Nutrients cause grassland biomass to outpace herbivory.

Human activities are transforming grassland biomass via changing climate, elemental nutrients, and herbivory. Theory predicts that food-limited herbivores will consume any additional biomass stimulated by nutrient inputs ('consumer-controlled'). Alternatively, nutrient supply is predicted to increase biomass where herbivores alter community composition or are limited by factors other than food ('resource-controlled'). Using an experiment replicated in 58 grasslands spanning six continents, we show that nutrient addition and vertebrate herbivore exclusion each caused sustained increases in aboveground live biomass over a decade, but consumer control was weak. However, at sites with high vertebrate grazing intensity or domestic livestock, herbivores consumed the additional fertilization-induced biomass, supporting the consumer-controlled prediction. Herbivores most effectively reduced the additional live biomass at sites with low precipitation or high ambient soil nitrogen. Overall, these experimental results suggest that grassland biomass will outstrip wild herbivore control as human activities increase elemental nutrient supply, with widespread consequences for grazing and fire risk.

Soil net nitrogen mineralisation across global grasslands.

Soil nitrogen mineralisation (Nmin), the conversion of organic into inorganic N, is important for productivity and nutrient cycling. The balance between mineralisation and immobilisation (net Nmin) varies with soil properties and climate. However, because most global-scale assessments of net Nmin are laboratory-based, its regulation under field-conditions and implications for real-world soil functioning remain uncertain. Here, we explore the drivers of realised (field) and potential (laboratory) soil net Nmin across 30 grasslands worldwide. We find that realised Nmin is largely explained by temperature of the wettest quarter, microbial biomass, clay content and bulk density. Potential Nmin only weakly correlates with realised Nmin, but contributes to explain realised net Nmin when combined with soil and climatic variables. We provide novel insights of global realised soil net Nmin and show that potential soil net Nmin data available in the literature could be parameterised with soil and climate data to better predict realised Nmin.

Changing headache from preschool age to puberty. A controlled study.

The characteristics of disturbing primary headache and the occurrence of headache types were studied by sending a questionnaire to 1132 Finnish families of 6-year-old children. Children with headache in the preceding 6 months and their controls were clinically examined at the ages of 6 and 13. During the follow-up, half of the headaches, classified as migraine at age 6 years, were unchanged and 32% turned into tension-type headache. In children with tension-type headache, the situation was unchanged in 35%, and in 38% of children the headache type had changed to migraine. At preschool age the most common location of headache was bilateral and supraorbital, and at puberty bilateral and temporal. During the follow-up, symptoms concurrent with headache, such as odour phobia, dizziness and balance disturbances became more typical, whereas restlessness, flushing and abdominal symptoms became less marked. The early manifestation of both migraine and tension-type headache predict equally often migraine in puberty with marked changes in concurrent symptoms and pain localization.

Pharmacological characterization and CNS effects of a novel highly selective alpha2C-adrenoceptor antagonist JP-1302.

BACKGROUND AND PURPOSE: Pharmacological validation of novel functions for the alpha2A-, alpha2B-, and alpha2C-adrenoceptor (AR) subtypes has been hampered by the limited specificity and subtype-selectivity of available ligands. The current study describes a novel highly selective alpha2C-adrenoceptor antagonist, JP-1302 (acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine). EXPERIMENTAL APPROACH: Standard in vitro binding and antagonism assays were employed to demonstrate the alpha2C-AR specificity of JP-1302. In addition, JP-1302 was tested in the forced swimming test (FST) and the prepulse-inhibition of startle reflex (PPI) model because mice with genetically altered alpha2C-adrenoceptors have previously been shown to exhibit different reactivity in these tests when compared to wild-type controls. KEY RESULTS: JP-1302 displayed antagonism potencies (KB values) of 1,500, 2,200 and 16 nM at the human alpha2A-, alpha2B-, and alpha2C-adrenoceptor subtypes, respectively. JP-1302 produced antidepressant and antipsychotic-like effects, i.e. it effectively reduced immobility in the FST and reversed the phencyclidine-induced PPI deficit. Unlike the alpha2-subtype non-selective antagonist atipamezole, JP-1302 was not able to antagonize alpha2-agonist-induced sedation (measured as inhibition of spontaneous locomotor activity), hypothermia, alpha2-agonist-induced mydriasis or inhibition of vas deferens contractions, effects that have been generally attributed to the alpha2A-adrenoceptor subtype. In contrast to JP-1302, atipamezole did not antagonize the PCP-induced prepulse-inhibition deficit. CONCLUSIONS AND IMPLICATIONS: The results provide further support for the hypothesis that specific antagonism of the alpha2C-adrenoceptor may have therapeutic potential as a novel mechanism for the treatment of neuropsychiatric disorders.

