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Resuscitation regimens for hemorrhagic shock must contain blood.

Endothelial cell dysfunction occurs during hemorrhagic shock (HS) and persists despite adequate resuscitation (RES) that restores and maintains hemodynamics. We hypothesize that RES from HS with crystalloid solutions alone aggravate the endothelial cell dysfunction. To test this hypothesis, anesthetized nonheparinized rats were monitored for hemodynamics, and the terminal ileum was studied with intravital video microscopy. HS was 50% of mean arterial pressure (MAP) for 60 min. Four hemorrhaged groups (10 animals in each group) were randomized for RES: group I with shed blood returned + equal volume of normal saline (NS); group II with shed blood returned + 2x NS; group III with 2x NS only; and group IV with 4x NS only. Two hours post-RES, endothelial cell function was assessed with the endothelial-dependent agonist acetylcholine (ACh, 10(-9)-10(-4) M). Maximum arteriolar diameter was elicited by the endothelial-independent agonist sodium nitroprusside (NTP, 10(-4) M). HS caused a selective vasoconstriction associated with low blood flow in inflow A1 arterioles in all hemorrhaged groups. Post-RES vasoconstriction developed in A1 and premucosal arterioles (pA3 and dA3) In all hemorrhaged groups regardless of the RES regimen. However, A1 vasoconstriction and flow were significantly worst in the animals RES with NS alone (-43% and -75%, respectively) compared with those resuscitated with blood and NS (-27% and -57%). Impaired dilation response to ACh was noted in all hemorrhaged animals. However, a significant shift to the right of the dose-response curve (decreased sensitivity) was observed in the animals resuscitated with NS alone irrespective of the RES volume. These animals required at least two orders of magnitude greater ACh concentration to produce a 20% dilation response. For all vessel types, Group II had the best preservation of endothelial cell function. In conclusion, HS causes a selective vasoconstriction of A1 arterioles, which was not observed in A3 vessels. RES from HS results in progressive vasoconstriction in all intestinal arterioles irrespective of the RES regimen. Crystalloid RES after HS does not restore hemodynamics to baseline and is associated with a marked endothelial cell dysfunction. Blood-containing RES regimens preserve and maintain hemodynamics and are associated with the least microvascular dysfunction. Therefore, regimens for RES from HS must contain blood. Endothelial cell dysfunction is not the sole etiologic factor of post-RES microvascular impairment.

Animals↗

After spontaneous hypothermia during hemorrhagic shock, continuing mild hypothermia (34 degrees C) improves early but not late survival in rats.

BACKGROUND: Spontaneous hypothermia is common in victims of severe trauma. Laboratory studies have shown benefit of induced (therapeutic) mild hypothermia (34 degrees C) during hemorrhagic shock (HS). Clinical data, however, suggest that hypothermia, which often occurs spontaneously in trauma patients, is detrimental. Because critically ill trauma patients are usually cool, the clinical question, which has not been explored in the laboratory with long-term outcome, is whether maintaining hypothermia or actively rewarming the patient improves outcome. We hypothesized that after spontaneous cooling during HS, continuing mild therapeutic hypothermia during resuscitation is beneficial compared with active rewarming. METHODS: In study A, under light isoflurane anesthesia, 24 Sprague-Dawley rats were bled over 10 minutes to, and maintained at, mean arterial pressure (MAP) of 40 mm Hg until reuptake of 30% of maximal shed blood volume was needed. Rectal temperature (Tr) decreased spontaneously to, and was then maintained at, 35 degrees C during HS. Fluid resuscitation included the remaining shed blood and up to 400 mL/kg of lactated Ringer's solution with 5% dextrose over 4 hours. During resuscitation, three groups (n = 8 each) were studied: normothermia (rapid rewarming to Tr 37.5 degrees C at the beginning of resuscitation); hypothermia-2 h (cooling to Tr 34 degrees C to resuscitation time 2 hours); and hypothermia-12 h (cooling to Tr 34 degrees C to 12 hours). Rats were observed to 72 hours. In study B, more severe HS than in study A was studied. HS was induced with 3 mL/100 g blood withdrawal over 15 minutes followed by maintenance of MAP of 40 mm Hg until 50% of maximal shed blood volume was needed. Two groups (n = 8 each) were studied: normothermia and hypothermia-12 h. Data are presented as mean +/- SD or median (range). RESULTS: In study A, both hypothermia groups had higher MAP and lower heart rates during resuscitation than the normothermia group (p < 0.01). Survival to 72 hours was achieved in three of eight rats in the normothermia group and two of eight in each hypothermia group. Thirteen of 17 deaths occurred after 24 hours. In study B, for resuscitation, the hypothermia group needed less fluid (53 +/- 6 mL vs. 79 +/- 32 mL, p < 0.05), but had higher MAP (p < 0.01), lower heart rate (p < 0.01), and lower lactate level (p = 0.06). All rats died before 72 hours. The hypothermia group had longer survival time (24.5 [13-48.5] hours) than the normothermia group (7.5 [1.5-19] hours) (p = 0.003 by life table analysis). CONCLUSION: After spontaneous cooling during moderately severe HS, mild, controlled hypothermia during resuscitation does not seem to affect long-term survival. After more severe HS, hypothermia increases survival time. Hypothermia supports arterial pressure during resuscitation from severe HS.

