Ventilator-Induced Inflammatory Response in Lipopolysaccharide-Exposed Rat Lung Is Mediated by Angiotensin-Converting Enzyme

Angiotensin-converting enzyme (ACE) mediates the ventilator-induced inflammatory response in healthy lungs via angiotensin II (Ang II). A rat model was used to examine the role of ACE and Ang II in the inflammatory response during mechanical ventilation of preinjured (ie, lipopolysaccharide [LPS]-exposed) lungs. When indicated, rats were pretreated with the ACE inhibitor captopril and/or intratracheal administration of LPS. The animals were ventilated for 4 hours with moderate pressure amplitudes. Nonventilated animals served as controls. ACE activity and levels of Ang II and inflammatory mediators (interleukin-6, Cytokine-induced Neutrophil Chemoattractant (CINC)-3, interleukin-1β, and interleukin-10) were determined in bronchoalveolar lavage fluid (BALF). The localization of ACE and Ang II type 1 receptor in lung tissue was determined by immunohistochemistry. The role of the Ang II pathway was assessed by using its receptor antagonist Losartan. Mechanical ventilation of LPS-exposed animals increased ACE activity and levels of inflammatory mediators in BALF compared with ventilated nonexposed and LPS-exposed nonventilated animals. Blocking ACE by captopril attenuated the lung inflammatory response. Furthermore, increased ACE activity in BALF was accompanied by increased levels of Ang II and enhanced expression of its receptor on alveolar cells. Blocking the Ang II receptor attenuated the inflammatory mediator response to a larger extent than by blocking ACE. In conclusion, during mechanical ventilation ACE, via Ang II, mediates the inflammatory response of both healthy and preinjured lungs.Acute respiratory distress syndrome (ARDS) is the most severe form of acute lung injury (ALI) and is characterized by severe hypoxemia, diffuse alveolar injury, pulmonary edema, and an excessive inflammatory response.¹ Although mechanical ventilation (MV) can be life-saving for patients with ALI/ARDS, it may induce lung injury, known as ventilator-induced lung injury (VILI), with characteristics similar to that caused by ARDS.^2,3,4 Mechanical ventilation of animals with lungs preinjured by intratracheal instillation of bacterial components such as lipopolysaccharide (LPS) resulted in markedly higher inflammatory responses compared with ventilated animals without preinjured lungs.^5,6,7,8Clinical and experimental studies found an association between the renin-angiotensin system (RAS) and ALI/ARDS.^9,10 RAS also plays a key role in the injurious effects of mechanical ventilation.^11,12 In healthy rats, inhibition of the RAS component angiotensin-converting enzyme (ACE) attenuated inflammation and lung injury during mechanical ventilation with high tidal volumes.¹¹ The effect of ACE on the inflammatory response may be explained by the fact that ACE generates the key factor of the RAS, angiotensin II (Ang II). Ang II stimulates expression of proinflammatory mediators such as interleukin-8/Cytokine-induced Neutrophil Chemoattractant (CINC)-3 and interleukin-6 via the type 1 and type 2 Ang II receptors.^13,14,15 Indeed, a similar attenuation of the inflammatory response was obtained during injurious mechanical ventilation by blocking the Ang II receptor or by treating with an ACE inhibitor.^11,12The present study investigates whether ACE mediates the exaggerated inflammatory response to mechanical ventilation of LPS-exposed lungs as reflected by inflammatory mediator levels in bronchoalveolar lavage fluid (BALF), and whether ACE inhibition dampens this response. The role of Ang II in this process was also assessed by using its specific receptor antagonist.     

Critical flicker-fusion frequency in age-related macular degeneration

Purpose  

To assess the influence of age-related macular degeneration (AMD) on critical flicker-fusion frequency (CFF).     

