Portal cytokine response and metabolic markers in the early stages of abdominal sepsis in pigs.

BACKGROUND: The portal vein could play a major role in disseminating the local inflammation of acute bacterial peritonitis since it is responsible for the venous drainage of the gastrointestinal tract. We hypothesized that after peritoneal exposure to Escherichia coli, a gradient between the portal and systemic levels of cytokines would be expected. METHODS: Acute peritonitis was induced by depositing 200 ml of broth with live E. coli in the peritoneal cavity of the animals in the B-group (n = 7). They were then observed for 4 h and compared with a control group (C-group, n = 7). Tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-10 and vascular endothelial growth factor were measured repeatedly in the portal vein and the femoral artery. Portal vein metabolic markers (microdialysis), haemodynamics, biochemistry, plasma volume (PV), fluid shifts and total tissue water content were recorded or calculated. RESULTS: The intervention led to PV contraction, increased fluid extravasation, increased pulmonary vascular resistance and reduced urinary output in the B-group as compared with the C-group. The levels of glucose in the portal vein were reduced in both study groups with no between-group differences. The levels of TNF-α and IL-6 increased markedly in the portal vein as well as in the systemic circulation of the B-group, but no gradient was seen between them. The corresponding levels of TNF-α and IL-6 remained low and stable in the C-group. CONCLUSION: The portal vein appears to play a minor role in supplying TNF-α and IL-6 to the systemic circulation after peritoneal exposure to a substantial dose of E. coli.

Molecular subtypes, histopathological grade and survival in a historic cohort of breast cancer patients.

Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. However, its clinical significance remains to be established. In this study, the main aims were to discover whether reclassification of breast cancer into molecular subtypes provides more precise information regarding outcome compared to conventional histopathological grading and to study breast cancer-specific survival in the different molecular subtypes. Cases of breast cancer occurring in a cohort of women born between 1886 and 1928 with long-term follow-up were included in the study. Tissue microarrays were constructed from archival formalin-fixed, paraffin-embedded tissue from 909 cases. Using immunohistochemistry and in situ hybridisation as surrogates for gene expression analyses, all cases were reclassified into the following molecular subtypes: Luminal A; Luminal B (HER2-); Luminal B (HER2+); HER2 subtype; Basal phenotype; and five negative phenotype. Kaplan-Meier survival curves and Cox proportional hazards models were used in the analyses. During the first 5 years after diagnosis, there were significant differences in prognosis according to molecular subtypes with the best survival for the Luminal A subtype and the worst for HER2 and five negative phenotype. In this historic cohort of women with breast cancer, differences in breast cancer-specific survival according to subtype occur almost exclusively amongst the histopathological grade 2 tumours. From 5 years after time of diagnosis until the end of follow-up, there appears to be no difference in survival according to molecular subtype or histopathological grade.

Does ß2-adrenergic stimulation attenuate fluid extravasation during hypothermic cardiopulmonary bypass? An experimental study in pigs.

OBJECTIVES: Hypothermic cardiopulmonary bypass (CPB) is associated with increased fluid filtration, edema formation and, occasionally, organ dysfunction. Cold-induced reduction in endothelial barrier function may play a role. ß(2)-adrenergic activation elevates cellular cyclic adenosine monophosphate (cAMP) which maintains endothelial barrier properties. In this study, we tested whether ß-adrenergic stimulation could influence the increase in fluid extravasation observed during hypothermic CPB. MATERIALS AND METHODS: Fourteen pigs randomly received terbutaline infusion (T-group) (n=7) or a control infusion (C-group) (n=7). All animals were given 60 min of normothermic CPB, followed by 90 min of hypothermic CPB. Fluid input and losses, plasma volume, colloid osmotic pressures (plasma, interstitial fluid), hematocrit, serum proteins and total tissue water content were measured and the fluid extravasation rates (FER) calculated. STATISTICS: by SPSS. Values presented as mean ± SD. Repeated measure analysis of variance was performed and a t-test used when appropriate. RESULTS: The commencement of normothermic CPB resulted in a 20% hemodilution, with an abrupt increase in fluid requirements during the first 10 min. FER increased from 0.18 (0.06) pre-bypass to 0.78 (0.27) ml/kg/min (T-group) (p=0.002) and from 0.16 (0.05) to 0.93 (0.26) ml/kg/min (C-group) (p<0.001) with no between-group differences. Thereafter, FER stabilized at a level of 0.32 (0.13) and 0.27 (0.14) ml/kg/min in the T-group and C-group, respectively. After the start of cooling, FER increased in the T-group to 0.55 (0.12) ml/kg/min (P=0.046) and in the C-group to 0.54 (0.13) ml/kg/min (P=0.006), with no between-group differences (P=0.738). CONCLUSION: In the present experimental study, we were unable to demonstrate any clinically relevant modulating effect of terbutaline on fluid extravasation during hypothermic cardiopulmonary bypass.

