Evaluation of procalcitonin as a contribution to antimicrobial stewardship in SARS-CoV-2 infection: a retrospective cohort study.

It can be a diagnostic challenge to identify patients with coronavirus disease 2019 in whom antibiotics can be safely withheld. This study evaluated the effectiveness of a guideline implemented at Sheffield Teaching Hospitals NHS Foundation Trust that recommends withholding antibiotics in patients with low serum procalcitonin (PCT), defined as ≤0.25 ng/mL. Results showed reduced antibiotic consumption in patients with PCT ≤0.25 ng/mL with no increase in mortality, alongside a reduction in subsequent carbapenem prescriptions during admission. The results support the effectiveness of this guideline, and further research is recommended to identify the optimal cut-off value for PCT in this setting.

Risk factors associated with detailed reproductive phenotypes in dairy and beef cows.

The objective of this study was to identify detailed fertility traits in dairy and beef cattle from transrectal ultrasonography records and quantify the associated risk factors. Data were available on 148 947 ultrasound observations of the reproductive tract from 75 949 cows in 843 Irish dairy and beef herds between March 2008 and October 2012. Traits generated included (1) cycling at time of examination, (2) cystic structures, (3) early ovulation, (4) embryo death and (5) uterine score; the latter was measured on a scale of 1 (good) to 4 (poor) characterising the tone of the uterine wall and fluid present in the uterus. After editing, 72,773 records from 44,415 dairy and beef cows in 643 herds remained. Factors associated with the logit of the probability of a positive outcome for each of the binary fertility traits were determined using generalised estimating equations; linear mixed model analysis was used for the analysis of uterine score. The prevalence of cycling, cystic structures, early ovulation and embryo death was 84.75%, 3.87%, 7.47% and 3.84%, respectively. The occurrence of the uterine heath score of 1, 2, 3 and 4 was 70.63%, 19.75%, 8.36% and 1.26%, respectively. Cows in beef herds had a 0.51 odds (95% CI=0.41 to 0.63, P<0.001) of cycling at the time of examination compared with cows in dairy herds; stage of lactation at the time of examination was the same in both herd types. Furthermore, cows in dairy herds had an inferior uterine score (indicating poorer tone and a greater quantity of uterine fluid present) compared with cows in beef herds. The likelihood of cycling at the time of examination increased with parity and stage of lactation, but was reduced in cows that had experienced dystocia in the previous calving. The presence of cystic structures on the ovaries increased with parity and stage of lactation. The likelihood of embryo/foetal death increased with parity and stage of lactation. Dystocia was not associated with the presence of cystic structures or embryo death. Uterine score improved with parity and stage of lactation, while cows that experienced dystocia in the previous calving had an inferior uterine score. Heterosis was the only factor associated with increased likelihood of early ovulation. The fertility traits identified, and the associated risk factors, provide useful information on the reproductive status of dairy and beef cows.

Clinical language fMRI with real-time monitoring in temporal lobe epilepsy: online processing methods.

The increasing demand for clinical fMRI data has resulted in a need to translate research methods to clinical use. Referrals for language lateralization prior to epilepsy surgery are becoming more common, but time constraints make this unachievable in many busy neuroimaging departments. This study examines whether a single covert verbal fluency paradigm with real-time monitoring and online processing (BrainWave) could replace conventional offline processing (SPM) for the purpose of establishing expressive language dominance prior to epilepsy surgery. We analyzed language fMRI results of 30 patients (17 female; 24 right-handed; median age: 30.5) with temporal lobe epilepsy. Concordance between visual assessment of SPM and BrainWave was 92.8%. Lateralization indices correlated closely with visual assessments of lateralization with a concordance of 85.7%. BrainWave provided a real-time, fast and accurate display of language lateralization easily applied in a clinical setting using only online image processing.

What predicts failed cannulation and therapy at ERCP? Results of a large-scale multicenter analysis.

