Striatal dopamine during sensorial stimulations: a [18F]FDOPA PET study in human and cats

Sensory stimulations of the forelimb in cats are known to increase dopamine release in the ipsilateral striatum and to decrease it in the homologous contralateral structure. Using positron emission tomography in both humans and cats, the present study shows that such sensory stimulations greatly reduce [(18)F]FDOPA accumulation ipsilateral to the stimulation (by 40.4% and 26.4% in the human caudate and putamen, respectively, and by 33.3% in the cat striatum). This decrease in striatal [(18)F]FDOPA uptake suggests a reduced DA storage resulting from the increased amine release. No change was observed in the contralateral striatum in neither human or cat suggesting, in contrast, that [(18)F]FDOPA accumulation is not facilitated by decreased DA release. These results support the hypothesis that sensory stimulations activate a non-synaptic mode of dopamine release.     

Extrastriatal D2 and striatal D2 receptors in depressive illness: pilot PET studies using [11C]FLB 457 and [11C]raclopride

BACKGROUND: Reduced dopaminergic function may occur in depressive disorders. In this paper the results of two pilot studies examining different aspects of the dopamine system in depression are presented. First, the binding of [(11)C]FLB 457 to extrastriatal D(2) receptors was measured in a group of depressed patients. Second, the hypothesis that selective serotonin reuptake inhibiting (SSRI) antidepressants affect the striatal binding of [(11)C]raclopride was tested. METHODS: In the first study the binding of [(11)C]FLB 457 was compared between 7 people with depression and 7 healthy controls. In the second study the binding of [(11)C]raclopride to striatal D(2/3) receptors was compared between 8 people taking SSRI antidepressant medication and 8 healthy controls. RESULTS: There was no difference in the binding of [(11)C]FLB 457 between the two groups. [(11)C]raclopride binding was reduced in the dorsal striatum of people taking antidepressants suggesting either that D(2/3) expression was reduced, or that dopamine release was increased, compared to untreated controls. LIMITATIONS: The depressed patients were not severely depressed and were not matched for gender with controls. In the raclopride group the patients and controls were not matched by gender and were taking different SSRI antidepressants. CONCLUSION: We found no support for the hypothesis that dopamine D(2) receptor expression is altered in extrastriatal brain regions in depression. SSRI antidepressants were associated with reduced [(11)C]raclopride binding in the dorsal striatum supporting the hypothesis that therapeutic effects of such drugs may, in part, be due to changes in the dopamine system.     

Perivascular nerves induce cardiorespiratory reflexes in response to algogens in anaesthetised rats

In the present study we measured cardiovascular and respiratory reflexes evoked by administration of bradykinin and capsaicin into the hindlimb vasculature of anaesthetised rats, whilst simultaneously recording activity of sensory afferents on the adventitial surface of femoral arteries and veins. Bradykinin (0.9 nmol) and capsaicin (0.3 nmol) caused a rapid reflex fall in mean arterial pressure (delta mmHg: -37 +/- 8 and -28 +/- 3, respectively; P < 0.01) and an increase in respiratory minute volume (delta ml min(-1): 180.0 +/- 39.2 and 156.1 +/- 24.5, respectively; P < 0.01), associated with an increase in neural discharge in arterial afferents (from basal 0.4 +/- 0.3 to 8.5 +/- 2.9 impulses s(-1) following intra-arterial administration of bradykinin, P < 0.05, n = 7; from basal 0.2 +/- 0.1 to 7.5 +/- 3.7 impulses s(-1) with capsaicin, P < 0.01, n = 18). The antagonists FR173657 and capsazepine confirmed bradykinin B2 and vanilloid VR1 receptors mediated the responses to bradykinin and capsaicin, respectively. Topical administration of algogen to the vessel surface, and electrical stimulation of the adventitia also evoked cardiovascular and respiratory responses. These data support the hypothesis that stimulation of sensory nerve endings within the hindlimb vasculature contributes to systemic cardiorespiratory reflexes in the rat.     