Expression of HAb18G is associated with tumor progression and prognosis of breast carcinoma

HAb18G is a recently identified hepatoma-associated antigen and its association with tumor growth, invasion, and angiogenesis has been studied in a variety of tumors. However, its role in the tumor progression of breast cancer has not been explored. HAb18G expression was examined by immunohistochemistry in pathological sections of 1,637 breast tissue samples and by in situ hybridization in 41 cases of invasive breast carcinomas (BC). While not detected in any cases of tumor-like conditions or benign tumors of breast, and only rarely in normal tissue (4.4%), HAb18G expression was gradually up-regulated from atypical ductal hyperplasia (27.3%), to ductal carcinoma-in situ (59.8%), and to BC (61.4%) (P < 0.01). Its expression in BC was correlated positively with C-erbB-2 expression and histologic grade (P < 0.001), and negatively with the expression of estrogen and progesterone receptors (P < 0.001). Significant differences of expression were also identified among the subgroups of BC examined: in decreasing order from invasive micropapillary carcinoma, ductal carcinoma, lobular carcinoma, papillary carcinoma, medullary carcinoma, to mucinous adenocarcinoma (P = 0.001), corresponding to their known clinical aggressiveness. In an expanded group of 186 BC patients with proper follow up, our previous findings were confirmed: HAb18G expression was significantly associated with local recurrence, distant metastasis and tumor mortality (P < 0.01). We also demonstrated that up-regulated tumor expression of HAb18G was a significant predictor of reduced disease progression-free survival rate and a shorter overall survival, independent of systemic therapies. In conclusion, this study suggests that HAb18G expression is associated with BC progression and prognosis. Further evaluation of this new marker in breast cancer is indicated.     

Effects of methylphenidate on working memory functioning in children with attention deficit/hyperactivity disorder

Background and aimsChildren with attention deficit/hyperactivity disorder (ADHD) often show deficits in working memory performance. Methylphenidate (MPH) is an effective medication to improve these cognitive difficulties. This study aimed to clarify which effect MPH induces on the underlying functional networks of working memory.MethodsFourteen boys diagnosed with ADHD and 12 healthy controls were investigated using functional magnetic resonance imaging (fMRI). Each patient was tested twice, once with medication and once without. The fMRI experiments consisted of three verbal N-back tasks with increasing difficulty. Functional images were acquired on a 3 Tesla head scanner.ResultsOn the behavioral level, medicated patients performed similar to healthy controls and significantly better than without medication. On the functional level, patients showed the expected frontal and parietal activations, which were more pronounced in the 2- and 3-back tasks. Healthy controls showed significantly more activation in these regions and additional activation in the cerebellum. Interestingly, patients showed an additional effect of laterality. Left-sided frontal and parietal activation in patients was significantly less pronounced than in controls.ConclusionFunctional data indicate different activation patterns in verbal working memory tasks between healthy controls and patients with ADHD irrespective of medication condition. Intake of MPH led to a clear improvement on a behavioral level. However, this effect was not reflected by changes in functional brain organization. MPH-induced changes leading to better performance in verbal working memory tasks might be very subtle and therefore not detectable by fMRI.     

Histopathological observations of a polylactic acid-based device intended for guided bone/tissue regeneration

Background: Barrier devices have been shown to support alveolar bone and periodontal regeneration, a procedure also known as guided bone/tissue regeneration (GBR/GTR). Popular demand and clinical convenience have raised an interest in bioresorbable barrier devices. Tissue reactions to such bioresorbable devices are, however, generally not well explored. Purpose: The objective of this study was to evaluate short‐ and long‐term tissue reactions following implantation of a bioresorbable polylactic acid (PLA)‐based barrier device using a rat model. Materials and Methods: Twenty‐one young adult male Sprague‐Dawley rats were used. The animals were divided into three groups including 15 animals receiving the PLA device and animals serving as sham surgery (five) or nonoperated (one) controls. Using aseptic techniques, the PLA device was surgically implanted in direct contact with the calvarial bone. Animals receiving the PLA device were sacrificed at 3, 5, 7, and 12 months postsurgery to provide longitudinal histopathological observations of tissue and biomaterials reactions. Control animals were sacrificed at 3 months. Results: Animals were maintained without adverse events. Sham surgery and nonoperated control animals showed no signs of new bone formation or resorption, or signs of inflammatory reactions in adjoining soft tissues. In contrast, extensive amounts of residual biomaterial with evidence of foreign body reactions and bone resorption were observed in animals receiving the PLA device over 12 months. Conclusions: The results suggest that the PLA device may induce bone resorbing foreign body reactions. Importantly, the PLA device does not resorb within a 12‐month healing interval. These biomaterials properties may influence new bone formation and maintenance when applying the device for GBR/GTR.     