UNLABELLED: STUDY BACKGROUND AND AIMS: Predicting outcome at endoscopic retrograde cholangiopancreatography (ERCP) remains difficult. Our aim was to identify the risk factors for failed ERCP. PATIENTS AND METHODS: A prospective multicenter study of ERCP was performed in 66 hospitals across England. Data on 4561 patients were collected using a structured questionnaire completed at the time of ERCP. RESULTS: In total 3209 patients had not had an ERCP prior to the study period. Considering their first ever ERCP, 2683 (84 %) were successfully cannulated, 2241(70 %) had all intended therapy completed, 360 (11 %) had some intended therapy completed, and 608 (19 %) were considered to have had a failed procedure. For first ever ERCP, factors associated with incomplete procedure (odds ratio and 95 % confidence interval) were: Billroth surgery (9.2, 3.2 - 26.7), precutting (2.0, 1.6 - 2.7), common bile duct (CBD) stone size and number (3.2, 2.1 - 4.8 for multiple, large stones), interventions in the pancreatic duct (3.4, 1.6 - 7.0), and CBD stenting (2.8, 2.2 - 3.5). Analysis of the 1352 patients who had undergone an ERCP prior to the study period indicated previous failed ERCP was also predictive of incomplete therapy (1.5, 1.1 - 2.1). The modified Schutz score correlated with ERCP completion, as did the Morriston score, even when modified to include only variables measurable before the procedure. CONCLUSION: This study confirms that patient- and procedure-based variables are key predictors of technical success and validates current methods of rating ERCP difficulty. Of note, a correlation between outcome and institutional factors, such as unit and endoscopist caseload, was not demonstrated.

Laser Doppler imaging for intraoperative human brain mapping.

The identification and accurate location of centers of brain activity are vital both in neuro-surgery and brain research. This study aimed to provide a non-invasive, non-contact, accurate, rapid and user-friendly means of producing functional images intraoperatively. To this end a full field Laser Doppler imager was developed and integrated within the surgical microscope and perfusion images of the cortical surface were acquired during awake surgery whilst the patient performed a predetermined task. The regions of brain activity showed a clear signal (10-20% with respect to the baseline) related to the stimulation protocol which lead to intraoperative functional brain maps of strong statistical significance and which correlate well with the preoperative fMRI and intraoperative cortical electro-stimulation. These initial results achieved with a prototype device and wavelet based regressor analysis (the hemodynamic response function being derived from MRI applications) demonstrate the feasibility of LDI as an appropriate technique for intraoperative functional brain imaging.

Plasma magnesium should be monitored perioperatively in patients undergoing colorectal resection.

OBJECTIVE: Hypomagnesemia has been shown to have several clinically important sequelae. The aims of this study were: to assess the impact of bowel preparation, with sodium picosulphate (Picolax), on plasma electrolytes, with particular regard to plasma magnesium, in patients undergoing bowel preparation for colonoscopy and colorectal resection and to evaluate the influence of perioperative magnesium levels on postoperative cardiac dysrhythmias. METHOD: Sixty-one patients receiving sodium picosulphate (Picolax) bowel preparation were studied in two groups: Colonoscopy (31 patients) and Colorectal resection (30 patients). Plasma sodium, potassium, magnesium, calcium, urea, creatinine and blood haematocrit were measured in all patients prior to commencement of bowel preparation, at the time of colonoscopy or colorectal resection and 24 h postoperatively (surgery group only). Mean electrolyte and haematocrit levels were then compared. Postoperative cardiac dysrhythmias were recorded and analysed. RESULTS: No significant changes following bowel preparation were observed in plasma sodium, potassium, calcium or creatinine. Plasma urea fell following bowel preparation (colonoscopy P < 0.001, resection P = 0.004) and rose following resection (P = 0.002). Magnesium levels increased following bowel preparation in both groups (colonoscopy P < 0.001, resection P = 0.007) and fell following resection (P < 0.001). Thirty-four per cent (21/60 patients) were hypermagnesemic following bowel preparation and 20% (6/30 patients) became hypomagnesemic following surgery. Postoperative cardiac dysrhythmias were associated with lower magnesium levels at induction and postoperatively (P = 0.022 and P = 0.033). CONCLUSION: Bowel preparation with Picolax does not appear to cause significant electrolyte disturbance, except in elevating plasma magnesium. Postcolorectal resection plasma magnesium dropped significantly suggesting perioperative monitoring and replacement should be routine following colorectal surgery.

The effects of Arcanobacterium pyogenes on endometrial function in vitro, and on uterine and ovarian function in vivo.