Dynamics of skeletal muscle oxygenation during sequential bouts of moderate exercise

In rat muscle, faster dynamics of microvascular P(O2) (approximately blood flow (Q(m) to O2 uptake (V(O2) ratio) after prior contractions that did not alter blood [lactate] have been considered to be a consequence of faster V(O2) kinetics. However, in humans, prior exercise below the lactate threshold does not affect the pulmonary V(O2) kinetics. To clarify this apparent discrepancy, we examined the effects of prior moderate exercise on the kinetics of muscle oxygenation (deoxyhaemoglobin, [HHb] alpha V(O2m)/Q(m)) and pulmonary V(O2) (V(O2p) in humans. Eight subjects performed two bouts (6 min each) of moderate-intensity cycling separated by 6 min of baseline pedalling. Muscle (vastus lateralis) oxygenation was evaluated by near-infrared spectroscopy and V(O2p) was measured breath-by-breath. The time constant (tau) of the primary component of V(O2p) was not significantly affected by prior exercise (21.5 +/- 9.2 versus 25.6 +/- 9.7 s; Bout 1 versus 2, P= 0.49). The time delay (TD) of [HHb] decreased (11.6 +/- 2.6 versus 7.7 +/- 1.5 s; Bout 1 versus 2, P < 0.05) and tau[HHb] increased (7.0 +/- 3.5 versus 10.2 +/- 4.6 s; Bout 1 versus 2, P < 0.05), while the mean response time (TD + tau) did not change (18.6 +/- 2.7 versus 17.9 +/- 3.9 s) after prior moderate exercise. Thus, prior moderate exercise resulted in shorter onset and slower rate of increase in [HHb] during subsequent exercise. These data suggest that prior exercise altered the dynamic interaction between V(O2m)and Q(m) following the onset of exercise.     

Increased thermogenic responsiveness to intravenous beta-adrenergic stimulation in habitually exercising humans is not related to skeletal muscle beta2-adrenergic receptor density

Habitually exercising adults demonstrate greater thermogenic responsiveness to beta-adrenergic receptor (beta-AR) stimulation compared with their sedentary peers, but the molecular mechanisms involved are unknown. To determine the possible role of increased beta-AR density, we studied 32 healthy adults: 17 habitual aerobic exercisers (age 45 +/- 5 years, 11 males) and 15 sedentary (49 +/- 5 years, 7 males). Maximal oxygen uptake (43.7 +/- 2.5 versus 31.6 +/- 2.9 ml kg(-1) min(-1), P = 0.002, mean +/- S.E.M.) and vastus lateralis muscle maximal citrate synthase activity (1.70 +/- 0.36 versus 0.58 +/- 0.11 micromol min(-1) g(-1), P = 0.008) were higher in the habitually exercising subjects. Resting energy expenditure (EE) adjusted for fat-free mass (FFM) was similar in the habitually exercising (5903 +/- 280 kJ day(-1)) and sedentary adults (6054 +/- 289 kJ day(-1), P = 0.43). The percentage increase in EE (DeltaEE%; indirect calorimetry, ventilated hood) above resting EE in response to beta-AR stimulation (intravenous isoproterenol at 6, 12 and 24 ng (kg FFM)(-1) min(-1)) was greater (7.1 +/- 1.2, 13.7 +/- 1.0, 20.7 +/- 1.3 versus 5.9 +/- 0.9, 9.9 +/- 1.4, 15.9 +/- 1.70%, respectively, P = 0.04), and the dose of isoproterenol required to increase EE by 10% above resting EE was lower (8.2 +/- 1.5 versus 17.1 +/- 4.1 ng (kg FFM)(-1) min(-1), P = 0.03) in the habitually exercising adults. In contrast, vastus lateralis muscle beta(2)-AR density was similar in the habitually exercising and sedentary subjects (7.46 +/- 0.29 versus 7.44 +/- 0.60 fmol (mg dry weight muscle)(-1), P = 0.98), and was not related to DeltaEE% (r = 0.02, P = 0.94) or to the isoproterenol dose required to increase EE by 10% above resting EE (r = -0.06, P = 0.76). These findings indicate that increased beta(2)-AR density is not a mechanism contributing to the greater thermogenic responsiveness to beta-AR stimulation in adult humans who regularly perform aerobic exercise.     