Animals↗

Ribulose 1,5-Bisphosphate Carboxylase Synthesis during Heat Shock.

Ribulose 1,5-bisphosphate carboxylase (RuBPCase) was chosen as a model protein to study how heat shock (HS) affects both chloroplast protein synthesis and the nuclear-chloroplast interaction in production of chloroplast proteins. Experiments were performed using highly chlorophyllous, soybean (Glycine max L. Merr. var Corsoy) cell suspension cultures active in chloroplast protein synthesis. Synthesis of RuBPCase large (L) and small (S) subunits was followed by in vivo labeling, and corresponding mRNA levels were examined by Northern and dot hybridization analyses. Results demonstrate that L and S synthesis declines with increasing HS temperatures (33-40 degrees C) and reaches minimum levels (20-30% of control) at temperatures of maximum HS protein synthesis (39-40 degrees C). Recovery of L and S synthesis following a 2-hour HS at 38 or 40 degrees C was also studied. The changes in S synthesis during HS and recovery correlate with the steady state levels of S mRNA. In contrast, changes in L synthesis show little relationship to the corresponding mRNA levels; levels of L mRNA remain relatively unchanged by HS. We conclude that chloroplast protein synthesis shows no greater sensitivity to HS than is observed for cytoplasmic protein synthesis and that transport of proteins into the chloroplast (e.g.S subunit) continues during HS. Furthermore, there is no apparent coordination of L and S subunit mRNA levels under the conditions examined.

Journal Article↗

Regulation of the heat shock response in soybean seedlings.

The transcriptional response of soybean (Glycine max) seedlings during heat shock (HS) was investigated under two different treatment regimes. During prolonged heat treatment at 40 degrees C, active transcription of the HS genes (as measured by "runoff" transcription assays) occurs only during the first few hours. Nonetheless, mRNAs for these genes are present at relatively high abundance even after 9 hours of exposure to 40 degrees C. Because HS mRNAs have a fairly short half-life (less than 3 hours) at 28 degrees C, these results indicate that HS mRNAs are inherently more stable at 40 degrees C. During a second type of heat treatment regime-short pulses of high (45 degrees C) heat followed by 1 to 2 hours at 28 degrees C-transcription of HS genes is comparable to that achieved at 40 degrees C for the first few hours, even though the tissue is maintained at non-HS temperatures. The transcriptional responses to these two different heat treatments indicate that regulatory controls for the transcription of the HS genes must involve more than a simple sensing of ambient temperature, since transcription of these genes can be turned off at 40 degrees C (in the case of prolonged exposure) and can continue at 28 degrees C (following a short, severe heat treatment). Additional results demonstrate that the response of soybean seedlings to a particular HS depends on their prior exposure to heat; seedlings given a preheat treatment (that is known to induce thermotolerance) respond more moderately to a short heat pulse at 45 degrees C. Overall, this research indicates that plants have mechanisms for both monitoring the severity of changes in temperature and for measuring the magnitude and duration of the stress. Such information is then used to regulate the plant's response to heat both transcriptionally and posttranscriptionally.

