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.     

Patient survival by Hsp70 membrane phenotype: association with different routes of metastasis

BACKGROUND: Heat shock proteins (HSPs) play important roles in tumor immunity. The authors prospectively investigated the correlation between the tumor-specific Hsp70 membrane expression as an independent clinicopathological marker and overall survival in tumor entities that differ in their route of metastasis. METHODS: Hsp70 membrane expression was examined by flow cytometry in 58 colon, 19 gastric, 54 lower rectal carcinoma, and 19 squamous cell carcinoma specimens and the corresponding normal tissues at time of first diagnosis. Kaplan-Meier survival curves were analyzed to determine the relation of Hsp70 expression to the patients' prognosis. RESULTS: An Hsp70 membrane-positive phenotype was found in 40% (colon), 37% (gastric), 43% (lower rectal), and 42% (squamous cell) of the analyzed tumor specimens. None of the corresponding normal tissues was found to be Hsp70 membrane-positive. In patients with colon (P = .032) and gastric (P = .045) carcinomas, an Hsp70 membrane expression correlated significantly with an improved overall survival; a negative association was seen in lower rectal (P = .085) and squamous cell carcinoma (P = .048). CONCLUSIONS: The authors hypothesized that differing relations between surface expression of Hsp70 on tumor cells and clinical outcomes may reflect differences in the route of metastases. Colon and gastric carcinomas metastasize into the liver where hepatic natural killer cells may have the capacity to recognize and kill Hsp70 membrane-positive tumor cells and thus account for a better overall survival.     

Accelerated partial breast irradiation: consensus statement of 3 German Oncology societies

BACKGROUND: Breast-conserving surgery followed by whole-breast radiotherapy (WBRT) has become the standard treatment for the majority of patients with early breast cancer. Whereas the indications for systemic adjuvant treatment have continuously expanded, there is a tendency to restrict postoperative radiotherapy to accelerated partial breast irradiation (APBI) instead of WBRT. METHODS: The different techniques of APBI are described and their respective advantages or potential drawbacks outlined. Moreover, the results described in the literature are briefly reviewed as a basis for the consensus statements and recommendations of the German Society of Radiation Oncology, the German Society of Senology, and the Working Group for Gynecological Oncology of the German Cancer Society. RESULTS: The methods mainly used for APBI are: interstitial radiotherapy with multicatheter technique, intraoperative radiotherapy (IORT) using either electrons produced by linear accelerators or 50 kV x-rays (Intrabeam), the balloon-catheter technique (MammoSite), or 3D conformal external beam radiotherapy. These techniques have marked differences in dose distribution and homogeneity. The published range of local recurrence rates varies between 0% to 37%, the median follow-up from 8 to 72 months. CONCLUSIONS: To date, follow-up times mostly do not yet permit a definite judgment concerning the long-term effectiveness and side effects of APBI. The relevant societies in Germany support randomized clinical studies comparing APBI with WBRT in a well-defined subset of low-risk patients. However, the authors expressly discourage the routine use of APBI outside clinical trials. Until definite results show that APBI neither impairs therapeutic outcome nor cosmetic results, WBRT remains the gold standard in the treatment of early breast cancer.