Early outcome of myomectomy by laparotomy, minilaparotomy and laparoscopically assisted minilaparotomy. A randomized prospective study

BACKGROUND: To compare in the first 7 days after surgery the outcome of myomectomy performed by three laparotomic approaches: laparotomy (LT), minilaparotomy (MLT) and laparoscopically assisted minilaparotomy (LA-MLT). METHODS: Fifty-one women with 5-15 cm total myoma diameter were randomized blindly using a computer randomization list, to LT (n = 17), MLT (n = 17) or LA-MLT (n = 17). RESULTS: Mean operation length was similar in the three groups. Mean (+/- SEM) time of paralytic ileus (55.0 +/- 4.5 versus 33.4 +/- 3.4 h; P < 0.01) and discharge (141.6 +/- 5.2 versus 81.5 +/- 8.2 h; P < 0.01) was longer in LT than LA-MLT or even MLT. In comparison with LA-MLT, LT induced a greater haemoglobin decline (-3.07 +/- 0.3 versus -1.8 +/- 0.15 mg/dl; P < 0.025), and a greater post-operative stress, as documented by increased prolactin (+15.1 +/- 3.8 versus +0.16 +/- 4.5 ng/ml; P < 0.03) and decreased insulin sensitivity (fasting glucose/insulin; -7.5 +/- 2.6 versus -0.7 +/- 2.1; P < 0.02). Seven days after surgery, abdominal pain (P < 0.05) was higher after LT (3.0 +/- 0.6) than MLT (0.5 +/- 0.2) and LA-MLT (0.9 +/- 0.4). CONCLUSIONS: In selected cases, myomectomy by LA-MLT offers some advantages versus LT and, to a smaller extent, MLT.     

Low day 3 luteinizing hormone values are predictive of reduced response to ovarian stimulation

The aim of the present work was to evaluate whether low day 3 luteinizing hormone (LH) values in the presence of normal follicle stimulating hormone (FSH) are predictive of poor response to ovarian stimulation. Two groups of women undergoing ovarian stimulation and differing only in the day 3 LH concentration (<3 mIU/ml, study group, n=30; >3 mIU/ml, control group, n=45) were retrospectively analysed. Study group patients developed a lower oestradiol peak (703+/-388 versus 955+/-400 ng/ml; P = 0.005) and a lower number of follicles >15 mm diameter at the time of human chorionic gonadotrophin (HCG) administration (2.6+/-1.3 versus 3.6+/-1.8; P=0.004) than the control group. Conversely, a similar ratio of oestradiol: follicles >15 mm diameter was observed (256+/-118 versus 269+/-93; P=0.563). The number of follicles >10 mm at the time of HCG administration appeared to be lower in the study group, but this difference was not statistically significant (6+/-3.9 versus 7.8+/-4.3). Our data indicate that day 3 LH values <3 mIU/ml are predictive of poor response to ovarian stimulation.      

Reduced complications during hemodialysis by automatic blood volume controlled ultrafiltration

BACKGROUND: Intradialytic morbid events (IMEs, mostly hypotension) are frequent complications during hemodialysis (HD). This study investigated whether automatic feedback control via adjustment of the ultrafiltration rate reduces IME frequency. METHODS: In this multi-center cross-over study, 56 hypotension-prone patients were treated both with standard HD (sHD, applying a constant ultrafiltration rate) and HD applying a blood volume controlled ultrafiltration rate (cHD).The relative blood volume (RBV) was continuously monitored. The individual relative blood volume limit (RBVcrit ) was determined from the measured RBV during initial sHD. During cHD, the ultrafiltration rate was automatically adjusted to keep the actual RBV above RBVcrit. RESULTS: In 3,081 HD treatments, slightly fewer IMEs were observed during cHD than during sHD (0.785+/-0.613 versus 0.695+/-0.547 per treatment, P=0.144). Less symptomatic events were seen during cHD: -13% for symptomatic hypotension (0.594 versus 0.685 per treatment, P=0.120), and -32% for cramps (0.049 versus 0.072 per treatment, P=0.009). Thirty-one patients with the highest IME rate (IME in at least every second treatment) especially benefited from cHD: 1.185+/-0.554 versus 0.979+/-0.543 IME per treatment (P=0.004). The reduction in blood pressure (BP) and the increase in heart rate were lower during the treatments with cHD than with sHD: systolic BP: -18.8+/-26.7 versus -22.2+/-28.9 mmHg (P=0.007), diastolic BP: -7.8+/-14.8 versus -9.1+/-15.3 mmHg (P=0.064), heart rate: 1.8+/-10.4 versus 2.3+/-11.6 per minute (P=0.014). Neither treatment duration nor ultrafiltration volume was significantly different between cHD and sHD. CONCLUSION: For cHD, less intradialytic morbid events were observed than for sHD, and pre- to post-dialytic changes in blood pressure and heart rate were less pronounced.     

