Hydroxyurea therapy of a murine model of sickle cell anemia inhibits the progression of pneumococcal disease by down-modulating E-selectin

Sickle cell anemia is characterized by chronic hemolysis coupled with extensive vascular inflammation. This inflammatory state also mechanistically promotes a high risk of lethal, invasive pneumococcal infection. Current treatments to reduce vaso-occlusive complications include chronic hydroxyurea therapy to induce fetal hemoglobin. Because hydroxyurea also reduces leukocytosis, an understanding of the impact of this treatment on pneumococcal pathogenesis is needed. Using a sickle cell mouse model of pneumococcal pneumonia and sepsis, administration of hydroxyurea was found to significantly improve survival. Hydroxyurea treatment decreased neutrophil extravasation into the infected lung coincident with significantly reduced levels of E-selectin in serum and on pulmonary epithelia. The protective effect of hydroxyurea was abrogated in mice deficient in E-selectin. The decrease in E-selectin levels was also evident in human sickle cell patients receiving hydroxyurea therapy. These data indicate that in addition to induction of fetal hemoglobin, hydroxyurea attenuates leukocyte-endothelial interactions in sickle cell anemia, resulting in protection against lethal pneumococcal sepsis.     

The role of visual attention in dyslexia: Behavioral and neurobiological evidence

Poor phonological processing has typically been considered the main cause of dyslexia. However, visuo‐attentional processing abnormalities have been described as well. The goal of the present study was to determine the involvement of visual attention during fluent reading in children with dyslexia and typical readers. Here, 75 children (8–12 years old; 36 typical readers, 39 children with dyslexia) completed cognitive and reading assessments. Neuroimaging data were acquired while children performed a fluent reading task with (a) a condition where the text remained on the screen (Still) versus (b) a condition in which the letters were being deleted (Deleted). Cognitive assessment data analysis revealed that visual attention, executive functions, and phonological awareness significantly contributed to reading comprehension in both groups. A seed‐to‐voxel functional connectivity analysis was performed on the fluency functional magnetic resonance imaging task. Typical readers showed greater functional connectivity between the dorsal attention network and the left angular gyrus while performing the Still and Deleted reading tasks versus children with dyslexia. Higher connectivity values were associated with higher reading comprehension. The control group showed increased functional connectivity between the ventral attention network and the fronto‐parietal network during the Deleted text condition (compared with the Still condition). Children with dyslexia did not display this pattern. The results suggest that the synchronized activity of executive, visual attention, and reading‐related networks is a pattern of functional integration which children with dyslexia fail to achieve. The present evidence points toward a critical role of visual attention in dyslexia.     

Insight into illness and attitudes toward medications among inpatients with schizophrenia

This study assessed symptoms, severity of illness functional level, insight into illness, and attitudes toward medication in a sample of psychiatric patients who were newly admitted to a state hospital. The patients were evaluated before and after treatment with atypical, conventional, or mixed (atypical plus conventional) antipsychotic medication regimens with the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression, the Global Assessment of Functioning, the Scale to Assess Unawareness of Mental Disorder, and the Drug Attitude Inventory. Overall, the patients showed significant improvement in symptoms, severity of illness, functional level, and insight into their illness during the course of hospitalization. Their attitudes toward medications changed minimally during treatment. Only the patients who were treated with conventional antipsychotics showed significant improvement in their attitudes toward medication. However, the change was not large enough to differentiate the conventional antipsychotic treatment group from the other treatment groups.     

Effect of pressure and gas type on intraabdominal, subcutaneous, and blood pH in laparoscopy

Background: According to the literature, the number of port-site metastases in laparoscopic surgery varies considerably depending on the type of gas used for the pneumoperitoneum. In order to investigate this observation we studied the changes in blood, subcutaneous, and intra-abdominal pH during laparoscopy with helium, CO₂ and room air in a rat model. In addition, we looked at the influence of intra-abdominal pressure and duration of pneumoperitoneum on the pH during the laparoscopy. Methods: pH was measured by tonometry, intra-abdominally and subcutaneously. A pH electrode was additionally placed into the subcutaneous tissue and the results compared to those measured by tonometry. Blood samples were taken from a catheter in the carotid artery. The intra-abdominal pressure was 0, 3, 6, 9 mmHg for 30 min in each case. We investigated the effect of pneumoperitoneum with CO₂, helium and air in randomized groups of 5 rats. In an additional series the pressure was held constant at 3 mmHg and the pH was measured every 30 min. Results: Due to the different absorption capacity of the peritoneum, laparoscopy with CO₂ decreases the subcutaneous pH from 7.35 to 6.81. Blood pH is reduced from 7.37 to 7.17 and the intra-abdominal pH from 7.35 to 6.24. Other, less absorbable gases induce smaller changes of blood and subcutaneous pH (only 10% of CO₂). In a variance analysis the p value is less than 0.001. The influence of duration of laparoscopy (30 min vs 90 min) on the subcutaneous pH is less compared to the influence of intra-abdominal pressure (0, 3, 6, 9 mmHg). Conclusions: Depending on the type of gas (CO₂, air, helium) used for laparoscopy blood, subcutaneous and intra-abdominal pH are influenced differently. Because lower pH is known to impair local defense mechanisms, these results may be one explanation for the higher incidence of port-site metastasis in laparoscopy with CO₂ than with other gases, as reported in the literature. Received: 11 June 1998/Accepted: 12 February 1999     

