Global average gray and white matter N-acetylaspartate concentration in the human brain

Since the amino acid derivative N-acetylaspartate (NAA) is almost exclusive to neuronal cells in the adult mammalian brain and its concentration has shown local (or global) abnormalities in most focal (or diffuse) neurological diseases, it is considered a specific neuronal marker. Yet despite its biological and clinical prominence, the relative NAA concentration in the gray and white matter (GM, WM) remains controversial, with each reported to be higher than, equal to, or less than the other. To help resolve the controversy and importantly, access the NAA in both compartments in their entirety, we introduce a new approach to distinguish and quantify the whole-brain average GM and WM NAA concentration by integrating MR-image segmentation, localized and non-localized quantitative (1)H-MRS. We demonstrate and validate the method in ten healthy volunteers (5 women) 27+/-6 years old (mean+/-standard-deviation) at 1.5T. The results show that the healthy adult human brain comprises significantly less WM, 39+/-3%, than GM 60+/-4% by volume (p<0.01). Furthermore, the average NAA concentration in the WM, 9.5+/-1.0 mM, is significantly lower than in GM, 14.3+/-1.1 mM (p<0.01).     

Semi-automatic brain region extraction (SABRE) reveals superior cortical and deep gray matter atrophy in MS

In multiple sclerosis (MS), atrophy occurs in various cortical and subcortical regions. However, it is unclear whether this is mostly due to gray (GM) or white matter (WM) loss. Recently, a new semi-automatic brain region extraction (SABRE) technique was developed to quantify parenchyma volume in 13 hemispheric regions. This study utilized SABRE and tissue segmentation to examine whether regional brain atrophy in MS is mostly due to GM or WM loss, correlated with disease duration, and moderated by disease course. We studied 68 MS patients and 39 normal controls with 1.5 T brain MRI. As expected, MS diagnosis was associated with significantly lower (P < 0.001) regional brain parenchymal fractions (RBPFs). While significant findings emerged in 11 GM comparisons, only four WM comparisons were significant. The largest mean RBPF percent differences between groups (MS < NC) were in the posterior basal ganglia/thalamus region (-19.3%), superior frontal (-15.7%), and superior parietal (-14.3%) regions. Logistic regression analyses showed GM regions were more predictive of MS diagnosis than WM regions. Eight GM RBPFs were significantly correlated (P < 0.001) with disease duration compared to only one WM region. Significant trends emerged for differences in GM, but not WM between secondary progressive (SP) and relapsing-remitting MS patients. Percent differences in GM between the two groups were largest in superior frontal (-9.9%), medial superior frontal (-6.5%), and superior parietal (-6.1%) regions, with SP patients having lower volumes. Overall, atrophy in MS is diffuse and mostly related to GM loss particularly in deep GM and superior frontal-parietal regions.     

Longitudinal changes in grey and white matter during adolescence

Brain development continues actively during adolescence. Previous MRI studies have shown complex patterns of apparent loss of grey matter (GM) volume and increases in white matter (WM) volume and fractional anisotropy (FA), an index of WM microstructure. In this longitudinal study (mean follow-up = 2.5 ± 0.5 years) of 24 adolescents, we used a voxel-based morphometry (VBM)-style analysis with conventional T1-weighted images to test for age-related changes in GM and WM volumes. We also performed tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) data to test for age-related WM changes across the whole brain. Probabilistic tractography was used to carry out quantitative comparisons across subjects in measures of WM microstructure in two fiber tracts important for supporting speech and motor functions (arcuate fasciculus [AF] and corticospinal tract [CST]). The whole-brain analyses identified age-related increases in WM volume and FA bilaterally in many fiber tracts, including AF and many parts of the CST. FA changes were mainly driven by increases in parallel diffusivity, probably reflecting increases in the diameter of the axons forming the fiber tracts. FA values of both left and right AF (but not of the CST) were significantly higher at the end of the follow-up than at baseline. Over the same period, widespread reductions in the cortical GM volume were found. These findings provide imaging-based anatomical data suggesting that brain maturation in adolescence is associated with structural changes enhancing long-distance connectivities in different WM tracts, specifically in the AF and CST, at the same time that cortical GM exhibits synaptic “pruning”.     