Differential aerobic exercise-induced changes in plasma aldosterone between African Americans and Caucasians

Aldosterone influences the kidney's regulation of blood pressure (BP), but aldosterone can contribute to the pathogenesis of hypertension. Blood pressure is reduced with aerobic exercise training (AEX), but the extent to which plasma aldosterone (PA) levels change is unclear. The purpose of this study was to determine whether 6 months of AEX changed PA levels, 24 h sodium (Na(+)) excretion and BP in prehypertensive and hypertensive subjects and whether these changes differed according to ethnicity. The study was performed in the Kinesiology Department at the University of Maryland, College Park, and 35 (22 Caucasian; 13 African American) sedentary prehypertensive and hypertensive subjects completed 6 months of AEX. Blood samples were collected under fasting and supine conditions, and PA was measured by radioimmunoassay. In total population aerobic exercise training increased maximal oxygen consumption (24 +/- 0.8 versus 28 +/- 1 ml kg(-1) min(-1), P < 0.001) and decreased PA levels (97 +/- 11 versus 72 +/- 6 pg ml(-1), P = 0.01), body mass index (28 +/- 0.5 versus 28 +/- 0.5 kg m(-2), P = 0.004) and weight (85 +/- 2 versus 83 +/- 2 kg, P = 0.003). Aerobic exercise training decreased PA levels (from 119 +/- 16 to 81 +/- 7 pg ml(-1), P = 0.02) in the Caucasians but there was no change in BP or Na(+) excretion. African American participants had no significant changes in PA levels, BP and Na(+) excretion. Plasma aldosterone levels were 47% lower at baseline (P = 0.01) and 30% lower after AEX (P = 0.04) in African American participants compared with Caucasians. Baseline (P = 0.08) and final PA levels (P = 0.17) did not differ between the two groups after accounting for baseline and final intra-abdominal fat, respectively. The reduction in PA levels with AEX appeared to be driven by the change in PA levels in Caucasian participants. Fat distribution contributed to the ethnic differences in PA levels.     

Somatosensory evoked magnetic fields following electric tongue stimulation using pin electrodes

Quantitative evaluation of the sensory disturbance of the tongue is important clinically. However, because the conventional electrophysiological approach to the peripheral nerve cannot be used in the mandible owing to the deep route of the lingual nerve, we applied evoked potentials in the central nervous system. Somatosensory evoked magnetic fields (SEFs) following electric stimulation were recorded in 10 healthy subjects by means of pin electrodes placed on the tongue mucosa. Three or four components (P25m, P40m, P60m, and P80m) were identified over the contralateral hemisphere with unilateral stimulation. Because none of the components were consistently detected in all subjects, we evaluated the root mean square (RMS) of 18 channels over the contralateral hemisphere. To estimate the activated cortical response, we calculated the difference in mean RMS amplitude between 10 and 150 ms and that of the baseline period (aRMS=RMS[10, 150]-RMS[-50, -5]). The aRMS values for right-sided and left-sided stimulation were 10.18+/-7.92 and 10.99+/-8.98 fT/cm, respectively, and the mean laterality index, expressed by [(left-right)/(left+right)] was 0.025+/-0.104. This parameter can be useful for evaluating patients with unilateral sensory abnormality of the tongue.     

Candida albicans stimulates arachidonic acid liberation from alveolar macrophages through alpha-mannan and beta-glucan cell wall components.

