Effect of low tidal volume ventilation on lung function and inflammation in mice

<p>Abstract</p> <p>Background</p> <p>A large number of studies have investigated the effects of high tidal volume ventilation in mouse models. In contrast data on very short term effects of low tidal volume ventilation are sparse. Therefore we investigated the functional and structural effects of low tidal volume ventilation in mice.</p> <p>Methods</p> <p>38 Male C57/Bl6 mice were ventilated with different tidal volumes (Vt 5, 7, and 10 ml/kg) without or with application of PEEP (2 cm H₂O). Four spontaneously breathing animals served as controls. Oxygen saturation and pulse rate were monitored. Lung function was measured every 5 min for at least 30 min. Afterwards lungs were removed and histological sections were stained for measurement of infiltration with polymorphonuclear leukocytes (PMN). Moreover, mRNA expression of macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)α in the lungs was quantified using real time PCR.</p> <p>Results</p> <p>Oxygen saturation did not change significantly over time of ventilation in all groups (P > 0.05). Pulse rate dropped in all groups without PEEP during mechanical ventilation. In contrast, in the groups with PEEP pulse rate increased over time. These effects were not statistically significant (P > 0.05). Tissue damping (G) and tissue elastance (H) were significantly increased in all groups after 30 min of ventilation (P < 0.05). Only the group with a Vt of 10 ml/kg and PEEP did not show a significant increase in H (P > 0.05). Mechanical ventilation significantly increased infiltration of the lungs with PMN (P < 0.05). Expression of MIP-2 was significantly induced by mechanical ventilation in all groups (P < 0.05). MIP-2 mRNA expression was lowest in the group with a Vt of 10 ml/kg + PEEP.</p> <p>Conclusions</p> <p>Our data show that very short term mechanical ventilation with lower tidal volumes than 10 ml/kg did not reduce inflammation additionally. Formation of atelectasis and inadequate oxygenation with very low tidal volumes may be important factors. Application of PEEP attenuated inflammation.</p

Prevalence of facet joint pain in chronic spinal pain of cervical, thoracic, and lumbar regions

BACKGROUND: Facet joints are a clinically important source of chronic cervical, thoracic, and lumbar spine pain. The purpose of this study was to systematically evaluate the prevalence of facet joint pain by spinal region in patients with chronic spine pain referred to an interventional pain management practice. METHODS: Five hundred consecutive patients with chronic, non-specific spine pain were evaluated. The prevalence of facet joint pain was determined using controlled comparative local anesthetic blocks (1% lidocaine or 1% lidocaine followed by 0.25% bupivacaine), in accordance with the criteria established by the International Association for the Study of Pain (IASP). The study was performed in the United States in a non-university based ambulatory interventional pain management setting. RESULTS: The prevalence of facet joint pain in patients with chronic cervical spine pain was 55% 5(95% CI, 49% – 61%), with thoracic spine pain was 42% (95% CI, 30% – 53%), and in with lumbar spine pain was 31% (95% CI, 27% – 36%). The false-positive rate with single blocks with lidocaine was 63% (95% CI, 54% – 72%) in the cervical spine, 55% (95% CI, 39% – 78%) in the thoracic spine, and 27% (95% CI, 22% – 32%) in the lumbar spine. CONCLUSION: This study demonstrated that in an interventional pain management setting, facet joints are clinically important spinal pain generators in a significant proportion of patients with chronic spinal pain. Because these patients typically have failed conservative management, including physical therapy, chiropractic treatment and analgesics, they may benefit from specific interventions designed to manage facet joint pain

Comparison of the effect of lps and pam3 on ventilated lungs

<p>Abstract</p> <p>Background</p> <p>While lipopolysaccharide (LPS) from Gram-negative bacteria has been shown to augment inflammation in ventilated lungs information on the effect of Gram-positive bacteria is lacking. Therefore the effect of LPS and a lipopetide from Gram-positive bacteria, PAM3, on ventilated lungs were investigated.</p> <p>Methods</p> <p>C57/Bl6 mice were mechanically ventilated. Sterile saline (sham) and different concentrations of LPS (1 μg and 5 μg) and PAM3 (50 nM and 200 nM) were applied intratracheally. Lung function parameters and expression of MIP-2 and TNFα as well as influx of neutrophils were measured.</p> <p>Results</p> <p>Mechanical ventilation increased resistance and decreased compliance over time. PAM3 but not LPS significantly increased resistance compared to sham challenge (P < 0.05). Both LPS and PAM3 significantly increased MIP-2 and TNFα mRNA expression compared to sham challenge (P < 0.05). The numbers of neutrophils were significantly increased after LPS at a concentration of 5 μg compared to sham (P < 0.05). PAM3 significantly increased the numbers of neutrophils at both concentrations compared to sham (P < 0.05).</p> <p>Conclusions</p> <p>These data suggest that PAM3 similar to LPS enhances ventilator-induced inflammation. Moreover, PAM3 but not LPS increases pulmonary resistance in ventilated lungs. Further studies are warranted to define the role of lipopetides in ventilator-associated lung injury.</p