Mapping the effect of APOE ε4 on gray matter loss in Alzheimer's disease in vivo

Previous studies suggest that in Alzheimer's disease (AD) the Apolipoprotein E (APOE) ε4 allele is associated with greater vulnerability of medial temporal lobe structures. However, less is known about its effect on the whole cortical mantle. Here we aimed to identify APOE-related patterns of cortical atrophy in AD using an advanced computational anatomy technique. We studied 15 AD patients carriers (ε4+, age: 72 ± 10 SD years, MMSE: 20 ± 3 SD) and 14 non-carriers (ε4−, age: 69 ± 9, MMSE: 20 ± 5) of the ε4 allele and compared them to 29 age-and-sex matched controls (age: 70 ± 9, MMSE: 28 ± 1). Each subject underwent a clinical evaluation, a neuropsychological battery, and high-resolution MRI. UCLA's cortical pattern matching technique was used to identify regions of local cortical atrophy. ε4+ and ε4− patients showed similar performance on neuropsychological tests (p > .05, t-test). Diffuse cortical atrophy was detected for both ε4+ (p = .0001, permutation test) and ε4− patients (p = .0001, permutation test) relative to controls, and overall gray matter loss was about 15% in each patients group. Differences in gray matter loss between carriers and non-carriers mapped to the temporal cortex and right occipital pole (20% greater loss in carriers) and to the posterior cingulate, left orbitofrontal and dorsal fronto-parietal cortex (5–15% greater loss in non-carriers). APOE effect in AD was not significant (p > .74, ANOVA), but a significant APOE by region (temporal vs fronto-parietal cortex) interaction was detected (p = .002, ANOVA), in both early and late-onset patients (p < .05, ANOVA). We conclude that the ε4 allele modulates disease phenotype in AD, being associated with a pattern of differential temporal and fronto-parietal vulnerability.     

Grey matter volume alterations in CADASIL: a voxel-based morphometry study

CADASIL is a hereditary disease characterized by cerebral subcortical microangiopathy leading to early onset cerebral strokes and progressive severe cognitive impairment. Until now, only few studies have investigated the extent and localization of grey matter (GM) involvement. The purpose of our study was to evaluate GM volume alterations in CADASIL patients compared to healthy subjects. We also looked for correlations between global and regional white matter (WM) lesion load and GM volume alterations. 14 genetically proved CADASIL patients and 12 healthy subjects were enrolled in our study. Brain MRI (1.5 T) was acquired in all subjects. Optimized-voxel based morphometry method was applied for the comparison of brain volumes between CADASIL patients and controls. Global and lobar WM lesion loads were calculated for each patient and used as covariate-of-interest for regression analyses with SPM-8. Compared to controls, patients showed GM volume reductions in bilateral temporal lobes (p < 0.05; FDR-corrected). Regression analysis in the patient group revealed a correlation between total WM lesion load and temporal GM atrophy (p < 0.05; uncorrected), not between temporal lesion load and GM atrophy. Temporal GM volume reduction was demonstrated in CADASIL patients compared to controls; it was related to WM lesion load involving the whole brain but not to lobar and, specifically, temporal WM lesion load. Complex interactions between sub-cortical and cortical damage should be hypothesized.     

A randomized controlled trial comparing one-operator versus two-operator technique in ultrasound-guided basilic vein cannulation