Candida albicans is an increasingly important fungal pathogen. Alveolar macrophages respond to fungal components such as zymosan by releasing arachidonic acid (AA) and AA metabolites. However, few studies hypothesized that macrophages respond to C. albicans by releasing AA and generating AA metabolites as a consequence of interaction of mannose and beta-glucan receptors with fungal cell wall components. [14C]AA-labeled rabbit alveolar macrophages released AA following stimulation with either live or heat-killed C. albicans. High-pressure liquid chromatography analysis revealed that 55% of the AA released was metabolized via cyclooxygenase and lipoxygenase pathways. The metabolites consisted of prostaglandin E2, prostaglandin F2 alpha, 6-ketoprostaglandin F1 alpha, thromboxane B2, and leukotrienes B4 and D4. We further examined the roles of alpha-mannan and beta-glucan components of C. albicans in mediating these alterations of eicosanoid metabolism. Prior work in our laboratory has shown that soluble alpha-mannan and beta-glucan inhibit macrophage mannose and beta-glucan receptors, respectively. Incubation of alveolar macrophages with soluble alpha-mannan derived from C. albicans (1 mg/ml) resulted in 49.8% +/- 2.6% inhibition of macrophage AA release during stimulation with intact C. albicans (P = 0.0001 versus control). Macrophage AA release in response to C. albicans was also inhibited to a significant but lesser degree by soluble beta-glucan (36.2% +/- 1.3%; P = 0.008 versus control). These results indicate that C. albicans stimulates macrophage AA metabolism and that these effects are partly mediated by alpha-mannan and beta-glucan constituents of the fungus.     

Effects of electrical stimulation of various midline thalamic nuclei on the bilateral release of dopamine from dendrites and nerve terminals of neurons in the nigro-striatal dopaminergic pathways

The effects of electrical stimulation of midline thalamic nuclei on the release of [³H]dopamine ([³H]DA) were determined in both substantiae nigrae (SN) and caudate nuclei of halothane-anesthetized cats using the push-pull cannula method. [³H]DA release was increased in the four structures following stimulation of the interanteromedialis nucleus (IAM) but only enhanced in both SN when nucleus reuniens (RE) was stimulated. In contrast, no effect was detected after delivery of the stimuli to nucleus centralis medialis. These results indicate that the anterior part of the thalamic massa intermedia (IAM and RE particularly) is involved in the bilateral regulation of DA release from nerve terminals and dendrites of the nigro-striatal dopaminergic neurons.     

Decreased [(3)H]spiperone binding in the anterior cingulate cortex of schizophrenia patients: an autoradiographic study

Abnormalities in the anterior cingulate cortex have been reported in patients with schizophrenia, and have been implicated in the pathophysiology of this disorder. In the present study, we have examined antipsychotic-sensitive binding sites in the left anterior cingulate cortex of schizophrenia patients and controls. Using quantitative autoradiography and [(3)H]spiperone as a ligand, both saturation and competition experiments were performed in post-mortem brain tissue obtained from six schizophrenia and six control cases. Saturation experiments revealed that the maximum number of [(3)H]spiperone binding sites was significantly reduced by 31% in the schizophrenia group as compared to the control group (65.3+/-5.6 fmol/mg tissue versus 94.2+/-7.3 fmol/mg tissue). Increased dissociation constant was also observed in the schizophrenia group (2.2+/-0.4 nM versus 1.3+/-0.2 nM), but was not statistically significant (P=0.07). Competition experiments were performed in order to examine the pharmacological profile of [(3)H]spiperone binding, and revealed that: (i) displacement of [(3)H]spiperone binding by clozapine and mianserin was significantly reduced in the schizophrenia group as compared to the control group (-26% and -16% respectively); (ii) the order of displacement potency of the drugs tested was: haloperidol>mianserin>butaclamol approximately risperidone>clozapine>2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene. Our results suggest a reduction of antipsychotic-sensitive binding sites in the anterior cingulate cortex of patients with schizophrenia. Such abnormality could lead to an imbalance in neurotransmitter regulation in the anterior cingulate cortex which may contribute to the emergence of some symptoms of schizophrenia.     

Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation

Reduced synthesis of collagen types I and III is characteristic of chronologically aged skin. The present report provides evidence that both cellular fibroblast aging and defective mechanical stimulation in the aged tissue contribute to reduced collagen synthesis. The reduction in collagen synthesis due to fibroblast aging was demonstrated by a lower in vitro production of type I procollagen by dermal fibroblasts isolated from skin of young (18 to 29 years) versus old (80+ years) individuals (82 +/- 16 versus 56 +/- 8 ng/ml; P < 0.05). A reduction in mechanical stimulation in chronologically aged skin was inferred from morphological, ultrastructural, and fluorescence microscopic studies. These studies, comparing dermal sections from young and old individuals, demonstrated a greater percentage of the cell surface attached to collagen fibers (78 +/- 6 versus 58 +/- 8%; P < 0.01) and more extensive cell spreading (1.0 +/- 0.3 vs. 0.5 +/- 0.3; P < 0.05) in young skin compared with old skin. These features are consistent with a lower level of mechanical stimulation on the cells in old versus young skin. Based on the findings presented here, we conclude that reduced collagen synthesis in chronologically aged skin reflects at least two different underlying mechanisms: cellular fibroblast aging and a lower level of mechanical stimulation.     

Fertility preservation in breast cancer patients: IVF and embryo cryopreservation after ovarian stimulation with tamoxifen

BACKGROUND: Breast cancer chemotherapy commonly causes premature ovarian failure and infertility. Because increased estrogen levels are thought to be potentially risky in breast cancer patients, natural cycle IVF (NCIVF) has been used to preserve fertility and treat infertility in these women. METHODS: Twelve women with breast cancer received 40-60 mg tamoxifen for 6.9 +/- 0.6 days beginning on days 2-3 of their menstrual cycle (15 cycles), and had IVF (TamIVF) with either fresh embryo transfer (six cycles) or cryopreservation (nine cycles). They were compared to a retrospective control group (n = 5) who had natural cycle IVF (NCIVF, nine cycles). RESULTS: Cycle cancellation was significantly less frequent in TamIVF, compared with NCIVF (1/15 versus 4/9, P < 0.05). Compared with NCIVF, TamIVF patients had a greater number of mature oocytes (1.6 +/- 0.3 versus 0.7 +/- 0.2, P = 0.03) and embryos (1.6 +/- 0.3 versus 0.6 +/- 0.2, P = 0.02) per initiated cycle. TamIVF resulted in the generation of embryo(s) in every patient (12/12) while only three out of five patients had an embryo following NCIVF. Two out of six patients in TamIVF, and 2/5 in NCIVF conceived. One patient in the TamIVF group delivered a set of twins. After a mean follow up of 15 +/- 3.6 months (range 3-54), none of the patients had a recurrence of cancer. CONCLUSIONS: Tamoxifen stimulation appears to result in a higher number of embryos and may provide a safe method of IVF and fertility preservation in breast cancer patients.     

Circulating monocytes in patients with acute coronary syndromes lack sufficient interleukin-10 production after lipopolysaccharide stimulation

Acute coronary syndromes (ACS) are associated with inflammation resulting from monocyte activation. We sought for differences in the production of pro- and anti-inflammatory cytokines by monocytes from patients with ACS. C-reactive protein (CRP) and neopterin were measured in 22 patients with acute coronary syndromes, 50 patients with stable vascular disease and 22 healthy controls. Production of tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 was determined after, respectively, 6 and 24 h of incubation of full blood with lipopolysaccharide (LPS). Levels of CRP [median, interquartile range (IQR)][1.5 mg/l (0.8-4.5) ACS patient versus 2.1 (0.9-3.6) stable disease versus 0.4 (0.3-1.2) healthy controls] (P < 0.001) and neopterin [7.4 nmol/l (6.0-8.7) ACS patient versus 7.1(6.0-8.9) stable disease versus 6.4 (5.6-7.3) healthy controls] (P = 0.07) were higher in both the patient groups. IL-10 production after LPS stimulation was greatly reduced in patients with acute coronary syndromes (16 175 pg/ml, 7559-28 470 pg/ml) as opposed to patients with stable disease (28 379 pg/ml, 12 601-73 968 pg/ml) and healthy controls (63 830 pg/ml, 22 040-168 000 pg/ml) (P = 0.003). TNF-alpha production was not signi fi cantly different between the groups [7313 pg/ml (4740-12 615) ACS patient versus 11 002 (5913-14 190) stable disease versus 8229 (5225-11 364) healthy controls] (P = 0.24). Circulating monocytes in unstable coronary syndromes produce equal amounts of TNF-alpha but less IL-10 after stimulation with LPS in vitro as compared with healthy controls. We hypothesize that, in acute coronary syndromes, the production proinflammatory cytokines is not counterbalanced by anti-inflammatory cytokines such as IL-10.     