Short- and long-term results after laparoscopic vs conventional colon resection in a tumor-bearing small animal model

BACKGROUND: We designed a study to evaluate the short- and long-term outcome of laparoscopic vs conventional colonic resection in a tumor-bearing small animal model. METHODS: We operated on male BD X rats (260-300 g), performing either laparoscopic (n = 9) or open colon resection (n = 9) in order to evaluate stress and immunological response to laparoscopic vs conventional colon resection. A third group (n = 9) underwent anesthesia only. Immediately before and after surgery, as well as at 1, 7, and 21 days postoperatively, a sample of 1 ml blood was taken from the retrobulbar venous plexus. Stress (corticosterone) and immune parameters (neopterine and IL-1 beta, IL-6) and body weight as a parameter of postoperative recovery were measured to identify short-term alterations. Long-term changes were evaluated in terms of survival time and at autopsy by measuring the tumor weight and the number of tumor infiltrated nodules (histology). RESULTS: The analysis of variance (ANOVA) showed significant differences between the three groups over a period of 1 week (p < 0.001 for corticosterone, p = 0.009 for neopterine, p = 0.04 for IL-1 beta, p = 0.024 for IL-6). Additionally, significant differences by t-test were found between the laparoscopic (minor alteration) and conventional (major alteration) group regarding corticosterone (p = 0.0015), neopterine (p = 0.0024), IL 1-beta (p = 0.033), and IL-6 (p = 0.015) at the end of the operation. One week after the operation, the body weight was different depending on the type of operative procedure: 7 days postoperatively the rats lost 8% of their body weight after open surgery but only 4.3% after laparoscopic surgery. After anesthesia only, body weight increased by approximately 4.8%. The medium survival time for the lap group was 44 days, whereas it was 44.1 days for the conventional group and 46 days for the anesthesia group (ANOVA p = 0.625). The number of nodules was 13.5 in the laparoscopic group 10.5 in the open group, and 7.4 in the anesthesia group, (ANOVA p = 0.119). The tumor weight was 6.8 g in the laparoscopic group, 6.4 g in the open group, and 5.04 g in the anesthesia group (ANOVA p = 0.874). CONCLUSION: In a tumor-bearing small animal model, laparoscopic colon resection alters the stress and immune system less than open colon resection. This observation has no implications for the long-term results as measured by survival time and at autopsy. Therefore, laparoscopic colon resection has a short-term benefit and has no negative effect on long-term results compared to conventional operative procedures.     

Changes of the extracellular matrix as a risk factor for anastomotic leakage after large bowel surgery

BACKGROUND: Despite improved surgical techniques, anastomotic leakage remains as a serious complication in colorectal surgery, producing increased morbidity and mortality. This prospective study was initiated to test the hypothesis that preexisting disorders in the extracellular matrix (ECM) may be a factor influencing the onset of anastomotic wound healing complications. METHODS: In this prospective study of 119 patients with colorectal anastomoses, 30 clinical parameters with possible influence on anastomotic complications were evaluated. From all patients, samples of macroscopically intact colonic tissue were obtained at the index operation. Crosspolarization microscopy was performed to analyze the collagen type I/III ratio, and immunohistochemical studies were done to determine the expression of matrix metalloproteinase (MMP) 1, 2, 9, and 13. The patients with uncomplicated postoperative healing were compared with those developing anastomotic leakage. RESULTS: Patients with impaired anastomotic healing exhibited a significantly lower collagen type I/III ratio compared with the controls. Significantly higher expression of MMP-1 and MMP-2 in the mucosal layers and of MMP-2 and MMP-9 in the submucosal layers was found in the normal bowel wall of the leakage group. These findings were statistically independent from the clinical parameters. CONCLUSION: The present study confirms the hypothesis that disturbances of the ECM play a role in the pathogenesis of anastomotic leakage after large bowel surgery.