Use of tamoxifen and raloxifene for breast cancer chemoprevention in 2010

PURPOSE: Two selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, have been shown in randomized clinical trials to reduce the risk of developing primary invasive breast cancer (IBC) in high-risk women. In 1998, the U.S. Food and Drug Administration (FDA) used these studies as a basis for approving tamoxifen for primary breast chemoprevention in both premenopausal and postmenopausal women at high risk. In 2007, the FDA approved raloxifene for primary breast cancer chemoprevention for postmenopausal women. METHODS: Data from the year 2010 National Health Interview Survey (NHIS) were analyzed to estimate the prevalence of tamoxifen and raloxifene use for chemoprevention of primary breast cancers among U.S. women. RESULTS: Prevalence of use of chemopreventive agents for primary tumors was 20,598 (95% CI, 518–114,864) for U.S. women aged 35 to 79 for tamoxifen. Prevalence was 96,890 (95% CI, 41,277–192,391) for U.S. women aged 50 to79 for raloxifene. CONCLUSION: Use of tamoxifen and raloxifene for prevention of primary breast cancers continues to be low. In 2010, women reporting medication use for breast cancer chemoprevention were primarily using the more recently FDA-approved drug raloxifene. Multiple possible explanations for the low use exist, including lack of awareness and/or concern about side effects among primary care physicians and patients

A phase II study of docetaxel in patients with metastatic squamous cell carcinoma of the head and neck

This study was designed to evaluate the activity, safety and tolerance of docetaxel (D) in a selected population with metastatic squamous cell carcinoma of the head and neck (SCCHN). Twenty-four patients with no prior palliative therapy were enrolled and received D 100 mg m−2 by 1 h of infusion, every 3 weeks. All but two patients had been evaluated for efficacy on lung metastatic sites. No prophylactic administration of anti-emetics or growth factors was given. A pharmacokinetic study was performed in 22 patients. Twenty-one patients were assessable for response and 24 for toxicity. One hundred and four cycles were administered with a median of 4.5 (range 1–9) per patient. The median cumulative dose was 449 mg m−2. Partial responses were achieved in five patients with a median duration of 18.7 weeks (range 13.1–50.3). The overall response rate was 20.8% with a median duration of 11.0 weeks (range 2.4–52.6). The most frequent side-effect was neutropenia (79.2% grade IV) but with a short duration (median 4 days) and no febrile neutropenia. The incidence of moderate/severe fluid retention was 29.2% with one treatment discontinuation. Other toxicities (all grades) were common (skin 75%, asthenia 50%, infection 29.2%, nausea 16.7%, diarrhoea 12.5%, stomatitis 16.7%, vomiting 8.3% and HSR 8.3%). A mean clearance of 19.6 l h−1 m−2 and an area under the curve of 6.00 μg ml−1 h−1 was found in the pharmacokinetic analysis. Docetaxel is active in this selected population with metastatic SCCHN, with a good tolerance. © 1999 Cancer Research Campaig

High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study

<p>Abstract</p> <p>Background</p> <p>To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses.</p> <p>Methods</p> <p>Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H₂O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured.</p> <p>Results</p> <p>Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed.</p> <p>Conclusions</p> <p>During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.</p

Maternal oral health status and preterm low birth weight at Muhimbili National Hospital, Tanzania: a case-control study

The study examined the relationship between oral health status (periodontal disease and carious pulpal exposure (CPE)) and preterm low-birth-weight (PTLBW) infant deliveries among Tanzanian-African mothers at Muhimbili National Hospital (MNH), Tanzania. A retrospective case-control study was conducted, involving 373 postpartum mothers aged 14-44 years (PTLBW--150 cases) and at term normal-birth-weight (TNBW)--223 controls), using structured questionnaire and full-mouth examination for periodontal and dentition status. The mean number of sites with gingival bleeding was higher in PTLBW than in TNBW (P = 0.026). No significant differences were observed for sites with plaque, calculus, teeth with decay, missing, filling (DMFT) between PTLBW and TNBW. Controlling for known risk factors in all post-partum (n = 373), and primiparaous (n = 206) mothers, no significant differences were found regarding periodontal disease diagnosis threshold (PDT) (four sites or more that had probing periodontal pocket depth 4+mm and gingival bleeding > or = 30% sites), and CPE between cases and controls. Significant risk factors for PTLBW among primi- and multiparous mothers together were age < or = 19 years (adjusted Odds Ratio (aOR) = 2.09, 95% Confidence interval (95% CI): 1.18-3.67, P = 0.011), hypertension (aOR = 2.44, (95% CI): 1.20-4.93, P = 0.013) and being un-married (aOR = 1.59, (95% CI): 1.00-2.53, P = 0.049). For primiparous mothers significant risk factors for PTLBW were age < or = 19 years (aOR = 2.07, 95% CI: 1.13 - 3.81, P = 0.019), and being un-married (aOR = 2.58, 95% CI: 1.42-4.67, P = 0.002). These clinical findings show no evidence for periodontal disease or carious pulpal exposure being significant risk factors in PTLBW infant delivery among Tanzanian-Africans mothers at MNH, except for young age, hypertension, and being unmarried. Further research incorporating periodontal pathogens is recommended