Altered phenotype and function of dendritic cells in children with type 1 diabetes

The importance of dendritic cells (DC) in the activation of T cells and in the maintenance of self-tolerance is well known. We investigated whether alterations in phenotype and function of DC may contribute to the pathogenesis of Type 1 diabetes (T1DM). Mature DC (mDC) from 18 children with T1DM and 10 age-matched healthy children were tested. mDC, derived from peripheral blood monocytes cultured for 6 days in presence of interleukin (IL)-4 and granulocyte-macrophage colony stimulating factor (GM-CSF) and stimulated with lipopolysaccharide (LPS) for the last 24 h, were phenotyped for the expression of the co-stimulatory molecules B7.1 and B7.2. In six patients and six controls allogenic mixed leucocyte reaction (AMLR) was performed using mDC and cord blood-derived naive T cells at a DC/T naive ratio of 1 : 200. Proliferation was assessed on day 7 by [(3)H]-thymidine incorporation assay. Mature DC derived from patients showed, compared with controls, a reduced expression of B7.1 [mean of fluorescence intensity (MFI): 36.2 +/- 14.3 versus 72.9 +/- 34.5; P = 0.004] and B7.2 (MFI: 122.7 +/- 67.5 versus 259.6 +/- 154.1; P = 0.02). We did not find differences in the HLA-DR expression (P = 0.07). Moreover, proliferative response of allogenic naive T cells cultured with mDC was impaired in the patients (13471 +/- 9917.2 versus 40976 +/- 24527.2 cpm, P = 0.04). We also measured IL-10 and IL-12 concentration in the supernatant of DC cultures. Interestingly, we observed in the patients a sevenfold higher level of IL-10 (P = 0.07) and a ninefold lower level of IL-12 (P = 0.01). Our data show a defect in the expression of the co-stimulatory molecules and an impairment of DC priming function, events that might contribute to T1DM pathogenesis.     

Renal biopsy findings predicting outcome in scleroderma renal crisis

Scleroderma renal crisis is irreversible in some patients despite aggressive treatment. This study was designed to identify pathologic prognostic features in scleroderma renal crisis. We retrospectively reviewed the pathology and the clinical records of 17 patients who underwent kidney biopsies during scleroderma renal crisis (group A, recovered renal function [n = 7]; group B, remained in renal failure or died [n = 10]). Multiple histologic features were assessed semiquantitatively (0-3) or as percentages. C4d staining of peritubular capillaries and small vessels was assessed semiquantitatively (0-3) in patients with scleroderma (n = 11), normotensive (n = 10), and hypertensive (n = 12) nonscleroderma native kidney controls. The percentage of thrombosed vessels (25.1 +/- 21.0 versus 5.6 +/- 12.3, P = .045) and the severity of glomerular ischemic collapse (2.9 +/- 0.3 versus 1.4 +/- 0.8, P = .001) were significantly higher in group B than in group A. Also, group B patients tended to have more severe acute tubular injury and vascular fibrinoid changes. The peritubular capillary C4d score in patients with scleroderma, normotensive controls, and hypertensive controls were 1.1 +/- 0.9, 0.3 +/- 0.7, and 0.3 +/- 0.5, respectively (P = .018, scleroderma versus other controls). Small vessel C4d score was higher in scleroderma compared to normotensive but not hypertensive controls. Within scleroderma samples, a significantly higher peritubular capillary C4d score (1.6 +/- 0.7 versus 0.3 +/- 0.5, P = .024) but not small vessel score was found in group B compared to group A. This tended to be associated with peritubular capillary leukocyte margination. Vascular thrombosis, severe glomerular ischemic collapse, and peritubular capillary C4d deposits in scleroderma renal crisis kidney biopsies correlated with increased risk of failure to recover renal function.     