Increased pulse pressure is associated with reduced baroreflex sensitivity.

Although pulse pressure (PP), heart rate variability (HRV) and baroreflex sensitivity (BRS) have been shown to predict cardiovascular events and mortality in various populations, their relationships have not been clarified. We examined these associations in two separate population-based samples of healthy middle-aged subjects. In population 1, data were obtained from 149 subjects (71 men and 78 women) aged 35-64 (mean 47.7) years, and in population 2, from 214 subjects (88 men and 126 women) aged 40-62 (mean 50.5) years. Increased 24-h ambulatory PP was related to decreased cross-spectral BRS independent of age and gender (beta=-0.28, P<0.001 for population 1; beta=-0.22, P=0.003 for population 2). This association remained significant when 24-h ambulatory diastolic blood pressure, body mass index, smoking and alcohol intake were added as covariates in the multivariate analysis. Increased ambulatory PP was also associated with increased beat-to-beat systolic arterial pressure variability. Associations between ambulatory PP and HRV were not significant after controlling for age and gender. Our results suggest that elevated PP does not affect overall HRV, but it interferes with baroreflex-mediated control of the heart rate. This association may be due to a common denominator, such as arterial stiffness, for PP and BRS.

Reduced heart rate variability in hypertension: associations with lifestyle factors and plasma renin activity.

Limited information exists on the relations between heart rate variability, hypertension, lifestyle factors and renin-angiotensin-aldosterone system. A total of 191 newly diagnosed yet untreated hypertensive men and women, 35-54 years of age, were compared with an age- and gender-stratified random population sample of 105 normotensive men and women to find out independent determinants of heart rate variability. Heart rate variability was computed from 5-min ECG time series using the standard deviation of normal-to-normal RR intervals (SDNN), the square root of the mean of squared differences between adjacent normal RR intervals (RMSSD) and the fast Fourier transform spectral analysis. All absolute measures of heart rate variability were reduced in hypertension (P<0.001 for each, ANOVA). In multivariate regression analyses, reduced heart rate variability was independently associated with higher heart rate (P<0.001 for all absolute measures of heart rate variability), higher age (P=0.001 for SDNN, total and LF powers; P<0.001 for RMSSD and HF power) and higher mean arterial pressure (P<0.05 for total power, P<0.01 for the other absolute measures) but not with sodium and alcohol intakes, body mass index and smoking. Increased plasma renin activity (PRA) was an independent attributor of reduced HF power (P<0.05) and reduced RMSSD (P<0.01). Increased blood pressure and heart rate are associated with decreased heart rate variability without any direct effects on heart rate variability of lifestyle factors. High PRA is an independent determinant of diminished modulation of vagal activity.

Changes in headache prevalence between pre-school and pre-pubertal ages.

The prevalence rates of headache in first-born children were determined at the ages of 6 and 12 years in over 1000 families. A headache questionnaire was mailed to 1132 families when the children were 6 years old, and to 1126 families when the children were 12 years old. Seven hundred and ninety-eight families responded to both questionnaires. The prevalence of headache before the 6 months preceding the questionnaire ('previous headache') was 19% when the children were 6 years of age and 31% when the children were 12 years of age. The corresponding prevalences of headache during the 6 months immediately proceeding the questionnaire ('present headache') were 16% and 19%. Variation in occurrence of headache was high during follow-up years. Maternal frequent headache (> or = 1/month) was significantly associated with the increase in prevalence of present headache in boys between the ages of 6 and 12 years. Frequent headache in mothers, fathers and siblings, and the occurrence of chronic illness, were also significantly associated with headache in the 12-year-old children.