A hyperosmolar-colloidal additive to the CPB-priming solution reduces fluid load and fluid extravasation during tepid CPB.

Cardiopulmonary bypass(CPB) is associated with fluid overload. We hypothesized that fluid gain during CPB could be reduced by substituting parts of a crystalloid prime with 7.2% hypertonic saline and 6% poly (O-2-hydroxyethyl) starch solution (HyperHaes). 14 animals were randomized to a control group (Group C) or to Group H. CPB-prime in Group C was Ringer's solution. In group H, 4 ml/kg of Ringer's solution was replaced by the hypertonic saline/hydroxyethyl starch solution. After 60 min stabilization, CPB was initiated and continued for 120 min. All animals were allowed drifting of normal temperature (39.0 degrees C) to about 35.0 degrees C. Fluid was added to the CPB circuit as needed to maintain a 300-ml level in the venous reservoir. Blood chemistry, hemodynamic parameters, fluid balance, plasma volume, fluid extravasation rate (FER), tissue water content and acid-base parameters were measured/calculated. Total fluid need during 120 min CPB was reduced by 60% when hypertonic saline/hydroxyethyl starch solution was added to the CPB prime (p < 0.01). The reduction was related to a lowered FER. The effect was most pronounced during the first 30 min on CPB, with 0.6 (0.43) (Group H) compared with 1.5 (0.40) ml/kg/min (Group C) (p < 0.01). Hemodynamics and laboratory parameters were similar in both groups. Serum concentrations of sodium and chloride increased to maximum levels of 148 (1.5) and 112 (1.6) mmol/l in Group H. To conclude: addition of 7.2% hypertonic saline and 6% poly (O-2-hydroxyethyl) starch solution to crystalloid CPB prime reduces fluid needs and FER during tepid CPB.

Reduced fluid gain during cardiopulmonary bypass in piglets using a continuous infusion of a hyperosmolar/hyperoncotic solution.

BACKGROUND: The aim of this study was to evaluate how a continuous infusion of a hyperosmolar/hyperoncotic solution influences fluid shifts and intracranial pressure during cardiopulmonary bypass in piglets. METHODS: Fourteen animals, randomized to the control (CT) group or the hypertonic saline/hydroxyethyl starch (HyperHaes) (HSH) group, received acetated Ringer's solution as prime and supplemental fluid. The HSH group received, in addition, HyperHaes 1 ml/kg/h. After 1 h of normothermic cardiopulmonary bypass, hypothermic cardiopulmonary bypass (28 degrees C) was initiated and continued for 90 min. Fluid balance, plasma volume, tissue water content, acid-base parameters and intracranial pressure were recorded, and protein masses and fluid extravasation rates were calculated. RESULTS: At the start of normothermic cardiopulmonary bypass, the fluid extravasation rates (ml/kg/min) increased from 0.19 (0.06) to 1.57 (0.71) and 0.19 (0.09) to 0.82 (0.14) in the CT and HSH groups, respectively, with no between-group differences (P = 0.081) During hypothermic cardiopulmonary bypass, the fluid extravasation rates (ml/kg/min) increased from 0.19 (0.14) to 0.51 (0.10) (P < 0.01) and 0.15 (0.08) to 0.33 (0.08) (P < 0.05), respectively, with significantly lower extravasation rates in the HSH group (P < 0.01). In the HSH group, the total fluid gain during cardiopulmonary bypass decreased by about 50% (P < 0.05) and the tissue water content was significantly lower in the left and right heart as well as in the lungs. The intracranial pressure remained stable in the HSH group, but increased in the CT group. CONCLUSIONS: A continuous infusion of HSH (HyperHaes) during cardiopulmonary bypass reduced the fluid extravasation rate and the total fluid gain during bypass. No electrolyte or acid-base disturbances were present. The intracranial pressure remained stable in the HSH group.

