen at all biopsies performed in the first 6 months after heart transplantation were analyzed in 108 patients who survived more than 6 months. The development of TCAD was assessed at routine follow-up coronary angiography in 101 patients and at necropsy in seven patients. This data was analyzed with Kaplan-Meier survival curves and Cox proportional hazard regression analysis. No significant association was found between either moderate rejection or any level of rejection and the later development of TCAD, nor did the absence of any rejection protect against its development.

Prospective study of transbronchial biopsies in the management of heart-lung and single lung transplant patients.

A prospective study of 219 bronchoscopies in 54 heart-lung and in 2 single lung transplant recipients was undertaken over a 12-month period by a single operator. For histologic study, an average of 17.3 transbronchial biopsy specimens (range, 6 to 56) were taken from three lobes (or from two lobes and lingula of one lung). A further two specimens were taken for culture. The average procedure time was 14.4 minutes (SE 0.31). An estimate of the probability of rejection being missed, depending on the number of specimens taken and based on the method of Gilman and Wang, suggests 18 biopsy specimens are required to have 95% confidence of diagnosing rejection. Sensitivity for diagnosing rejection by histologic study of transbronchial biopsy specimens was 94%, and specificity was 90%. The simple grading of severity of rejection that was used was related both to the number of specimens demonstrating rejection and to the severity of graft airway mucosal inflammation seen at bronchoscopy. The major complication encountered, on 27 occasions, was bleeding of more than 100 ml. On no occasion did bleeding result in any long-term complication. Extensive transbronchial biopsy is a simple, relatively safe, and quick procedure, with a high sensitivity and specificity for diagnosing rejection and lung infection.

HLA types in American black juvenile diabetics strong associations with Dw3 and Dw4.

The distributions of HLA-A, -B, -C and -D antigens in 38 black American insulin-dependent juvenile diabetics were studied. Antigens A1, A2, B8 and Cw3 were slightly increased, but the corrected probability values were not statistically significant. As determined by mixed lymphocyte culture, the frequency of Dw3 was 89% in the juvenile diabetics and that of Dw4 was 42% in comparison with 14 and 8%, respectively, in the controls. The relative risks for juvenile diabetes were 52 for Dw3 (p = 10(-8) and 9 for Dw4 (p = 10(-6). Dw2 was significantly decreased in the diabetics (p equals 0.008). All of these deviations in A, B, C and D locus specificities have been previously reported by others in white juvenile diabetics. Because there are white genes in the American black gene pool and juvenile diabetes is rare in blacks in western Africa, many cases of juvenile diabetes in American blacks could be the result of genes ultimately derived from the white genes. This hypothesis is supported by the similar HLA associations in juvenile diabetes in the black and white ethnic groups.