Uterine bacterial infection after parturition causes endometritis, perturbs ovarian function and leads to infertility in cattle. Although endometritis is caused by mixed infections, endometrial pathology is associated with the presence of Arcanobacterium pyogenes. The aims of the present study were to determine the effects of A. pyogenes on endometrial function in vitro, and on uterine and ovarian function in vivo. Heat-killed A. pyogenes did not affect the production of prostaglandin F2alpha (PGF) or prostaglandin E(2) (PGE) from endometrial explants, or purified populations of endometrial epithelial or stromal cells. However, the explants produced more PGF and PGE than controls when treated with a bacteria-free filtrate (BFF) cultured from A. pyogenes. Similarly, BFF stimulated PGF and PGE production by epithelial and stromal cells, respectively. So, BFF or control PBS was infused into the uterus of heifers (n=7 per group) for 8 days, starting the day after estrus. Emergence of the follicle wave, dominant follicle or corpus luteum diameter, and peripheral plasma FSH, LH, estradiol, progesterone, PGFM, or acute phase protein concentrations were unaffected by the BFF infusion. In the live animal it is likely that the intact uterine mucosa limits the exposure of the endometrial cells to the exotoxin of A. pyogenes, whereas the cells are readily exposed to the toxin in vitro.

The relationship between uterine pathogen growth density and ovarian function in the postpartum dairy cow.

In cattle, the first postpartum dominant follicle grows slower and produces less oestradiol in animals with high numbers of bacteria contaminating the uterine lumen. However, only bacteria that are uterine pathogens are correlated with severe clinical disease and an increased inflammatory response. It is unknown whether the effect on the ovary in relation to uterine bacterial contamination is associated with the presence of recognised uterine pathogens. Therefore, the present study examined the relationship between pathogenic bacteria in the postpartum uterine lumen, follicle growth and function and the formation of a competent corpus luteum. In addition, peripheral plasma concentrations of immune mediators were quantified. Swabs were collected from the uterine lumen of cattle on day 7 postpartum. Bacteria were cultured and identified and bacterial growth was scored semi-quantitatively. Animals were categorized into high or low recognized uterine pathogen contamination groups based on the number of colonies. Ovarian structures were monitored by daily transrectal ultrasonography and blood samples were collected. In animals with high numbers of uterine pathogens on day 7 postpartum, the diameter of the first postpartum dominant follicle was smaller and plasma oestradiol concentrations were lower. In addition, these animals had smaller corpora lutea, which produced less progesterone. Furthermore, animals with a high day 7 uterine pathogen growth density had higher peripheral concentrations of acute phase proteins. Thus, contamination of the uterus with recognized uterine pathogens is associated with ovarian dysfunction during the postpartum period. Furthermore, infection results in an increase in the production of inflammatory mediators.

Selective inhibition of fibroblast growth factor (FGF)-stimulated mitogenesis by a FGF receptor-1-derived phosphopeptide.

The activated fibroblast growth factor receptor (FGFR)-1 is phosphorylated on five tyrosine residues outside the catalytic site. Although one such residue, Tyr730, is flanked by potential binding sites for phosphotyrosine-interacting molecules, a physiological role for this region is still controversial. We report that a cell-permeant phosphopeptide mimic of this site, FGFR730(p)Y, inhibits FGF-mediated mitogenesis in cells with no effect on responses stimulated by other growth factors. A similar phosphopeptide corresponding to the phospholipase Cgamma binding site on the receptor had no effect on the mitogenic response. The FGFR730(p)Y peptide did not inhibit phosphorylation of p90/FRS2 or Erk, suggesting that it does not act by inhibiting the Erk-kinase cascade. However, the FGFR730(p)Y peptide bound Shc in a manner requiring both phosphorylated tyrosine and a putative PTB domain binding determinant. These data suggest that the peptide might inhibit mitogenesis by competing with the corresponding site on the FGFR for the ability to bind SHC.

Incidence and types of adverse events and negligent care in Utah and Colorado.