The basilic vein offers an alternative site for peripheral intravenous access for emergency access. The use of a two-operator ultrasound-guided basilic vein cannulation technique has been shown to be a safe and effective technique for use on Emergency Department patients. However, the one-operator technique is more customary by other services. We sought to compare the more customary one-person technique to the two-person technique in basilic vein cannulation in novice operators. This was a prospective, randomized controlled trial of two techniques of ultrasound-guided basilic vein cannulation (one-operator vs. two-operators) in healthy adult volunteers. Each volunteer underwent each technique, one technique on each arm. We selected the initial arm and technique using computer-generated block randomization. In the one-operator technique, a single operator held the transducer in transverse short-axis plane while attempting cannulation using a 20-gauge, 1.88-inch catheter. In the two-operator technique, a second operator held the transducer in place while the first operator attempted cannulation. The primary outcome variable was first-attempt cannulation success. Secondary outcome variables were overall success, number of attempts, time-to-cannulation, complications, and ease-of-technique rated by the operators. There were 32 subjects enrolled. One-operator first-attempt success was 18/32 (56%); two-operator was 21/32 (65%), with a mean difference in proportion of −9% (95% confidence interval [CI] −33–14%). Overall success for one operator was 23/32 (72%) and two-operator was 24/32 (75%), with mean difference in proportion of −3% (95% CI −24–18). The median number of attempts for one-operator was 1.6 (interquartile range [IQR] 1–5) and two-operator was 1.4 (IQR 1–5) (p = 0.8). Time to cannulation for one-operator was 57 s (± 62) and two-operator was 44 s (± 37) (p = 0.33). The median score for ease-of-technique for one-operator was 4.3 (IQR 1–6) and for two-operator was 3.6 (IQR 1–6) (p = 0.26). There were no complications with either technique (95% CI 0–10%). Novice operators can reliably perform a basilic vein cannulation using ultrasound guidance. However, we were unable to demonstrate any advantage for any particular technique in cannulating the basilic vein.     

Skin vasoreactivity to insulin iontophoresis is reduced in elderly subjects and is absent in treated non-insulin-dependent diabetes patients

We investigated the skin vasoreactivity to insulin in normal subjects and in treated non-insulin-dependent diabetes mellitus (NIDDM) patients. We measured cutaneous perfusion by laser-Doppler flowmetry (LDF) at rest and during skin cathodal iontophoresis (six pulses of 0.1 mA each for 20 s, with 40 s interval between stimulations) of insulin (0.1 ml Humulin R 100 IU/ml diluted 1/10 with of 0.9% saline solution) in 45 healthy subjects (HS), (25 males, 20 females, aged 45 ± 18 years), and in 15 treated NIDDM patients (13 males), aged 66 ± 8 years. Fifteen of the HS were used as controls. In these 15 sex- and age-matched HS and in the patients, we assessed also the skin postischemic hyperemia by LDF. In HS cutaneous blood flux response (CBF) to iontophoresis of insulin in saline (expressed as percent changes from baseline) was significantly higher than CBF response to iontophoresis of pure saline (maximum response: 360 ± 51% versus 172 ± 42%, respectively; P < 0.001, ANOVA for repeated measures). The maximum “net” CBF response to insulin (response to insulin minus response to saline) showed a negative correlation (r = –0.361; P < 0.01) with age in HS, and resulted significantly lower in the oldest than in the youngest HS (105 ± 40% versus 307 ± 45%, respectively; P < 0.01). No significant correlation was observed between the maximum CBF response to saline and the age of subjects. In NIDDM patients the “net” CBF response to insulin iontophoresis resulted significantly lower than in 15 sex- and age-matched control subjects (maximum response: –50 ± 89% versus 201 ± 81%, respectively; P < 0.001, ANOVA for repeated measures). No significant difference was observed between diabetics and controls, nor in basal perfusion (6.5 ± 1.3 IU versus 6.8 ± 1.7 IU, respectively) neither in the skin postischemic hyperemia (250 ±14% versus 258 ± 27%, respectively). These results confirm that insulin iontophoresis induces a skin vasodilatatory effect in normal subjects and show that this effect is reduced by aging and is absent in treated NIDDM patients. The local skin vasodilatatory effect induced by insulin seems to involve mechanisms different from those underlying the skin postischemic hyperemia.     

The topographical distribution of tissue injury in benign MS: a 3T multiparametric MRI study

We compared the global and regional distribution of white matter (WM) and gray matter (GM) damage and T2-visible lesion between patients with benign (B) and relapsing remitting (RR) multiple sclerosis (MS). BMS and RRMS patients did not differ in terms of global volumes and diffusion tensor (DT) MRI metrics of the WM and GM. Compared to controls, BMS and RRMS patients had bilateral thalamic loss. Compared to controls, BMS and RRMS patients had lower WM fractional anisotropy (FA) in the corpus callosum (CC) and in several regions of temporal and occipital lobes. BMS also had a decreased WM FA in the parietal lobes. RRMS patients had also lower WM FA in several regions of the frontal lobes. Compared to BMS, RRMS patients had decreased WM FA in the frontal lobes, while the opposite comparison showed lower WM FA in the CC, the temporal lobes and the cuneus in BMS. Contrasted to controls, both MS groups showed several regions of increased MD in WM and GM, but no difference was found between MS sub-groups. T2-visible lesions were mainly located in the posterior regions of the brain in BMS patients, while they involved also regions in the frontal lobes, in RRMS patients. BMS and RRMS patients differ in terms of the topographical distribution of WM damage rather than in the overall extent of brain structural changes. The less prominent involvement of the frontal lobe WM and of the NAWM in general in BMS might be associated to their favorable clinical status.     