低氧诱导因子-1α和内皮素-1基因在大鼠低氧性肺动脉高压中的表达

目的　探讨低氧诱导因子 1(HIF 1α)和内皮素 1(ET 1)基因表达在低氧性肺动脉高压发病过程中的变化和作用。方法　复制低氧性肺动脉高压大鼠模型 ,测定平均肺动脉压 ,弹力纤维染色显示腺泡内肺动脉 ,用放射免疫法测ET含量 ,原位杂交方法进行检测HIF 1αmRNA。结果　HIF 1αmRNA在低氧各组腺泡内肺动脉有表达 ,低氧 14d组 (0 2 5 6 9± 0 0 46 8)和低氧 2 8d组 (0 2 2 5 8±0 0 45 3)染色强于低氧 5d组 (0 145 5± 0 0 2 72 )和正常组 (0 110 9± 0 0 2 2 4) ;ET 1mRNA在低氧各组腺泡内肺动脉有表达 ,低氧 14d组 (0 412 2± 0 0 783)和低氧 2 8d组 (0 36 84± 0 0 72 9)染色强于低氧5d组 (0 2 0 17± 0 0 34 9)和正常组 (0 185 5± 0 0 36 1) ,HIF 1α和ET 1基因表达在H14d组和H2 8d组明显增加 (P <0 0 5 )。肺动脉血中ET 1含量在H14d组 [(15 8 78± 2 5 14)pg/ml]和H2 8d组 [(142 93± 2 3 38)pg/ml]明显高于H5d组 [(79 6 8± 12 5 4)pg/ml]和正常组 [(6 5 37± 10 82 )pg/ml](P <0 0 5 ) ;H14d组 [(34 0± 5 8)mmHg]和H2 8d组 [(2 9 0± 4 7)mmHg]的mPAP也明显高于H5d组[(19 0± 3 5 )mmHg]和正常组 [(17 0± 2 8)mmHg](P <0 .0 5 ) ,并且与肺动脉血中ET 1含量呈正比(rs=0     

Depletion of ovarian reserve in young women after treatment for cancer in childhood: detection by anti-Müllerian hormone, inhibin B and ovarian ultrasound

BACKGROUND: Treatment of cancer during childhood may result in loss of primordial follicles from the ovary. METHODS: Ten cancer survivors and 11 controls with regular menstrual cycles, in addition to 10 cancer survivors and 10 controls taking the combined oral contraceptive pill (COCP) were recruited. Subjects were investigated on days 3-5 of a menstrual cycle, or week 3 of COCP administration before and 24 h after administration of 225 IU FSH. RESULTS: Serum FSH levels were elevated in cancer survivors with regular menstrual cycles (7.5 +/- 1.4 versus 4.2 +/- 0.3 IU/l; P = 0.02), while anti-Müllerian hormone (AMH) levels were lower (13.0 +/- 3.0 versus 21.0 +/- 3.4 pmol/l; P < 0.05). Other hormone levels were unchanged. Ovarian volume was smaller in cancer survivors than controls (3.0 +/- 0.5 versus 5.0 +/- 0.8 ml; P < 0.05), but antral follicle count (AFC) was similar. During COCP administration, inhibin B remained undetectable in six cancer survivors after FSH administration, whereas all controls showed a rise in inhibin B levels. The AFC was lower in cancer survivors than in controls (4.2 +/- 0.8 versus 7.2 +/- 0.8; P = 0.02). Ovarian volume was low in both groups, but did not differ between them. CONCLUSIONS: The study results demonstrate both hormonal and biophysical evidence of partial loss of the ovarian reserve in young cancer survivors. This was detected both in women with normal menstrual cycles and during COCP administration.