Journal Article↗

Studies on herediatary spherocytosis in Iceland.

Thirty members with typical hereditary spherocytosis (HS) and over 90 apparently unaffected members belonging to 12 families have been studied. Splenectomy has been performed on 22 HS patients. Of nine HS individuals, who had not undergone surgical treatment in 1957, four suffered from temporary severe anaemia, presumably due to aplastic crisis associated with influenza. One of them died, a male 18 years of age. Pedigree studies on one of the families indicate that the HS gene or genes have been transmitted through six generations over the past 200 years. Marked deficiency in the number of affected compared with the apparently unaffected members in the HS families is present. The most striking example of uneven genetic ratio is a sibship of 15 members investigated haematologically, with one suffering from typical HS. Much reduced penetration of the HS gene or the presence of the socalled "mild form" is upheld as the main explanation for the unevenness in the genetic ratio. However, families are also present in which abortions and death at an early age indicated that selection against the affected could also disturb the genetic ratio in HS families.

Adolescent↗

Role of cell surface glycosaminoglycans of human T cells in human immunodeficiency virus type-1 (HIV-1) infection.

To investigate the role of cell surface glycosaminoglycans (GAGs), including heparan sulfate (HS), on HIV-1 infection in human T cells, HIV-1 binding and infection were determined after treatment of T-cell lines and CD4+ T cells from normal peripheral blood mononuclear cells (PBMC) with GAG-degrading enzyme or a GAG metabolic sulfation inhibitor. Heparitinase I (hep I) and sodium chlorate prevented binding of HIV-1/IIIB to MT-4 cells as revealed by indirect immunofluorescence procedures, thereby inhibiting infection. Hep I was less effective in the binding inhibition of the macrophage-tropic strain HIV-1/SF162 than that of the T-cell line-tropic strain HIV-1/IIIB. The binding of HIV-1/SF162 was about 100-fold less dependent on cell surface HS than HIV-1/IIIB. Human HTLV-I positive T-cell lines expressed more HS than HTLV-I negative T-cell lines or normal CD4+ T cells when stained with anti-HS mAbs against either native or heparitinase-treated HS. With the exception of endo-beta-galactosidase (endo-beta-gal), GAG-degrading enzymes, including hep I, chondroitinase ABC (chon ABC), chondroitinase AC II (chon AC II) and keratanase, did not prevent the binding of HIV-1/IIIB to CD4+ T cells from normal PBMC. These results indicate that the cell surface HS of human T cells participates in HIV-1 infection by facilitating HIV-1/IIIB binding to MT-4 cells. In particular, the sulfation of HS chains is critical. Since the expression of cell surface HS varies among T cells, which are not consistently sensitive to hep I treatment in HIV-1 binding inhibition, other GAG-like molecules may also be involved.

CD4-Positive T-Lymphocytes↗

Morphologic and morphometric light and electron microscopic studies of the spleen in patients with hereditary spherocytosis and autoimmune haemolytic anaemia.

With the aim of contributing to a better understanding of the haemolytic function of the spleen, a morphologic and morphometric study of this organ fixed by arterial perfusion was performed in nine patients with hereditary spherocytosis (HS), three with autoimmune haemolytic anaemia (AHA) and six with Hodgkin's disease without splenic involvement (controls). The spleen weight in HS and AHA (621 +/- 429 g, mean +/- SD) was significantly increased with respect to controls (168 +/- 36 g) (P = 0.003). In HS the red cell retention in the cords of Billroth was significantly increased (203 +/- 68 per 10(4) microns 2) with respect to the cases with AHA (93 +/- 35 per 10(4) microns 2) and to the controls (57 +/- 28 per 10(4) microns 2) (P = 0.004). In HS and AHA the number of macrophages per 10(4) microns 2 of red pulp was significantly increased (5.41 +/- 1.10 and 7.52 +/- 2.91, respectively) with respect to the controls (3.25 +/- 0.58) (P less than 0.003). There was no statistically significant difference between the number of macrophages in HS and AHA. The transmission (TEM) and scanning electron microscopy (SEM) studies demonstrated predominantly red cell retention in the cords of HS spleens, red cell phagocytosis by cordal macrophages in AHA spleens and in a lesser intensity in HS spleens, and phagocytosis of haematic corpuscles by sinus endothelial cells (SEC) in the cases of HS. These quantitative studies allow a better understanding of splenic red cell destruction in haemolytic syndromes.