Direct quantitative comparison between cross-relaxation imaging and diffusion tensor imaging of the human brain at 3.0 T

Cross-relaxation imaging (CRI) describes the magnetization transfer within tissues between mobile water protons and macromolecular protons. Whole-brain parametric maps of the principle kinetic components of magnetization transfer, the fraction of macromolecular protons (f) and the rate constant (k), revealed detailed anatomy of white matter (WM) fiber tracts at 1.5 T. In this study, CRI was first adapted to 3.0 T, and constraints for transverse relaxation times of water and macromolecular protons were identified to enable unbiased f and k estimation. Subsequently, whole-brain CRI and diffusion tensor imaging (DTI) were performed in five healthy subjects. The parameters f and k were compared to DTI indices (fractional anisotropy (FA), apparent diffusion coefficient (ADC), radial diffusivity (RD), and axial diffusivity (AD)) across a range of anatomic regions. In WM, neither f nor k was significantly correlated to FA, RD, and AD. In contrast, both f (r = 0.90 and r = − 0.80) and k (r = 0.92 and r = − 0.89) in gray matter (GM) were strongly correlated to FA and RD, respectively. A moderate correlation between ADC and k (r = 0.48) was identified in WM, while an inverse correlation was identified in GM (r = − 0.72). The lack of association between CRI and FA in WM is consistent with differences in the underlying physical principles between techniques — fiber density vs. directionality, respectively. The association in GM may be attributable to variable axonal density unique to each structure. Our findings suggest that whole-brain CRI provides distinct quantitative information compared to DTI, and CRI parameters may prove constructive as biomarkers in neurological diseases.     

N-Acetyl-β-d-glucosaminidase (NAG) and NAG isoenzymes in children with upper and lower urinary tract infections

The use of N-acetyl-β-d-glucosaminidase (NAG) to diagnose the site of urinary tract infection was studied in pediatric patients. Differentiation between upper and lower tract infections (UTI) was based on clinical grounds and on elevated erythrocyte sedimentation rate, C-reactive protein and fever. NAG excretion expressed as nmol · h⁻¹ · mg⁻ of urinary creatinine was higher in children with upper UTI (mean ± SE 906 ± 236) than in those with lower UTI (145 ± 23) or healthy children (151.6 ± 10) (p<0.01 by Duncan's test). In children with upper UTI, NAG excretion fell in parallel with the remission due to antibiotic treatment. This however was not seen in children treated with aminoglycosides. A specific and significant elevation (p < 0.01) of the B isoenzyme of NAG was documented in children with upper UTI but not in those with lower UTI (B form in upper UTI 49.2% ± 3.9 versus 21.9 ± 3.3 in lower UTI; healthy children 18.9 ± 3.4). The percentage of B isoenzyme excreted was high in two children with upper UTI but was low total NAG urinary excretion, suggesting that the quantification of isoenzymes offers further specificity in diagnosis. We conclude that the measurement of NAG and its isoenzymes in children with UTI provides useful information in the diagnosis of the site of infection.     

Determinants of lung volumes in chronic spinal cord injury

Stepp EL, Brown R, Tun CG, Gagnon DR, Jain NB, Garshick E. Determinants of lung volumes in chronic spinal cord injury.

Objective

To characterize determinants of lung volumes in chronic spinal cord injury (SCI).

Design

Cross-sectional.

Setting

VA Boston Healthcare System.

Participants

White men (N=330) with chronic SCI.

Interventions

Not applicable.

Main Outcome Measures

Questionnaire responses and measurements of lung volumes.