Low arterial pressure during cardiopulmonary bypass in piglets does not decrease fluid leakage.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with increased fluid filtration occasionally leading to post-operative organ dysfunction. One of the factors determining fluid filtration is the capillary hydrostatic pressure which depends on arterial pressure, venous pressure and pre- to post-capillary resistance ratio. The purpose of this study was to assess whether lowering of the mean arterial pressure and/or the central venous pressure could reduce fluid extravasation during normothermic and hypothermic CPB. METHODS: Seven piglets were given nitroprusside to a mean arterial pressure of 35-40 mmHg during 60 min of normothermic and 90 min of hypothermic CPB (LP group). They were compared with a control group (C group, n = 7) without blood pressure interventions. Blood chemistry, net fluid balance, plasma volume, colloid osmotic pressure in plasma and interstitial fluid, intravascular protein masses, fluid extravasation rate and total tissue water content were measured or calculated. RESULTS: Mean arterial pressure was significantly lower in the LP group than in the C group during CPB. Plasma volume tended to increase in the LP group (P > 0.05), but remained essentially unchanged in the C group. Net fluid balance in the LP group was more positive than in the C group 30 min after CPB start [1.02 (0.15) vs. 0.56 (0.13) ml/kg/min (Mean (SEM) P < 0.05)]. Fluid extravasation rate tended to be higher in the LP group and total tissue water content of the gastrointestinal tract, left myocardium and skin was significantly elevated compared with the C group. CONCLUSION: During CPB, lowering of the mean arterial pressure using nitroprusside did not reduce fluid extravasation. On the contrary, the data may implicate an increase in edema formation during low pressure CPB.

Fluid shift is moderate and short-lived during acute crystalloid hemodilution and normothermic cardiopulmonary bypass in piglets.

BACKGROUND: Crystalloids are commonly used as priming solutions during cardiopulmonary bypass (CPB). Consequently, hemodilution is a regular occurrence at the start of a CPB. This study describes the time-course variations of hemodynamic parameters, plasma volume (PV) and fluid exchange following crystalloid hemodilution at start of normothermic CPB. METHODS: Forty-five anesthetized piglets were given 60-min normothermic CPB. Ringer's solution was used as priming solution and maintenance fluid. Fluid input/losses, PV, colloid osmotic pressures (plasma/interstitium), hematocrit, and s-proteins were measured, and fluid extravasation rates (FER) and intravascular protein-masses calculated. RESULTS: Start of CPB resulted in a 25-30% hemodilution. To keep the fluid level of the CPB-reservoir constant after start of bypass, fluid addition [2.08 +/- 0.36 (mean +/- SEM) ml kg(-1) min(-1)] was necessary during the first 5 min. Thereafter the fluid needs to be leveled off [0.17 +/- 0.03 ml kg(-1) min(-1) (10-60 min), P < 0.001]. Fluid extravasation rate increased immediately following hemodilution from a baseline value of 0.08 +/- 0.01 to 1.75 +/- 0.34 ml kg(-1) min(-1) with a delayed decrease compared to fluid additions, to reach a 'steady-state' level of 0.22 +/- 0.03 ml kg(-1) min(-1) after 30 min (P < 0.001). Differences in time-course variations between fluid added and fluid extravasated were accompanied by changes in PV and mean arterial pressure. The colloid osmotic gradient decreased about 50% throughout the study and could partly explain the increased FER. CONCLUSION: Acute crystalloid hemodilution contributes to fluid overload during normothermic CPB. The resulting increase in fluid extravasation is, however, moderate, short-lived and levels off to baseline values within 30 min.