Hyaluronic acid in incision wound fluid: a clinical study with the Cellstick device in children.

When inserted into a human incision wound, the Cellstick device harvests inflammatory cells and collects wound fluid, reflecting time-related changes in cell populations and in wound fluid composition. Hyaluronic acid has been postulated to be an important factor in scar reduction in wound healing and in scarless fetal wound healing. The aim of this work was to determine the concentration and variation of hyaluronic acid and proportions of wound cells in closed surgical wounds in children at two time points. The Cellstick device was inserted subcutaneously into the wound at the end of an elective inguinal hernia operation on 37 healthy boys, and the devices were removed 3+/-1 or 24+/-3 hours after surgery. Haluronic acid concentration was measured from the wound fluid and a differential count of the wound cells was performed. There was a significant decrease in hyaluronic acid concentration from 3+/-1 to 24+/-3 hours after surgery (p<0.001, Kruskal-Wallis anova). The variance of hyaluronic acid concentration in wound fluid differed between the wounds at the two time points (p<0.01, Levene test for homogeneity of variance). A positive correlation between hyaluronic acid concentration and patient age (r=0.91, p<0.05, Spearman) at 3+/-1 hours post surgery and between HA and wound lymphocytes (r=0.38, p<0.05, Spearman) was also found. We conclude that the hyaluronic acid concentration in wound fluid peaks early in children and decreases significantly by 3 to 24 hours after surgery, and the concentrations in the wound fluid of healthy boys are more variable 3 hours than at 24 hours after surgery.

Expression of estrogen receptor (ER) in oral mucosa and salivary glands.

OBJECTIVES: To assess the expression of estrogen receptor (ER) in oral mucosa and salivary glands, buccal mucosal biopsies from ten postmenopausal women (taken before and during the hormone replacement therapy), as well as, single biopsies from 20 healthy 19-year-old women were analyzed for ER expression. Salivary gland biopsies were taken from the minor labial salivary glands (n=6), submandibular glands (n=5) and parotid gland (n=1) from women at different ages. METHODS: total RNA extracted from the tissue samples was reverse-transcripted (RT) to single-stranded cDNA, and the RT-polymerase chain reaction (RT-PCR) product was subjected to nucleotide sequencing to confirm the match with ER cDNA. Immunohistochemistry (IHC) with a monoclonal ER antibody (ER-ICA, Abbott) and Western blot analysis with monoclonal antibody against ER-related antigen (ER-D5, Amersham) were performed on the biopsies taken from the postmenopausal women. RESULTS: ER mRNA was expressed in 18/20 (90%) and 20/20 (100%) of the mucosal biopsies in the postmenopausal and 19-year-old women, respectively. The expression of mRNA was detected in all the submandibular gland samples, in the single parotid gland, as well as, in 4/6 (67%) of the labial glands. ER expression could not be detected by IHC, indicating either a very low level of expressed protein or difficulties in recognizing the epitopes by IHC. However, Western blot demonstrated 8/8 (100%) of the mucosal biopsies of postmenopausal women positive for ER-related antigen. CONCLUSIONS: the presence of ER mRNA and immunoreactive ER protein suggests that estrogens have a biological role in oral mucosa and salivary glands.

The effect of hormone replacement therapy on salivary calcium concentrations in menopausal women.

Hormone replacement therapy in menopausal women is known to affect the general calcium turnover of the body. No information is available about the effects of hormone therapy on salivary electrolytes and on calcium in particular. A group of 16 healthy peri- and postmenopausal women, all recommended to start hormone replacement therapy, were studied longitudinally for 5 months. Paraffin-stimulated whole saliva was collected at baseline, at 3 and at 5 months after the onset of therapy, and analysed for calcium, sodium and potassium concentrations. In response to hormone replacement therapy, calcium concentration decreased (p = 0.037), that of sodium increased (p = 0.019), while no change was observed in the potassium concentrations during the follow-up period.

The effects of a specific alpha(2)-adrenoceptor antagonist, atipamezole, on cognitive performance and brain neurochemistry in aged Fisher 344 rats.