Results

Adjusted for SCI severity and stature, greater body mass index (BMI) was associated (all P<.05) with lower total lung capacity (TLC) (−38.7mL·kg⁻¹·m⁻²), functional residual capacity (FRC) (−73.9mL·kg⁻¹·m⁻²), residual volume (RV) (−40.4mL·kg⁻¹·m⁻²), and expiratory reserve volume (ERV) (−32.2mL·kg⁻¹·m⁻²). The effect of BMI on RV was most pronounced in quadriplegia (−72mL·kg⁻¹·m⁻²). Lifetime smoking was associated with a greater FRC (5.3mL/pack-year) and RV (3.1mL/pack-years). The effects of lifetime smoking were also greatest in quadriplegia (11mL/pack-year for FRC; 7.8mL/pack-year for RV). Time since injury, independent of age, was associated with a decrease in TLC, FRC, ERV, and RV (P<.05). Age was not a predictor of TLC once time since injury was considered.

Conclusions

Determinants of FRC, TLC, ERV, and RV in chronic SCI include factors related and unrelated to SCI. The mechanisms remain to be determined but likely involve the elastic properties and muscle function of the respiratory system and perhaps the effects of systemic inflammation related to adiposity. Addressing modifiable factors such as obesity, muscle stiffness, and smoking may improve respiratory morbidity and mortality in SCI by improving pulmonary function.     

Electrical neuromodulation improves myocardial perfusion and ameliorates refractory angina pectoris in patients with syndrome X: fad or future?

At present, there is no reliable antianginal drug therapy for patients with cardiac syndrome X. Therefore, the effect of electrical neuromodulation on refractory angina pectoris and myocardial perfusion in cardiac syndrome X was assessed. Eight patients (aged 55±7 years) with heterogeneous myocardial perfusion and no esophageal abnormalities were included. The subjects were nonresponders to antianginal drug therapy. Angina pectoris attacks and myocardial perfusion dynamics were evaluated by positron emission tomography at baseline and following 4 weeks of (transcutaneous electrical nerve stimulation) TENS. Following TENS there was a reduction of angina pectoris episodes (baseline 20±3, TENS 3±1; p=0.012), and short acting nitroglycerin intake per week (baseline 10±3, TENS 2±1; p=0.008). The rate pressure product (mmHgmin⁻¹) during the cold pressor test (CPT) was reduced during TENS (baseline 12 800±1200, TENS 11 500±900; p=0.02). Following TENS, the perfusion reserve ratio between rest and dipyridamole flow increased (baseline 1.59±0.15, TENS 1.90±0.11 mlmin⁻¹×100 g; p=0.05). The coronary vascular resistance had a trend towards a reduction (baseline 0.96±0.04, TENS 0.85±0.06 mmHgmin⁻¹×100 g/ml; p=0.06) during CPT. This observation may suggest that neurostimulation improves angina pectoris with a concomitant improvement of myocardial perfusion in cardiac syndrome X.     

Antinociceptive effects of high dose remifentanil in male methadone-maintained patients

The treatment of acute pain in patients maintained on methadone is difficult due to increased pain sensitivity (hyperalgesia) and cross-tolerance to other opioids. This study aimed to investigate whether remifentanil elicits antinociception in methadone-maintained subjects in a dose-dependent manner. Eight chronic methadone-maintained subjects attended the testing session approximately 20 h after their normal methadone dose (range 50–110 mg day⁻¹). Following a 20 min saline infusion, subjects were administered intravenous remifentanil in seven increasing doses ranging from 0.5 to 3.5 μg kg⁻¹ min⁻¹, each for 20 min. Testing was performed in the last 10  min of each infusion. The testing measures included nociception, as measured by the cold pressor test, withdrawal using the subjective opiate withdrawal scale (SOWS), and subjective opioid effects using the morphine–benzedrine group scale (MBG). Results showed dose-dependent increase in cold pressor tolerance time from baseline of 15.6 ± 3.5 (mean ± SEM) s up to 77.3 ± 24.7 s during this dosing protocol. During the infusion typical μ-opioid receptor agonist side effects were observed, but with no withdrawal. Methadone-maintained patients demonstrate significant tolerance to remifentanil and may require opioid doses 20–30 higher than required for the treatment of acute pain in opioid-naïve patients.     