A prospective study of shoulder pain in primary care: Prevalence of imaged pathology and response to guided diagnostic blocks

<p>Abstract</p> <p>Background</p> <p>The prevalence of imaged pathology in primary care has received little attention and the relevance of identified pathology to symptoms remains unclear. This paper reports the prevalence of imaged pathology and the association between pathology and response to diagnostic blocks into the subacromial bursa (SAB), acromioclavicular joint (ACJ) and glenohumeral joint (GHJ).</p> <p>Methods</p> <p>Consecutive patients with shoulder pain recruited from primary care underwent standardised x-ray, diagnostic ultrasound scan and diagnostic injections of local anaesthetic into the SAB and ACJ. Subjects who reported less than 80% reduction in pain following either of these injections were referred for a magnetic resonance arthrogram (MRA) and GHJ diagnostic block. Differences in proportions of positive and negative imaging findings in the anaesthetic response groups were assessed using Fishers test and odds ratios were calculated a for positive anaesthetic response (PAR) to diagnostic blocks.</p> <p>Results</p> <p>In the 208 subjects recruited, the rotator cuff and SAB displayed the highest prevalence of pathology on both ultrasound (50% and 31% respectively) and MRA (65% and 76% respectively). The prevalence of PAR following SAB injection was 34% and ACJ injection 14%. Of the 59% reporting a negative anaesthetic response (NAR) for both of these injections, 16% demonstrated a PAR to GHJ injection. A full thickness tear of supraspinatus on ultrasound was associated with PAR to SAB injection (OR 5.02; <it>p </it>< 0.05). Ultrasound evidence of a biceps tendon sheath effusion (OR 8.0; <it>p </it>< 0.01) and an intact rotator cuff (OR 1.3; <it>p </it>< 0.05) were associated with PAR to GHJ injection. No imaging findings were strongly associated with PAR to ACJ injection (<it>p </it>≤ 0.05).</p> <p>Conclusions</p> <p>Rotator cuff and SAB pathology were the most common findings on ultrasound and MRA. Evidence of a full thickness supraspinatus tear was associated with symptoms arising from the subacromial region, and a biceps tendon sheath effusion and an intact rotator cuff were associated with an intra-articular GHJ pain source. When combined with clinical information, these results may help guide diagnostic decision making in primary care.</p

Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

<p>Abstract</p> <p>Background</p> <p>Glioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival.</p> <p>Methods</p> <p>A novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers.</p> <p>Results</p> <p>A total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. <it>Pik3r1</it>, <it>E2f3, Akr1c3</it>, <it>Csf1</it>, <it>Jag2</it>, <it>Plcg1</it>, <it>Rpl37a</it>, <it>Sod2</it>, <it>Topors</it>, <it>Hras</it>, <it>Mdm2, Camk2g</it>, <it>Fstl1</it>, <it>Il13ra1</it>, <it>Mtap </it>and <it>Tp53 </it>were associated with multiple survival events.</p> <p>Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for <it>Syne1</it>, <it>Pdcd4</it>, <it>Ighg1</it>, <it>Tgfa</it>, <it>Pla2g7</it>, and <it>Paics</it>. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. <it>C2</it>, <it>Egfr</it>, <it>Prkcb</it>, <it>Igf2bp3</it>, and <it>Gdf10 </it>had gender-dependent associations; <it>Sox10</it>, <it>Rps20</it>, <it>Rab31</it>, and <it>Vav3 </it>had race-dependent associations; <it>Chi3l1</it>, <it>Prkcb</it>, <it>Polr2d</it>, and <it>Apool </it>had therapy-dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death.</p> <p>Conclusions</p> <p>Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.</p

History of clinical transplantation

The emergence of transplantation has seen the development of increasingly potent immunosuppressive agents, progressively better methods of tissue and organ preservation, refinements in histocompatibility matching, and numerous innovations is surgical techniques. Such efforts in combination ultimately made it possible to successfully engraft all of the organs and bone marrow cells in humans. At a more fundamental level, however, the transplantation enterprise hinged on two seminal turning points. The first was the recognition by Billingham, Brent, and Medawar in 1953 that it was possible to induce chimerism-associated neonatal tolerance deliberately. This discovery escalated over the next 15 years to the first successful bone marrow transplantations in humans in 1968. The second turning point was the demonstration during the early 1960s that canine and human organ allografts could self-induce tolerance with the aid of immunosuppression. By the end of 1962, however, it had been incorrectly concluded that turning points one and two involved different immune mechanisms. The error was not corrected until well into the 1990s. In this historical account, the vast literature that sprang up during the intervening 30 years has been summarized. Although admirably documenting empiric progress in clinical transplantation, its failure to explain organ allograft acceptance predestined organ recipients to lifetime immunosuppression and precluded fundamental changes in the treatment policies. After it was discovered in 1992 that long-surviving organ transplant recipient had persistent microchimerism, it was possible to see the mechanistic commonality of organ and bone marrow transplantation. A clarifying central principle of immunology could then be synthesized with which to guide efforts to induce tolerance systematically to human tissues and perhaps ultimately to xenografts