Uptake of pneumococcal polysaccharide vaccine in at-risk populations in England and Wales 1999-2005

The UK has had a pneumococcal polysaccharide vaccination (PPV) programme for groups at higher risk of invasive disease since 1992. This paper presents data from a sample of primary-care practices (Q-RESEARCH) of PPV uptake in patients according to their risk status. Of 2.9 million registered patients in 2005, 2.1% were vaccinated with PPV in the preceding 12 months and 6.5% in the preceding 5 years. Twenty-nine per cent of the registered population fell into one or more risk groups. The proportion of each risk group vaccinated in the previous 5 years ranged from 69% (cochlear implants), 53.4% (splenic dysfunction), 36.5% (chronic heart disease), 34.7% (diabetes), 22.9% (immunosuppressed), 28.7% (chronic renal disease), 15.9% (sickle cell disease) to 12.6% (chronic respiratory disease). Uptake was lower in areas where the non-white proportion of population was >10%. In conclusion, there remain large gaps in the uptake of PPV in several high-risk populations in the United Kingdom. Effective strategies need to be developed to address these deficiencies.     

Sex-differences in grey-white matter structure in normal-reading and dyslexic adolescents

MR images were used to look for brain structure irregularities in adolescent children with dyslexia by use of combined grey and white matter volume measurements and fractal dimension (FD) of the grey-white matter border. The data were collected from 13 dyslexic adolescent (8 boys and 5 girls) that were compared with 18 control subjects (8 boys and 10 girls). The MR images were first segmented, and the volume as well as the FD of the grey/white matter border for the whole brain and for each hemisphere was computed. Changes were found in the measured volumes of both grey and white matter and were best reflected in the ratio of grey/white matter and in FD values, especially in the left hemisphere. The results showed that, although dyslexia is less frequent in women, the structural differences in the brain are more pronounced in their case, pointing to an increased vulnerability of the female brain to morphological changes associated with dyslexia.     

Efficacy of 2- and 4-week rifampicin treatment on the <Emphasis Type="Italic">Wolbachia</Emphasis> of <Emphasis Type="Italic">Onchocerca volvulus</Emphasis>

The microfilaricidal and temporarily sterilizing drug ivermectin is used for mass treatment of filarial infections. Filariae containing Wolbachia endobacteria can also be treated by the antibiotic doxycycline. The loss of Wolbachia results in sterilization of Onchocerca volvulus and macrofilaricidal effects. Besides doxycycline, other antibiotics may be effective in depleting Wolbachia. A preliminary study on the effects of rifampicin on the endobacteria, embryogenesis and microfilariae production of O. volvulus was carried out in the year 2000 in Ghana. Twenty-six onchocerciasis patients were treated for 2 or 4 weeks with 10 mg/kg/day rifampicin. From 17 treated and nine untreated patients, all palpable nodules were extirpated 1 or 18 months after the start of the study and examined for Wolbachia and embryogenesis using immunohistology. One and 18 months after rifampicin treatment, the proportion of Wolbachia-positive worms was significantly reduced compared to the untreated group. In patients treated 4 weeks with rifampicin, only 21% and 18% of living female filariae contained Wolbachia after 1 and 18 months, respectively, compared to 92% in the untreated patients. The reduction of Wolbachia after 2 weeks rifampicin was less but also significant. Embryogenesis and microfilariae production were reduced after 4 weeks rifampicin treatment, rendering rifampicin an antibiotic with anti-wolbachial efficacy in human onchocerciasis. This treatment is less efficient than treatment with 6 weeks doxycycline, but might be an alternative for cases that cannot be treated with doxycycline, e.g. children, or might be further developed for combination therapy.