Relating neocortical pathology to disability progression in multiple sclerosis using MRI

Cortical grey matter (cGM) develops a substantial burden of pathology in multiple sclerosis (MS). Previous cross-sectional studies have suggested a relationship between measures of cortical atrophy and disability. Our objective was to develop a method for automatically measuring the apparent cGM thickness as well as the integrity of the interface between cGM and subcortical white matter (GM/WM) both globally and regionally on T(1)-weighted MRI, and use this method in a longitudinal investigation of how these measures differed between patients with stable MS and patients with progressing disability. Measurements were made over the whole brain and for anatomically specified cortical regions, both cross-sectionally at baseline and longitudinally on two MRI scans performed on average 1 year apart. We found a higher average rate of apparent loss of cGM thickness across the whole brain in the group that progressed over the interscan interval compared to the group that remained stable (progressing = -3.13 +/- 2.88%/year, stable = 0.06 +/- 2.31%/year, P = 0.002). This difference was detected with regional measures in parietal and precentral cortex. In contrast, change in the GM/WM interface integrity did not show detectable regional differences, although the group of MS patients whose disability progressed showed a significant decrease in GM/WM interface integrity compared to the stable group (P = 0.003). Regional measures of apparent loss of cGM thickness enhance sensitivity to cortical pathological changes. A measure of integrity offers a new index of disease-associated cortical changes at the GM/WM interface. The results suggest that progression of disability in MS is associated with the progression of MRI-detectable cortical pathology.     

Longitudinal changes in patients with traumatic brain injury assessed with diffusion-tensor and volumetric imaging

Traumatic brain injury (TBI) is associated with brain volume loss, but there is little information on the regional gray matter (GM) and white matter (WM) changes that contribute to overall loss. Since axonal injury is a common occurrence in TBI, imaging methods that are sensitive to WM damage such as diffusion-tensor imaging (DTI) may be useful for characterizing microstructural brain injury contributing to regional WM loss in TBI. High-resolution T1-weighted imaging and DTI were used to evaluate regional changes in TBI patients compared to matched controls. Patients received neuropsychological testing and were imaged approximately 2 months and 12.7 months post-injury. Paradoxically, neuropsychological function improved from Visit 1 to Visit 2, while voxel-based analyses of fractional anisotropy (FA), and mean diffusivity (MD) from the DTI images, and voxel-based analyses of the GM and WM probability maps from the T1-weighted images, mainly revealed significantly greater deleterious GM and WM change over time in patients compared to controls. Cross-sectional comparisons of the DTI measures indicated that patients have decreased FA and increased MD compared to controls over large regions of the brain. TBI affected virtually all of the major fiber bundles in the brain including the corpus callosum, cingulum, the superior and inferior longitudinal fascicules, the uncinate fasciculus, and brain stem fiber tracts. The results indicate that both GM and WM degeneration are significant contributors to brain volume loss in the months following brain injury, and also suggest that DTI measures may be more useful than high-resolution anatomical images in assessment of group differences.     

Relationship between ventilator-associated pneumonia and intramucosal gastric pHi: A case-control study

Prior investigations have suggested a clear relationship between nosocomial pneumonia and intramucosal gastric pH (pHi), a probable marker of bacterial translocation. We studied 33 patients (18 with pneumonia and 15 without) admitted to an intensive care unit and hospitalized longer than 72 hours with the aim of assessing the relationship between nosocomial pneumonia, pHi, and outcome. pHi was estimated at the time of inclusion of patients into the study. Arterial pH (pHa) and bicarbonate and stomach pH and tonometer Ptco₂ were also recorded. Values of <7.32 or ΔpHa - pHi of>+0.06 were used to differentiate between normal and low pHi. Quantitative cultures of pharyngeal swabs, gastric lumen, and protected specimen brush from lower airways were also done. The mean pHi values were 7.397 ± 0.105 (range, 7.14 to 7.53) and 7.452 ± 0.059 (range, 7.37 to 7.56) for patients with and without pneumonia, respectively (P = .073). Five patients, all with pneumonia, had pHi < 7.32. No patients without pneumonia had pHi < 7.32 (P = .04). The mean ΔpHa - pHi was 0.04 ± 0.07 (range, −0.11 to 0.13) and 0.05 ± 0.09 (range, −0.09 to 0.28; P = .72) for patients with and without pneumonia, respectively. However, there were significant differences when tonometer Ptco₂ values of both groups were compared (38.9 ± 8.3 and 30.6 ± 4.7 mm Hg, respectively; P = .025). Patients with pneumonia had higher alkaline gastric lumen pH (5.2 ± 1.0) than those without pneumonia (3.8 ± 1.4; P = .006). Nonsurvivors (n = 7) had more acidic pHi (7.33 ± 0.11) than survivors (7.44 ± 0.06; P = .045). The mean gastric lumen bacterial concentration was 4.14 ± 1.01 Log₁₀ CFU/mL in patients with pneumonia and 4.28 ± 1.22 Log₁₀ CFU/mL in patients without pneumonia (P = NS). When patients with and without intramucosal gastric acidosis (pHi < 7.32) were compared, the gastric bacterial burden was 4.42 ± 0.82 Log₁₀ CFU/mL and 4.32 ± 1.03 Log₁₀ CFU/mL (P = .08), respectively. Most patients with nosocomial pneumonia had no associated intramucosal gastric acidosis. However, low pHi was associated with increased mortality.     