Adolescent↗

Symptoms of inattention and hyperactivity in children with habitual snoring: evidence from a community-based study in Istanbul.

BACKGROUND: Neurobehavioural symptoms of inattention and hyperactivity are common in children with sleep-disordered breathing (SDB). Prevalence rates of habitual snoring and attention deficit hyperactivity disorder (ADHD) are very similar and both have a substantial negative effect on children's behavioural health. OBJECTIVE: We examined the differences for subjective attentional and hyperactivity measures reported by parents and teachers among primary school children with habitual snoring and age- and sex-matched controls in a community-based case-control study in Istanbul. Methods In 2002, a survey was carried out to determine the prevalence of snoring in 2147 primary school children. After one year, in 2003, 151 children with habitual snoring and 302 controls from this survey were studied with parental SDB questionnaire, Conners' Parent (Conners-P) and Teacher Scales, and an inattention hyperactivity scale (IHS). Exclusion criteria included history of ADHD diagnosis, controls who started to snore and habitual snorers (HS) who no longer snored in this follow-up study. RESULTS: Ninety-six HS and 190 control subjects (mean age: 9.4 +/- 1.3) were evaluated. HS had significantly more symptoms of hyperactivity (Conners-ADHD index) (P: 0.033), attentional (P: 0.019), and conduct and oppositional defiant in subscales (P: 0.001) of Conners-P and IHS-Parents. A pooled score of Conners-P ADHD Index > 60 and IHS-Parent score > 1.25 showed considerable difference in HS when compared with controls (5.1% vs. 1.4%) (P < 0.0001). Daytime hyperactivity and excessive daytime sleepiness reported by parents correlated with scores of Conners-P and IHS-P (P < 0.01). Teachers' observations showed significant correlations with learning disability and the level of academic performance in HS (P < 0.01). Other behavioural parameters related to SDB were not significantly correlated with teachers' ADHD ratings in HS. CONCLUSION: Increased rates of moderate hyperactivity as well as conduct and oppositional defiant symptoms in HS reported by the parents might reflect a negative impact on overall neurobehavioural health. The teachers' scores yielded no significant results among HS and controls. This may be caused by the limitation due to shared method variance. The negative effect of crowded classes on teachers' evaluations must be also taken into consideration. After exclusion of a diagnosis of ADHD in children presenting with hyperactivity and inattention, children with habitual snoring with prominent scores of behavioural measures should be considered as candidates for further assessment by a sleep specialist.

Adolescent↗

No evidence for an independent role of anti-heparan sulphate reactivity apart from anti-DNA in lupus nephritis.

The presence of anti-heparan sulphate (HS) reactivity in serum is closely related to the occurrence of nephritis in patients with systemic lupus erythematosus (SLE). Since patients with lupus nephritis in general also have high titres of anti-DNA antibodies, we wanted to clarify the relationship between anti-HS and anti-DNA reactivity in serum. Therefore, we studied longitudinally six patients with lupus nephritis who experienced 12 exacerbations of their disease, and five SLE patients without nephritis experiencing 10 periods of non-renal disease exacerbations. In addition, we tested single serum samples of another 24 patients obtained during a renal disease exacerbation and 22 sera of patients without nephritis. The sera of all patients were tested for anti-DNA (Farr assay) and anti-HS reactivity (ELISA). We confirmed that SLE patients during renal exacerbations have a significantly higher anti-HS reactivity than patients without nephritis (P < 0.003). In addition, patients with nephritis also had higher titres of anti-DNA antibodies during renal exacerbations than during non-renal exacerbations (P < 0.01). A correlation between anti-DNA and anti-HS reactivity was observed (r = 0.40, P < 0.02), which in itself explains the correlation between nephritis and anti-HS reactivity. Comparing sera from nephritis and non-nephritis patients matched for anti-DNA titre, we found no difference in anti-HS reactivity, and therefore must conclude that the anti-HS reactivity is a direct reflection of anti-DNA reactivity.