New intravascular contrast agent applied to dynamic contrast enhanced MR imaging of human breast cancer.

PURPOSE: To evaluate the feasibility of using dynamic contrast-enhanced MR imaging with a new intravascular contrast agent in grading human breast cancer. MATERIAL AND METHODS: 23 patients with 27 breast tumors (21 carcinomas and 6 fibroadenomas) were examined with dynamic MR imaging after administration of Clariscan, an iron oxide nanoparticle with large T1 relaxivity and a long plasma half life. A 3D T1-weighted gradient echo sequence with an acquisition time of 60 s was repeated at regular intervals of 3-5 min before and up to 1 h after injection of 2 mg/kg b.w. of Clariscan. The endothelial transfer constant, Kps, which reflects overall vascular permeability, and the fractional plasma volume, fPV, were estimated from time-intensity curves acquired from three separate regions of interest (ROIs): whole tumor, a permeability hot spot, and a blood volume hot spot. Kps and fPV were compared to the results of histologic tumor grading (Scarff-Bloom-Richardson, SBR) and microvascular density, MVD. RESULTS: A statistically significant correlation between the MR-derived Kps parameters and the SBR score was obtained for the whole tumor ROI (R = 0.70), and for the permeability hot spot ROIs (R = 0.67). A correlation between fPV and SBR was detected for the blood volume hot spot ROIs (R = 0.48). There was no statistically significant correlation between Kps or fPV with MVD. CONCLUSION: The results support the hypothesis that dynamic MR with the intravascular contrast agent Clariscan may be used for non-invasive tumor grading.

[Forensic medical aspects of intracranial hemorrhage]. / Rettsmedisinske aspekter ved intrakraniale blødninger.

BACKGROUND: Intracranial haemorrhage may be due to pathological processes or trauma even in the absence of a fracture. Since the circumstances surrounding death in such cases are often obscure, the police are notified and a forensic autopsy is performed. MATERIAL AND METHODS: We have retrospectively analysed 116 cases (66 males and 50 females) of intracranial haemorrhages without a concomitant fracture occurring in a series of 4,040 forensic autopsies. RESULT: Intracerebral haemorrhage was most frequently encountered (46%), while subarachnoidal haemorrhage occurred in 38 cases (32.8%), of which only 27 (71%) had aneurysms. In two cases, traumatic subarachnoidal haemorrhage occurred after a fight. Subdural haematomas were found in 24 cases (21%); they were significantly more frequent among men than among women. Intracerebral haemorrhage was often associated with cardiac hypertrophy, while subdural haematomas were strongly associated with alcohol abuse and falls. Intracerebral bleeding in the younger age group was related to arteriovenous malformations, abuse of heroin or amphetamine. In the majority of cases, the haemorrhage occurred at home. In 21 cases there was information about accidents, mainly falls. Eight cases were later brought to court and the perpetrator charged with manslaughter or murder. Hospital admission occurred in 18% of the cases; only half of the patients underwent surgery and died from cerebral complications. INTERPRETATION: This investigation underlines the importance of performing a forensic autopsy in fatalities with head injury or intracranial haemorrhage in order to specify the type of bleeding and possible aetiological factors involved.

Refractive development in children with Down's syndrome: a population based, longitudinal study.