Antipseudomonal activity of piperacillin/tazobactam: more than a decade of experience from the SENTRY Antimicrobial Surveillance Program (1997–2007)

We evaluated the susceptibility rates for piperacillin/tazobactam tested against Pseudomonas aeruginosa isolates from the Asia-Pacific (APAC), Europe (EU), Latin America (LA), and North America (NA) for 1997 to 2007. A total of 25 460 isolates were tested originating from APAC (4441), EU (7695), LA (4277), and NA (9047). All testing was performed by reference broth microdilution methods. The samples were collected from >110 medical centers and samples averaging >30 nations/year. For this analysis, results from 1997 to 2007, 1997 to 1999, 2005 to 2007, APAC, EU, LA, and NA were assessed against several broad-spectrum β-lactams, including cefepime, ceftazidime, imipenem, meropenem, and piperacillin alone, for a total of 12 agents overall. Using P. aeruginosa breakpoints (≤64 μg/mL), piperacillin/tazobactam had the broadest coverage (% susceptible) in 2 regions (EU, LA) and, overall, at 83.6% followed by meropenem (83.0%) > imipenem (79.7%) > piperacillin (79.5%) > cefepime (77.5%) > ceftazidime (75.8%). Other non–β-lactam activity results were ciprofloxacin at only 71.5% susceptible, but tobramycin and polymyxin B had higher susceptibility rates (81.0% and 99.5%, respectively). Trends toward piperacillin/tazobactam resistance were noted between 1997 to 1999 and 2000 to 2007 in APAC (−11.6% susceptibility), NA (−4.0%), and EU (−2.3%). LA susceptibility rates were lowest overall but actually increased recently by +2.9% (current rate, 79.4% susceptible). For β-lactamase inhibitor combinations, susceptibility rates were higher for piperacillin/tazobactam when compared in all regions with piperacillin alone (+2.6–7.1%) and greatest for LA isolates. In contrast, ticarcillin/clavulanate susceptibility rates were lower than ticarcillin tested alone in NA (−1.5%, antagonism), and this agent only inhibited 70.3% of isolates worldwide. In conclusion, piperacillin/tazobactam remained a very active β-lactam when tested in vitro against clinical isolates of P. aeruginosa found in the SENTRY Program (1997–2007). Trends toward slightly decreased susceptibility were noted in all regions over the last decade (except LA); only polymyxins had susceptibility rates at >90%. Resistance surveillance programs should be sustained to document emerging resistance patterns of old and newer agents for difficult-to-treat pathogens such as P. aeruginosa.     

Postreperfusion syndrome: Hypotension after reperfusion of the transplanted liver