Antibodies, Antinuclear↗

Relationship of nonalcoholic hepatic steatosis to overnight low-dose dexamethasone suppression test in obese individuals.

OBJECTIVES: To examine the association between nonalcoholic hepatic steatosis (HS) and the activity of the hypothalamo-pituitary-adrenal (HPA) axis, as evaluated by a low-dose dexamethasone suppression test, in obese subjects. DESIGN AND PATIENTS: In a cross-sectional study, we examined 54 obese, otherwise healthy, individuals with a negligible or zero daily alcohol consumption. MEASUREMENTS: HS (by ultrasonography), glucose tolerance status (by oral glucose load), insulin resistance [by homeostasis model assessment (HOMA)] and 1.0 mg postdexamethasone (postdex) suppression cortisol levels were measured. RESULTS: Subjects with nonalcoholic HS (n = 39) had markedly less suppressed circulating cortisol levels than those without HS (n = 15) (21.9 +/- 2.6 vs. 11.0 +/- 1.4 nmol/l, P < 0.001). In addition, subjects with nonalcoholic HS had significantly higher values of HOMA-insulin resistance score and circulating liver enzymes than their counterparts without HS. Age, body mass index (BMI), waist/hip ratio, plasma glucose concentration (both at fasting and after glucose load), lipids and blood pressure values did not differ significantly between the groups. Females were more represented among those without HS. The marked differences in postdex suppression cortisol levels that were observed between the groups were little affected by adjustment for sex, age, BMI, waist/hip ratio, HOMA-insulin resistance score, plasma lipids and liver enzyme levels. Similarly, in a logistic regression analysis, cortisol levels significantly predicted the presence of nonalcoholic HS (P = 0.032), independently of potential confounders. CONCLUSIONS: These results suggest that nonalcoholic hepatic steatosis is closely correlated with a subtle, chronic activation of the HPA axis in obese, otherwise healthy, individuals.

Adult↗

Effects of hypertonic saline on myocardial contractility in anaesthetized pigs.

The cardiac effects of hypertonic saline (HS, 7.5% NaCl) were evaluated using a number of indices derived from the left ventricular (LV) pressure-volume relationship. Left ventricular end-systolic elastance (elastance), the slope of the end-systolic pressure-volume relationship, end-systolic elastance normalized for end-diastolic volume (elastance(norm)), the rate of rise of LV pressure (dP/dtmax), and dP/dtmax/end-diastolic volume were used to assess myocardial contractility. Pigs were anaesthetized with isoflurane and instrumented for haemodynamic measurements, LV pressure, and volume (conductance catheter) determinations. Elastance was determined during transient (8-10 s) caudal vena caval balloon occlusion. Following instrumentation, the end-tidal isoflurane concentration was reduced and maintained at 1 minimum alveolar concentration (1.5%). Pigs were randomly administered either 0.9% NaCl (n = 7) or HS (n = 9) at a dose of 4 ml/kg, over 3 min into the right atrium. There were no significant differences in LV or haemodynamic measurements between isotonic saline and HS treated pigs at any time point. Elastance, elastase(norm) and dP/dtmax/end-diastolic volume did not change in either treatment group. In contrast, dP/dtmax increased significantly (P < 0.015) at 5 min compared to baseline after treatment with HS. End-diastolic volume increased significantly from 5 to 30 min following treatment with HS. Left ventricular end-diastolic pressure increased significantly at 5 and 60 min in HS treated pigs. Central venous and pulmonary arterial wedge pressures,and cardiac index increased significantly at 5 min after treatment with HS. Total peripheral resistance decreased significantly at 5 min, followed by a return to baseline in the HS group.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

Failure of hypertonic saline to resuscitate intestinal ischemia shock in the rat.