BACKGROUND: The ongoing debate on the incidence and types of iatrogenic injuries in American hospitals has been informed primarily by the Harvard Medical Practice Study, which analyzed hospitalizations in New York in 1984. The generalizability of these findings is unknown and has been questioned by other studies. OBJECTIVE: We used methods similar to the Harvard Medical Practice Study to estimate the incidence and types of adverse events and negligent adverse events in Utah and Colorado in 1992. DESIGN AND SUBJECTS: We selected a representative sample of hospitals from Utah and Colorado and then randomly sampled 15,000 nonpsychiatric 1992 discharges. Each record was screened by a trained nurse-reviewer for 1 of 18 criteria associated with adverse events. If > or =1 criteria were present, the record was reviewed by a trained physician to determine whether an adverse event or negligent adverse event occurred and to classify the type of adverse event. MEASURES: The measures were adverse events and negligent adverse events. RESULTS: Adverse events occurred in 2.9+/-0.2% (mean+/-SD) of hospitalizations in each state. In Utah, 32.6+/-4% of adverse events were due to negligence; in Colorado, 27.4+/-2.4%. Death occurred in 6.6+/-1.2% of adverse events and 8.8+/-2.5% of negligent adverse events. Operative adverse events comprised 44.9% of all adverse events; 16.9% were negligent, and 16.6% resulted in permanent disability. Adverse drug events were the leading cause of nonoperative adverse events (19.3% of all adverse events; 35.1% were negligent, and 9.7% caused permanent disability). Most adverse events were attributed to surgeons (46.1%, 22.3% negligent) and internists (23.2%, 44.9% negligent). CONCLUSIONS: The incidence and types of adverse events in Utah and Colorado in 1992 were similar to those in New York State in 1984. Iatrogenic injury continues to be a significant public health problem. Improving systems of surgical care and drug delivery could substantially reduce the burden of iatrogenic injury.

Costs of medical injuries in Utah and Colorado.

Patient injuries are thought to have a substantial financial impact on the health care system, but recent studies have been limited to estimating the costs of adverse drug events in teaching hospitals. This analysis estimated the costs of all types of patient injuries from a representative sample of hospitals in Utah and Colorado. We detected 459 adverse events (of which 265 were preventable) by reviewing the medical records of 14,732 randomly selected 1992 discharges from 28 hospitals. The total costs (all results are discounted 1996 dollars) were $661,889,000 for adverse events, and $308,382,000 for preventable adverse events. Health care costs totaled $348,081,000 for all adverse events and $159,245,000 for the preventable adverse events. Fifty-seven percent of the adverse event health care costs, and 46% of the preventable adverse event costs were attributed to outpatient medical care. Surgical complications, adverse drug events, and delayed or incorrect diagnoses and therapies were the most expensive types of adverse events. The costs of adverse events were similar to the national costs of caring for people with HIV/AIDS, and totaled 4.8% of per capita health care expenditures in these states.

Evidence for and against a pivotal role of PI 3-kinase in a neuronal cell survival pathway.

PI 3-kinase has emerged as a key enzyme for regulating neuronal cell survival. However, it has not as yet been demonstrated whether activation of the endogenous pool of the enzyme, that is regulated by the p85 subunit, is sufficient to promote a survival response. It is also not known whether the FGF family of growth factors promote survival via a PI 3-kinase-dependent pathway. We have previously developed a cell permeable p85 binding peptide and shown that it can stimulate a mitogenic response in muscle cells that is dependent on a PI 3-kinase/p70 S6 kinase pathway. In the present study we show that this peptide can rescue cerebellar granule cells from death induced by serum deprivation and that this response is comparable to a growth factor response (FGF2). Experiments with wortmannin, LY294002, and rapamycin suggest that the peptide survival response is dependent on PI 3-kinase activity, but not p70 S6 kinase activity. The peptide response was correlated with a PI 3-kinase-dependent phosphorylation of Akt, an established downstream effector in the PI 3-kinase survival cascade. In contrast to the survival response stimulated by the p85 binding peptide, the response stimulated by FGF2 was not inhibited by wortmannin or LY294002, nor was it associated with phosphorylation of Akt. Thus we can conclude that activation of the endogenous pool of PI 3-kinase that is regulated by p85 is sufficient for cell survival; however, growth factors such as FGF2 can clearly support survival in a PI 3-kinase-independent manner.

Stimulation of mitogenesis by a cell-permeable PI 3-kinase binding peptide.

The binding of small phosphopeptides to the SH2 domains of the p85 regulatory subunit of PI 3-kinase can activate the enzyme in vitro. In the present study a cell-permeable peptide that binds specifically to the SH2 domains of p85 has been evaluated for its ability to stimulate a mitogenic response in the C2 muscle cell line. This peptide, in contrast to four other SH2-binding peptides, was as effective as serum, EGF, and FGF at stimulating entry into S-phase. The response to the p85 binding peptide, but not FGF, was inhibited by wortmannin and rapamycin, indicating that the peptide activates the PI 3-kinase/S6 kinase signalling pathway. The peptide response was not inhibited by the MEK inhibitor (PD098059) and did not stimulate Erk phosphorylation. Thus, there would appear to be no direct cross-talk between the pathway activated by the p85 binding peptide and the p42/p44 MAPK cascade.