Sixty-nine patients undergoing liver transplantation were evaluated to elucidate the relationship between hypotension and physiological changes seen on reperfusion of the grafted liver. Measured variables included hemodynamic profiles, core temperature, serum potassium, ionized calcium levels, arterial blood-gas tensions, and acid-base state. Measurements were taeen 60 minutes after skin incision (baseline), 5 minutes before reperfusion, and 30 seconds and 5 minutes after reperfusion. On the basis of changes in mean arterial pressure (MAP) patients were divided in two groups. Group 1 (n = 49) maintained MAP greater than 70% and group 2 (n = 20) had MAP less than 70% of the baseline value for at least 1 minute within 5 minutes after reperfusion. On reperfusion, changes common to both groups were 27% increase in cardiac filling pressures, 23% base deficit, and 30% serum potassium level and a decrease of 16% in cardiac output and 9% in temperature. Compared with group 1, group 2 had greater decrease in systemic vascular resistance (SVR) (1097 ± 868 and 741 ± 399 dyn · s⁻¹. cm⁻⁵, respectively, P < .05) and higher potassium level (4.5 ± 0.8 and 5.3 ± 0.8 mmol/L,P < .05). Collectively in both groups, there was no correlation between MAP and physiological variables; however, there was a poor correlation with SVR (r = .32, P < .01). Reperfusion hypotension seen in group 2 patients correlated only with a decrease in systemic vascular resistance (r = .5, P < .05). Acute hyperkalemia, hypothermia, and acidosis do not appear to be major causes of reperfusion hypotension.     

Evidence for axonal pathology and adaptive cortical reorganization in patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis

Previous work has suggested that functional reorganization of cortical areas might have a role in limiting the clinical impact of axonal pathology in patients with established multiple sclerosis (MS). Since there is evidence for irreversible tissue damage even in patients with early MS, we assessed, using functional MRI (fMRI) and a general search method, the brain pattern of movement-associated cortical activations in patients at presentation with clinically isolated syndromes (CIS) suggestive of MS. To elucidate the role of cortical reorganization in these patients, we also investigated the extent to which the fMRI changes correlated with the extent of overall axonal injury of the brain. From 16 right-handed patients at presentation with CIS and 15 right-handed, age- and sex-matched healthy volunteers, we obtained: (1). fMRI (repetitive flexion-extension of the last four fingers of the right hand), (2). conventional MRI scans, and (3). a new, unlocalized proton MR spectroscopy ((1)HMRS) sequence to measure the concentration of N-acetylaspartate of the whole brain (WBNAA). Compared to controls, patients with CIS had more significant activations of the contralateral primary somatomotor cortex (SMC), secondary somatosensory cortex, and inferior frontal gyrus. They also had significant decreased WBNAA concentration. Relative activation of the contralateral primary SMC was strongly correlated with WBNAA levels (r = -0.78, P < 0.001). This study shows that axonal pathology and functional cortical changes over a rather distributed sensorimotor network occur in patients at presentation with CIS suggestive of MS and that these two aspects of the disease are strictly correlated. This suggests that the increased functional recruitment of the cortex in these patients might have an adaptive role in limiting the clinical impact of irreversible tissue damage.     

The nitric oxide synthase inhibitor N-nitro-l-arginine decreases defibrillation-induced free radical generation

Objectives: To demonstrate that nitric oxide (NO) contributes to free radical generation after epicardial shocks and to determine the effect of a nitric oxide synthase (NOS) inhibitor, N^G-nitro-l-arginine (l-NNA), on free radical generation. Background: Free radicals are generated by direct current shocks for defibrillation. NO reacts with the superoxide (O₂⁻) radical to form peroxynitrite (O=NOO⁻), which is toxic and initiates additional free radical generation. The contribution of NO to free radical generation after defibrillation is not fully defined. Methods and results: Fourteen open chest dogs were studied. In the initial eight dogs, 40 J damped sinusoidal monophasic epicardial shocks was administered. Using electron paramagnetic resonance, we monitored the coronary sinus concentration of ascorbate free radical (Asc⁻), a measure of free radical generation (total oxidative flux). Epicardial shocks were repeated after l-NNA, 5 mg/kg IV. In six additional dogs, immunohistochemical staining was done to identify nitrotyrosine, a marker of reactive nitrogen species-mediated injury, in post-shock myocardial tissue. Three of these dogs received l-NNA pre-shock. After the initial 40 J shock, Asc⁻ rose 39±2.5% from baseline. After l-NNA infusion, a similar 40 J shock caused Asc⁻ to increase only 2±3% from baseline (P<0.05, post-l-NNA shock versus initial shock). Nitrotyrosine staining was more prominent in control animals than dogs receiving l-NNA, suggesting prevention of O=NOO⁻ formation. Conclusions: NO contributes to free radical generation and nitrosative injury after epicardial shocks; NOS inhibitors decrease radical generation by inhibiting the production of O=NOO⁻.