The effects of resuscitation with hypertonic saline (HS), administered as a bolus injection or infusion, were studied in a model of intestinal ischemia shock in rats. The model is characterized by severe intestinal mucosal lesions, release of cardioinhibitory substances and endogenous opioid peptides, and it results in high mortality rates. The blood pressure improved after HS given as an infusion for 1 h. The effects on blood pressure of HS given as a bolus and of normotonic saline (NS) were not significant. Plasma volume was not different from unshocked control animals in either HS infusion or NS infusion groups 2 and 4 h after infusion. Liver metabolic consequences of intestinal shock did not differ comparing the HS and NS groups, and the same result was found concerning the mucosal lesions in the small intestine. The 7-day survival decreased in the HS infusion group (14%) compared to untreated shock (46%) or NS infusion (54%) groups. We conclude that HS failed to resuscitate intestinal ischemia shock. These experiments indicate that HS treatment could even, in contrast to previous reports on hemorrhagic shock, be disadvantageous or dangerous in shock states characterized by extensive tissue injury.

Animals↗

Arterial structural changes in hypertensive rats induced by capsaicin and salt loading.

1. The objective of the present study was to investigate the arterial structural changes in a salt-sensitive hypertensive rat model induced by treatment with capsaicin. 2. Newborn male Wistar rats were treated with 50 mg/kg capsaicin subcutaneously for 2 days. Control rats were treated with vehicle solution (5% ethanol and 5% Tween 80 in saline). After weaning at 3 weeks, rats were divided into four groups: (i) control with a normal salt diet (0.5% NaCl; CON + NS); (ii) control with a high-salt diet (4% NaCl; CON + HS); (iii) capsaicin plus normal salt diet (CAP + NS); and (iv) capsaicin plus a high-salt diet (CAP + HS). Treatment with different salt diets was initiated at 3 weeks of age and lasted for 18 weeks. Tail-cuff systolic blood pressure (BP) and bodyweight were examined. At the end of the treatment period, blood vessels were prepared by perfusion fixation. Heart weight and vascular dimensions were measured in the thoracic (artery) aorta, renal artery and mesenteric artery. 3. Two weeks after the initiation of the salt diet treatment, BP became significantly higher in the CAP + HS group than in any of the other groups and this difference was maintained until the end of the treatment period. 4. Beginning at 8 weeks after the initiation of the salt diet treatment (11 weeks of age), BP became higher in the CON + HS group than in the CON + NS and CAP + NS groups. Blood pressure was not significantly different between the CON + NS and CAP + NS groups. 5. Media thickness, media thickness to lumen ratio and cross-sectional area of the aorta, renal artery and mesenteric artery were significantly increased in the CAP + HS group compared with the other groups. Heart weight was also increased in the CAP + HS and CON + HS groups compared with the other groups. 6. Similar structural changes in the blood vessels and heart were also found in the CON + HS group compared with the CON + NS group. Lumen diameter was not altered by the treatments in any of the arteries studied. 7. We conclude that treatment with capsaicin increased the sensitivity of the BP of these rats to salt and this increase in BP is correlated with hypertrophy of the arteries (vascular remodelling) with no change in lumen size. A long-term high-sodium load induced hypertension in normal Wistar rats, which was accompanied by cardiovascular hypertrophy.

Animals↗

Different patterns of cytokines, ECP and immunoglobulin profiles at two adverse drug reactions in a patient.

OBJECTIVES: Drug-induced hypersensitivity syndrome (HS) is a rare but life-threatening disease. We experienced carbamazepine-induced HS in a 14-year-old boy, who had cefaclor-induced cutaneous eruptions 15 months later. To clarify the mechanisms of HS and the differences between two diseases we studied this case in detail. METHODS: We investigated the associated viral agents by polymerase chain reaction and the specific antibodies. We also studied the mechanism of diseases by measuring chemical mediators including cytokines, ECP and immunoglobulins. RESULTS: The patient was diagnosed as having carbamazepine-induced HS associated with reactivation of human herpesvirus 6 based on the clinical course and laboratory data including drug-induced lymphocyte stimulation tests. Similarly, the diagnosis of cefaclor-induced eruption without any viral reactivation was made. Serum levels of IFN-gamma, IL-6, TNF-alpha, IL-5 and ECP were increased significantly at HS but mildly at cefaclor-induced eruptions. Furthermore, we detected transient hypogammaglobulinemia only at HS. CONCLUSIONS: This is the first report of anticonvulsant-induced HS followed by antibiotic-induced eruptions in a patient. In addition, we demonstrated difference in serum levels of inflammatory cytokines, immunoglobulins, activated eosinophils and viral reactivation between these diseases. This case would contribute to the understanding of the pathophysiology of adverse drug reactions including HS.

