Enantiomorphic normalization of focally lesioned brains

In order to make spatial inferences about the brain across a group of patients, it is usually necessary to employ some means of bringing each brain image into register with either a group mean image or a standard template. In the presence of focal brain lesions, automated methods for performing such so-called normalization are liable to distortion from the abnormal signal within the lesion, especially when the non-linear warping necessary for maximum registration fidelity is used. The most frequently used method for minimizing this distortion--cost function masking--simply eliminates the lesioned area when deriving the normalization parameters. As lesion size increases, however, the normalization error may be expected to rise steeply since the volume of brain from which the parameters are derived falls with it. Here we propose an alternative non-linear registration method that exploits a natural redundancy in the brain--the enantiomorphic relation between the two hemispheres--to correct the signal within the lesion using information from the undamaged homologous region within the contralesional hemisphere. As lesion size increases, the normalization error should theoretically asymptote to inter-hemispheric differences, which are both quantifiable and much lower than the inter-subject difference. Using SPM's non-linear normalization routines, we evaluate this technique with images of normal brains to which lesions selected from a large dataset have been artificially applied. Our results show the enantiomorphic method to be vastly superior to cost function masking across subjects, lesion characteristics, and brain voxels. We therefore propose that it should be the method of choice for normalizing images of focally lesioned brains.     

Similarities in stress physiology among patients with chronic pain and headache disorders: evidence for a common pathophysiological mechanism?

One common feature of chronic musculoskeletal pain and headaches are that they are both influenced by stress. Among these, tension-type headache (TTH), fibromyalgia (FMS) and chronic shoulder/neck pain (SNP) appear to have several similarities, both with regard to pathophysiology, clinical features and demographics. The main hypothesis of the present study was that patients with chronic pain (TTH, FMS and SNP) had stress-induced features distinguishing them from migraine patients and healthy controls. We measured pain, blood pressure, heart rate (HR) and skin blood flow (BF) during (1 h) and after (30 min) controlled low-grade cognitive stressor in 22 migraine patients, 18 TTH patients, 23 FMS patients, 29 SNP patients and 44 healthy controls. FMS patients had a lower early HR response to stress than migraine patients, but no differences were found among FMS, TTH and SNP patients. Finger skin BF decreased more in FMS patients compared to migraine patients, both during and after the test. When comparing chronic pain patients (chronic TTH, FMS and SNP) with those with episodic pain (episodic TTH and migraine patients) or little or no pain (healthy controls), different adaptation profiles were found during the test for systolic and diastolic blood pressure, HR and skin BF in the chronic group. In conclusion, these results suggest that TTH, FMS and SNP patients may share common pathophysiological mechanisms regarding the physiological responses to and recovery from low-grade cognitive stress, differentiating them from episodic pain conditions such as migraine.     

Activity-dependent potentiation of calcium signals in spinal sensory networks in inflammatory pain states

The second messenger calcium is a key mediator of activity-dependent neural plasticity. How persistent nociceptive activity alters calcium influx and release in the spinal cord is not well-understood. We performed calcium-imaging on individual cell bodies and the whole area within laminae I and II in spinal cord slices from mice in the naïve state or 24 h following unilateral hindpaw plantar injection of complete Freund’s adjuvant. Calcium signals evoked by dorsal root stimulation at varying strengths displayed a steep rise and slow decay over 15–20 s and increased progressively with both increasing intensity and frequency of stimulation in naïve mice. Experiments with pharmacological inhibitors revealed that both ionotropic glutamate receptors and intracellular calcium stores contributed to maximal calcium signals in laminae I and II evoked by stimulating dorsal roots at 100 Hz frequency. Importantly, as compared to naïve mice, we observed that in mice with unilateral hindpaw inflammation, calcium signals were potentiated to 159 ± 10% in the ipsilateral dorsal horn and 179 ± 8% in the contralateral dorsal horn. In addition to the contribution from NMDA receptors, GluR-A-containing AMPA receptors were found to be critically required for the above changes in spinal calcium signals, as revealed by analysis of genetically modified mouse mutants, whereas intracellular calcium release was not required. Thus, these results suggest that there is an important functional link between calcium signaling in superficial spinal laminae and the development of inflammatory pain. Furthermore, they highlight the importance of GluR-A-containing calcium-permeable AMPA receptors in activity-dependent plasticity in the spinal cord.     

Liberal vs. conservative vasopressor use to maintain mean arterial blood pressure during resuscitation of septic shock: an observational study

OBJECTIVE: The optimal role of vasopressor therapy in septic shock is not known. We hypothesized that the variability in the use of vasopressors to treat hypotension is associated with subsequent organ failures. DESIGN: Retrospective observational single-center cohort study. SETTING: Tertiary care hospital. PATIENTS AND PARTICIPANTS: Consecutive patients with septic shock. MEASUREMENT AND RESULTS: Ninety-five patients were enrolled. Serial blood pressure recordings and vasopressor use were collected during the first 12h of septic shock. Median duration of hypotension that was not treated with vasopressors was 1.37h (interquartile range [IQR] 0.62-2.66). Based on the observed variability, we evaluated liberal (duration of untreated hypotension < median) vs. conservative (duration of untreated hypotensionn > median) vasopressor therapy. Compared with patients who received conservative vasopressor therapy, patients treated liberally had similar baseline organ impairment [median Sequential Organ Failure Assessment (SOFA) score 8 vs. 8, p = 0.438] were more likely to be younger (median age 70 vs. 77 years, p = 0.049), to require ventilator support (78 vs. 49%, p < 0.001), and to have progression of organ failures after 24h (59 vs. 37%, p = 0.032). When adjusted for age and mechanical ventilation, early therapy aimed at achieving global tissue perfusion [odds ratio (OR) 0.33, 95% confidence interval (CI) 0.11-0.88), and early adequate antibiotic therapy (OR 0.27, 95% CI 0.09-0.76), but not liberal vasopressor use (OR 2.13, 95% CI 0.80-5.84), prevented progression of organ failures. CONCLUSIONS: In our retrospective study, early adequate antibiotics and achieving adequate global perfusion, but not liberal vasopressor therapy, were associated with improved organ failures after septic shock. Clinical trials which compare conservative vs. liberal vasopressor therapy are warranted.     

Pseudoaneurysm after Ponseti percutaneous Achilles tenotomy: a case report

The Ponseti method has become a popular technique to treat idiopathic clubfoot. In most cases, a percutaneous Achilles tenotomy is required to correct residual equinus contracture. Bleeding has been reported as a complication of percutaneous tenotomy. We present a case of a baby who developed a pseudoaneurysm after undergoing an appropriate Ponseti percutaneous Achilles tenotomy at the age of 8 weeks. The diagnosis of pseudoaneurysm was confirmed by color ultrasonography, which showed active flow in the base of the mass. This complication has not been previously described after Ponseti percutaneous Achilles tenotomy. The large pseudoaneurysm mass together with an incomplete correction made bracing with straight last shoes and Denis Browne bar impossible, and the patient developed an immediate relapse of the clubfoot deformity. The relapsed deformity was successfully treated with 4 weeks of additional Ponseti casting, with an emphasis on applying pressure over the pseudoaneurysm by molding the cast. Repeat ultrasonogram at that time showed that the pseudoaneurysm completely resolved, making invasive treatment of the pseudoaneurysm unnecessary. Physicians should be aware that vascular injury could lead to pseudoaneurysm after performing this otherwise simple office procedure.     

From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activity of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae

As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to HI0065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gene products that are not present in eukaryotic cells can identify novel antibacterial agents.