Cell proliferation, migration and CAM-dependent neurite outgrowth as developmental in vitro endpoints for screening teratogenic potential: Application to valproic acid and related analogues of varying potency.

The in vivo teratogenic potential of valproic acid (VPA) and related teratogenic and non-teratogenic analogues has been correlated with their effects on specific in vitro endpoints of cell proliferation, migration and CAM-dependent neurite outgrowth, as these events are common to crucial epochs of development. The (+/-)-2-n-propyl-4-pentynoic acid [(+/-)-4-yn-VPA] and S-2-n-propyl-4-pentynoic acid [S(-)-4-yn-VPA] analogues increased the incidence of neural tube defects in mouse embryos exposed to a single dose, whereas the E-2-n-propyl-2-pentenoic acid (E-2-en-VPA) analogue and R-2-n-propyl-4-pentynoic acid [R( + )-4-yn-VPA] enantiomer were without effect. VPA and related analogues tested exerted comparable G1 phase antiproliferative effects in C6 glioma and limb bud cells in a dose range of 0-3 mM; however, their relative potency did not correlate with in vivo teratogenicity. In contrast, VPA and all teratogenic analogues, at 3 mM, inhibited neuronal cell aggregation and limb bud chondrocyte differentiation in a manner that exhibited a reasonable correlation with their in vivo teratogenicity. The teratogenic S(-)-4-yn-VPA and non-teratogenic R( + )-4-yn-VPA enantiomers exhibited a differential inhibition of primary neurone outgrowth of neuntes stimulated by cell adhesion molecules [L1 and N-cadherin (NCAD)]. Half-maximal inhibition was observed at approximately 150 muM for the teratogenic S(-)-4-yn-VPA enantiomer, but not the non-teratogenic R( + )-4-yn-VPA form. These results suggest that in vitro perturbations of differentiation are likely to provide the greatest discriminatory power for in vivo teratogenicity.

Selective inhibition of growth factor-stimulated mitogenesis by a cell-permeable Grb2-binding peptide.

The activation of the mitogen-activated protein kinase (MAPK) cascade by a variety of growth factors and other agents is central to a mitogenic response. In the case of polypeptide growth factors such as the epidermal growth factor (EGF) and platelet-derived growth factor (PDGF), the steps leading to activation of MAPK require the function of the adaptor protein Grb2 (growth factor receptor binding protein 2), which can bind either directly or indirectly via its Src homology 2 domain to activated receptor tyrosine kinases. A cell-permeable mimetic of the EGF receptor Grb2 binding site has been investigated for its ability to inhibit biological responses stimulated by a variety of growth factors. Pretreatment of cells with this peptide results in the accumulation of the peptide in cells and its association with Grb2. This is associated with a complete inhibition of the mitogenic response stimulated by EGF and PDGF. In contrast, the peptide has no effect on the mitogenic response stimulated by fibroblast growth factor. The peptide could also inhibit the phosphorylation of MAPK stimulated with EGF and PDGF in the absence of an effect on the fibroblast growth factor response. These data demonstrate that cell-permeable mimetics of Src homology 2 binding sites can selectively inhibit growth factor-stimulated mitogenesis, and also directly demonstrate specificity in the coupling of activated receptor tyrosine kinases to the MAPK cascade.

Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs.

The cell adhesion molecules (CAMs) NCAM, N-cadherin, and L1 are homophilic binding molecules that stimulate axonal growth. We have postulated that the above CAMs can stimulate this response by activating the fibroblast growth factor receptor (FGFR) in neurons. In the present study, we demonstrate that activation of NCAM and L1 can lead to phosphorylation of the FGFR. Both this and the neurite outgrowth response stimulated by all three of the above CAMs are lost when a kinase-deleted, dominant negative form of FGFR1 is expressed in PC12 cells. In addition, we have generated transgenic mice that express the dominant negative FGFR under control of the neuron-specific enolase (NSE) promoter. We show that cerebellar neurons isolated from these mice have also lost their ability to respond to NCAM, N-cadherin, and L1. A peptide inhibitor of phospholipase C gamma (PLCgamma) that inhibits neurite outgrowth stimulated by FGF also inhibited neurite outgrowth stimulated by the CAMs. Thus, we conclude that activation of the FGFR is both necessary and sufficient to account for the ability of the above CAMs to stimulate axonal growth, and that PLCgamma is a key downstream effector of this response.