Adolescent↗

Relationship of non-alcoholic hepatic steatosis to cortisol secretion in diet-controlled Type 2 diabetic patients.

AIMS: To examine the association of non-alcoholic hepatic steatosis (HS) with the activity of the hypothalamo-pituitary-adrenal (HPA) axis in Type 2 diabetic individuals. METHODS: The activity of the HPA axis, as measured by 24-h urinary free cortisol (UFC) excretion and serum cortisol levels after 1.0 mg dexamethasone, was measured in 40 diet-controlled, predominantly overweight, Type 2 diabetic patients with non-alcoholic HS and in 40 diabetic patients without HS who were comparable for age, sex and body mass index (BMI). RESULTS: Subjects with non-alcoholic HS had significantly higher 24-h UFC excretion (191 +/- 4 vs. 102 +/- 3 nmol/24 h; P < 0.001) and post-dexamethasone cortisol concentrations (29.1 +/- 2 vs. 14.4 +/- 1 nmol/l; P < 0.001) than those without HS. Patients with HS had significantly higher values for HOMA insulin resistance score, plasma triglycerides and liver enzymes. Age, sex, BMI, waist-hip ratio (WHR), diabetes duration, HbA1c, LDL-cholesterol and blood pressure values were not different between the groups. The differences in urinary and serum cortisol concentrations between the groups remained significant after adjustment for age, sex, BMI, WHR, HOMA insulin resistance score, plasma triglycerides, HbA1c and liver enzymes. In multiple logistic regression analyses, 24-h UFC or serum cortisol concentrations (P < 0.05 and P = 0.02, respectively), along with age and HOMA insulin resistance, predicted the presence of HS, independently of potential confounders. CONCLUSIONS: These results demonstrate that non-alcoholic HS is closely associated with a subtle, chronic overactivity of the HPA axis in diet-controlled Type 2 diabetic individuals.

Blood Glucose↗

Non-alcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men. Role of visceral adipose tissue.

AIMS: To compare plasma biomarkers of inflammation and endothelial dysfunction in individuals with and without non-alcoholic hepatic steatosis (HS), and to evaluate whether such differences were mediated by the adverse metabolic pattern, typically found in these subjects. METHODS: HS (by ultrasound and computed tomography), visceral fat (by computed tomography), insulin resistance (by homeostasis model assessment-HOMA), plasma biomarkers of inflammation and endothelial dysfunction (hs-C reactive protein, fibrinogen, von Willebrand factor, plasminogen activator inhibitor-1 activity) were measured in 100 non-smoking, healthy, male volunteers. RESULTS: Plasma hs-CRP, fibrinogen, v-WF and plasminogen activator inhibitor-1 (PAI-1) activity levels were markedly higher (P < 0.01 or less) in subjects with non-alcoholic HS (n = 35) than in those without HS (n = 65). The former also had significantly higher values for body mass index (BMI), visceral fat, diastolic blood pressure, HOMA insulin resistance score, plasma insulin (both fasting and after glucose load), triglycerides, liver enzymes, and lower high-density lipoprotein (HDL)-cholesterol concentration. While the marked differences in these pro-inflammatory biomarkers observed between the groups were little affected by adjustment for age, BMI, blood pressure values, HOMA insulin resistance score, plasma triglyceride and liver enzyme concentrations, they were completely abolished after controlling for visceral fat. Similarly, in multivariate regression analyses, increased visceral fat significantly predicted the pro-inflammatory biomarkers, independently of HS and other potential confounders. CONCLUSIONS: These results indicate that, in non-smoking, non-diabetic men, the significant increase of plasma biomarkers of inflammation and endothelial dysfunction in the presence of non-alcoholic HS is largely mediated by abdominal visceral fat accumulation.