AIMS: To study the refractive development in children with Down's syndrome longitudinally. METHODS: An unselected population of 60 children with Down's syndrome was followed with repeated retinoscopies in cycloplegia for 2 years or more (follow up 55 (SD 23) months). Accommodation was assessed with dynamic retinoscopy. RESULTS: From longitudinal spherical equivalent values of the right eye, three main categories of refraction were defined: stable hypermetropia (<1.5 D difference between the first and last visit) (n=34), increasing hypermetropia ("hypermetropic shift"; >/=1.5 D difference) (n=11), and decreasing hypermetropia/development of myopia ("myopic shift"; >/=1.5 D difference) (n=9). Patients with anisometropia (n=6) were evaluated separately. In the stable hypermetropia group three sublevels were chosen: low (+4.0 D). An accommodation weakness was found in 55% of the children. Accommodation weakness was significantly less frequent in the stable, low grade hypermetropia group (22%) than in all the other groups (p=0.008). The frequency of astigmatism >/=1.0 D at the last visit was 57%, the direction of axis being predominantly "with the rule." All the eyes with oblique astigmatism had a side specific direction of axis; the right eyes belonging to the 135 degrees axis group and the left eyes to the 45 degrees axis group. CONCLUSION: A stable, low grade hypermetropia was significantly correlated with a normal accommodation. Accommodation weakness may be of aetiological importance to the high frequency of refractive errors encountered in patients with Down's syndrome. A striking right-left specificity in the oblique astigmatic eyes suggests that mechanical factors on the cornea from the upward slanting palpebral fissures may be a major aetiological factor in the astigmatism.

Strabismus and binocular function in children with Down syndrome. A population-based, longitudinal study.

PURPOSE: We have performed a population-based, longitudinal study on strabismus in children with Down syndrome. The aims of the study were to examine the frequency and type of strabismus, the age at onset, and the binocular potential. METHODS: An unselected population of 60 children with Down syndrome born 1988-1999 was followed with repeated examinations. Mean follow-up time was 55+/-23 months (range 24--115). The alignment of the eyes was examined using Hirschberg corneal reflex test and cover test for near fixation. To evaluate binocular function, Titmus House Fly Test and Lang's stereo test were used. RESULTS: Twenty-five patients (42%) had strabismus (21 esotropias, two exodeviations and two vertical deviations). Only one case of infantile esotropia was found, the other esotropias were acquired forms. The mean age at "onset" (e.g. when strabismus was first noticed) was 54+/-35 months. In the acquired esotropia group (n=20), 15 (75%) were associated with hypermetropia (mean spherical equivalent +4.3+/-1.7 D). Seventeen of the strabismic patients had an accommodation weakness. Eleven of the strabismus patients gave a clearly positive response to one or both stereotests. CONCLUSIONS: The majority of the Down syndrome children with strabismus have an acquired esotropia and hence a potential for binocularity. Hypermetropia and accommodation weakness are probably important factors in esotropia in Down syndrome patients.

Corneal grafting for keratoconus in mentally retarded patients.

PURPOSE: To compare the results of penetrating and non-penetrating corneal grafting procedures in mentally retarded keratoconus patients. METHODS: In the years 1974-2000 41 mentally retarded patients with keratoconus (33 with Down syndrome) were operated with corneal grafting. Mean age at operation was 36.7+/-10.8 years. Three different surgical procedures were used (no randomization): penetrating keratoplasty (n=16), lamellar keratoplasty (n=5) and epikeratophakia (n=20). In a retrospective study, the non-penetrating procedures (lamellar keratoplasty and epikeratophakia) were compared to the penetrating keratoplasties with regard to graft survival and frequency of serious complications. Mean follow-up time of all grafting procedures was 80+/-58 months. RESULTS: All cases of serious complications (irreversible rejection, wound leakage or perforation) occurred in the penetrating keratoplasty group (p=0.0005). Older age at operation (p=0.011) adversely influenced the frequency of serious complications. Overall five-year survival was 74.9%. Graft survival was not related to surgical procedure, but rather to age at operation (poorer survival in older age, p=0.012) and degree of retardation (poorer survival in patients with more severe retardation, p=0.051). CONCLUSIONS: Because of the safety and low frequency of complications, epikeratophakia is recommended as the grafting procedure of choice in the majority of mentally retarded with keratoconus. In selected cases (good cooperation, age < or =40 years, and a good peripheral corneal thickness) penetrating keratoplasty may be performed, which, if uncomplicated, often will give better functional/optical results.