Use of subvoxel registration and subtraction to improve demonstration of contrast enhancement in MRI of the brain.

To assess the potential of registration of images before and after contrast medium for improving the demonstration of contrast enhancement, we compared conventional 2D T1-weighted spin-echo images with precisely registered 3D volume images and subtraction images derived from them in 2 normal subjects and 30 patients with a variety of brain disease. The volume images were registered to subvoxel accuracy using a rigid body translation and rotation, sinc interpolation and a least-squares fit; subtraction images were obtained from these. Normal contrast enhancement was demonstrated better with positionally registered volume and subtraction images than with conventional images in the meninges, ependyma, diploic veins, scalp, skin, orbit and sinuses. Abnormal enhancement was seen better in meningeal disease, multiple sclerosis and tumours as well as on follow-up studies. Subvoxel registration of images before and after contrast medium may be of considerable value in the recognition of contrast enhancement where there are small changes, or where the changes affect tissues with high or low baseline signal values. The technique also appears likely to be of value in demonstrating contrast enhancement in tissues at interfaces and at other areas of complex anatomy, and in follow-up studies.

Assessment of brain changes with registered MR before and after bone marrow transplantation for chronic myeloid leukemia.

PURPOSE: To determine the frequency and nature of changes to the brain resulting from chemotherapy, radiation therapy, and bone marrow transplantation for chronic myeloid leukemia and to compare the sensitivity of conventional and registered MR scans for detecting these changes. METHODS: In 15 patients, conventional T1-weighted, T2-weighted, and fluid-attenuated inversion recovery MR sequences, as well as T1-weighted radio frequency spoiled 3-D volume MR scans were performed before, 4 to 6 days after, and up to 339 days after transplantation (13 allografts, two autografts). A subvoxel registration program was used to match the volume images precisely so that small changes could be detected after subtraction of scans. Five healthy adult control subjects were also studied on two occasions 1 month apart. RESULTS: Studies performed 4 to 339 days after transplantation showed ventricular enlargement and cortical atrophy in all 13 patients who had allografts. The changes were evident at 4 to 6 days after transplantation and became more obvious during later follow-up examinations. Similar changes were seen in one patient with an autograft but no significant change was seen in the other patient with an autograft or in the five control subjects. Accurately registered volume scans were more sensitive than unregistered conventional scans in detecting early (9/10 versus 0/10), intermediate (12/13 versus 3/12), and late (10/10 versus 4/9) ventricular enlargement on follow-up examinations. The same applied to cortical atrophy (9/10 versus 0/10, 12/13 versus 0/12, and 10/10 versus 0/9). CONCLUSION: The specific cause and clinical significance of these changes are uncertain. Subvoxel registration of serial MR images may reveal changes that are poorly seen or not apparent on conventional scans.

Detection of subtle brain changes using subvoxel registration and subtraction of serial MR images.

OBJECTIVE: The aim of this study was to examine the potential of accurate image registration for detecting subtle changes in the brain. MATERIALS AND METHODS: Isotropic T1-weighted volume images were obtained in 10 normal subjects and five patients on two or more occasions (including pre- and postcontrast studies). The images were segmented and a 3D rigid body translation and rotation technique was used with sinc interpolation to precisely match the images using a chi 2-test. The registered images and the subtraction images produced from them were used to detect changes in signal intensity, sit, shape, and size of the brain. RESULTS: Small changes due to differences in orientation of the head, growth, and development as well as inhalation of oxygen and carbogen (95% O2/5% CO2) were observed in normal subjects. Changes were also observed in patients with minor head trauma, a meningioma, an astrocytoma, and multiple sclerosis. Differences due to contrast enhancement and surgery and/or anesthesia were also seen. CONCLUSION: With use of subvoxel registration, subtle changes in the brain were detected in a variety of physiological and clinical situations where differences have hitherto been difficult or impossible to detect.