Adipose Tissue↗

Biomechanical comparison of the Herbert and AO cortical bone screws for compression of an equine third carpal bone dorsal plane slab osteotomy.

OBJECTIVE: To assess feasibility of insertion of 4.5-mm Herbert cannulated bone screws (HS) using fluoroscopic guidance and compare the mechanical shear strength of these HS and 4.5-mm AO cortical bone screws (AO) for fixation of dorsal plane slab osteotomies in equine cadaver third carpal bones (C3). ANIMALS OR SAMPLE POPULATION: Eight equine cadavers. METHODS: Bone mineral composition and density of contralateral C3 were confirmed to be equivalent using dual-energy x-ray absorptiometry. A standard 10-mm C3 slab osteotomy was reduced using HS or AO instrumentation under fluoroscopic guidance. Specimens were loaded in shear until failure, using a materials testing apparatus. RESULTS: HS and AO instrumentation allowed accurate reconstruction of the osteotomy, but there was difficulty encountered seating the HS proximal self-tapping threads. There was no significant difference in maximal load to failure, stiffness, or mode of failure of constructs created with the HS and AO screws. CONCLUSIONS: Use of 4.5-mm HS for repair of C3 radial facet, dorsal plane slab fractures may result in a mechanically comparable fixation to a repair using a 4.5-mm AO. Equine dorsal C3 may be too dense, however, to allow placement of the proximal self tapping threads of the HS without potentially excessive application of torque to the screw itself. CLINICAL RELEVANCE: Dorsal plane, radial facet slab fractures of the equine C3 are a significant clinical problem. Accurate reconstruction and stabilization are necessary for return to athletic function.

Absorptiometry, Photon↗

Heparan sulfate proteoglycans of Ras-transformed 3T3 or neuroblastoma cells. Differing functions in adhesion on fibronectin.

Initial studies described the significance of heparan sulfate proteoglycans of Balb/c 3T3 cells in their adhesion on fibronectin matrices, including their binding to multiple domains in FN, the importance of this binding in microfilament and close contact formation, and the cooperativity of both HS-PG and 140k glycoprotein integrin's binding to FN to achieve tight-focal contacts under cells. These analyses utilized model HS-binding proteins, such as platelet factor 4, and proteolytic fragments of FN with differing binding activities in both cell biological analyses of adhesion responses and in biochemical analyses of the HS-PG in the adhesion sites. In contrast, dermatan sulfate proteoglycans (DS-PG) inhibit 3T3 adhesion on FN but not on collagen; of special note is the discovery that certain integrin-binding fragments of FN also contain a third HS/DS-binding domain that is cryptic and that provides a more effective mechanism for inhibiting integrin: FN binding. Kirsten Ras oncogene-transformed 3T3 cells and their nude-mouse-derived primary or lung metastatic tumors are also being analyzed by similar approaches. HS-PGs in the adhesion sites of these tumor populations undergo extensive catabolism, resulting in alteration of their binding to FN affinity columns (and by implication alteration in adhesion responses of these tumor cells on FN matrices). Functions for HS-PG on the surface of neuronal cell derivatives, e.g., neuroblastoma cells derived from the neural crest of the embryo and potentially related in some ways to peripheral neurons, are also being explored. HS-binding fragments of FN or PF4 facilitate attachment and spreading of neuroblastoma cells but not neurite outgrowth, contrasting with the ability of dorsal root ganglion neurons to extend neurites on HS-binding substrata. The catabolism of HS-PG in neuroblastoma adhesion sites is minimal, indicating that this cannot be the explanation for incompetence in neurite extension. Neurite extension by neuroblastoma cells on FN results from three different and overlapping binding activities of non-PG receptors on the cell surface--RGDS-dependent binding to integrin, an RGDS-independent mechanism (perhaps a cell type-specific domain), and a ganglioside-dependent process. However, these neurite-extending reactions can be modulated either by exogenous addition of proteoglycans acting in a "trans" manner with the cell surface or by endogenous HG-PG acting in a "cis" manner with one or more of these receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Axons↗