Biometric measurements of the eyes in teenagers and young adults with Down syndrome.

PURPOSE: To examine ocular biometric variables in subjects with Down syndrome. METHODS: In a population-based study we have compared ocular biometric variables in a group of 47 individuals with Down syndrome (20.0+/-3.9 years) with 51 control subjects (21.0+/-4.6 years). RESULTS: A thinner cornea (0.48+/-0.04 mm vs. 0.55+/-0.03 mm, p<0.001) and higher keratometry values (46.39+/-1.95 D vs. 43.41+/-1.40 D, p<0.001) were found in the Down syndrome group than in the control group. Oblique astigmatism was commonly found in the Down syndrome individuals, showing a strong right-left specificity (right eyes' axes in the 135 degrees -meridian, left eyes' axes in the 45 degrees -meridian). The lens was thinner (3.27+/-0.29 mm vs. 3.49+/-0.20 mm) and the calculated lens power was weaker (17.70+/-2.36 D vs. 19.48+/-1.24 D) in the Down syndrome group than in the control group (p<0.001 in both cases). CONCLUSIONS: Thinning of the corneal stroma may account for the steeper cornea and the high frequency of astigmatism in Down syndrome due to lower corneal rigidity. It may also be of etiological importance to the increased incidence of keratoconus in Down syndrome.

Human papillomavirus (HPV) in high-grade cervical intraepithelial neoplasia (CIN) detected by morphology and polymerase chain reaction (PCR)-- a cytohistologic correlation of 277 cases treated by laser conization.

The aims of this study were to evaluate the cytohistologic correlation in women treated for high-grade lesions of the cervix uteri (HG CIN), to assess the distribution of HPV features and finally to test the validity of the morphological criteria of HPV infection. The smears and biopsy specimens from 277 women treated for HG CIN by laser conization were re-evaluated blindly. Tissue blocks (n = 188) and 52 archival smears were examined for HPV DNA using PCR. HPV changes were detected with equal frequency in the smears and biopsy specimens by light microscopy; 63% and 65%, respectively. The prevalence of HPV DNA in biopsies was 88% and in archival smears 85%; agreement was found in 89% of the cases. Using PCR as the gold standard, we found a sensitivity of 63% for cytology and 70% for histology; the specificity was 41% and 37%, respectively. The positive predictive value was > 80%, but the negative predictive value was < 20%. Our study confirms that HPV features are frequently associated with HG CIN and that morphology is a non-specific method of identifying HPV infection and should be followed by PCR, also allowing detection of oncogenic HPV types and latent infections.

[Death behind the wheel]. / Dødsfall bak rattet.

In Norway traffic accidents are increasing with 12,000 casualties and more than 300 deaths every year. This retrospective study is based on 230 forensic reports of drivers involved in fatal car accidents. There was a male preponderance (85%) and the average age was 42.5 years. In 78% of the cases the cause of death was a direct consequence of the accident, multitraumas and head injuries representing the majority, while drowning occurred in 11% of the cases. Death from natural causes was established in 27 cases; the main cause was acute cardiovascular disease. These accidents occurred at low speed. In 17 cases (7%) serious cardiac disease, CNS pathology or diabetic complications contributed significantly to the accidents that inflicted greater injuries on the vehicles and occupants. Raised blood alcohol levels were found in 21% of the drivers. Hepatic steatosis was observed in 16% of all drivers, most of whom were not under the influence of alcohol. Suicide was recorded in six cases (2.5%). This study shows that in addition to drunkenness, organic disease, especially cardiovascular disease and alcoholic liver disease represent risk factors of major importance in fatal road accidents.