The present experiments investigated the effects of a specific and potent alpha(2)-adrenoceptor antagonist, atipamezole, on cognitive performance and neurochemistry in aged rats. Aged control Fisher 344 rats, which had lower activities of choline acetyltransferase in the frontal cortex, were impaired in the acquisition of the linear arm maze task both in terms of repetition errors and their behavioural activity (the speed of arm visits), and they needed longer time to complete this task as compared to adult control rats. Atipamezole treatment (0.3 mg/kg) facilitated the acquisition of this task in the aged rats as they committed fewer errors and completed the task more quickly than saline-treated aged control rats. A separate experiment indicated that atipamezole enhanced the turnover of noradrenaline both in the adult and aged rats, but this effect was more pronounced in the aged rats. Furthermore, atipamezole enhanced significantly the turnover of serotonin and dopamine only in the aged rats when analysed in the whole brain samples. As alpha(2)-adrenoceptor antagonists are known to alleviate akinesia in the experimental models of Parkinson's disease, the present results could be especially relevant for the development of palliative treatment for demented Parkinsonian patients.

Antinociceptive and hemodynamic effects of a novel alpha2-adrenergic agonist, MPV-2426, in sheep.

BACKGROUND: alpha2-Adrenergic agonists produce analgesia primarily by a spinal action and hypotension and bradycardia by actions at several sites. Clonidine is approved for epidural use in the treatment of neuropathic pain, but its wider application is limited by hemodynamic side effects. This study determined the antinociceptive and hemodynamic effects of a novel alpha2-adrenergic agonist, MPV-2426, in sheep. METHODS: Forty sheep of mixed Western breeds with indwelling catheters were studied. In separate studies, antinociception to a mechanical stimulus, hemodynamic effects, arterial blood gas tensions, cerebrospinal fluid pharmacokinetics, and spinal cord blood flow was determined after epidural, intrathecal, and intravenous injection of MPV-2426. RESULTS: MPV-2426 produced antinociception with greater potency intrathecally (ED50 = 49 microg) than epidurally (ED50 = 202 microg), whereas intravenous administration had no effect. Intrathecal injection, in doses up to three times the ED95, failed to decrease systemic or central arterial blood pressures or heart rate, whereas larger doses, regardless of route, increased systemic arterial pressure. Bioavailability in cerebrospinal fluid was 7% after epidural administration and 0.17% after intravenous administration. Intrathecal MPV-2426, in an ED95 dose and three times this dose, produced a dose-independent reduction in thoracic and lumbar spinal cord blood flow. CONCLUSIONS: MPV-2426 shares many characteristics of other alpha2-adrenergic agonists examined in sheep, but differs from clonidine and dexmedetomidine by lack of antinociception and minimal reduction in oxygen partial pressure after large intravenous and epidural injections. No hemodynamic depression was observed after intrathecal injection at antinociceptive doses. These results suggest this compound may be an effective spinal analgesic in humans with less hypotension than clonidine, although its relative potency to cause sedation was not tested in this study.

Oral ulcers in AIDS patients frequently associated with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections.

Oral ulcers are common in AIDS patients, with a wide spectrum of underlying causes, including different viruses. In the present study, the presence of cytomegalovirus (CMV), Epstein-Barr virus (EBV) and human herpesvirus-8 (HHV-8) DNA was analysed in 21 biopsies from oral ulcers of 17 male homosexual AIDS patients. The methods used were in situ hybridization (ISH) and the polymerase chain reaction (PCR) with subsequent non-radioactive Southern blot hybridization to confirm the specificity of PCR products. With ISH, 4 biopsies were CMV DNA-positive and 11 contained EBV-DNA. Using PCR, an additional 4 CMV- and 7 EBV-positive samples were detected, and HHV-8 DNA was present in three oral ulcers. Six of the patients (35%) had oral ulcers co-infected by two or three viruses. The overall figures for patients with the detectable EBV-, CMV-, and HHV-8 DNA were 82% (14/17), 35% (6/17) and 18% (3/17), respectively. This is the first study to show the frequent presence of EBV-DNA in oral ulcers of AIDS patients. Because ISH-positivity signifies active virus replication, these results implicate an etiological role of EBV in AIDS-associated oral ulcers. The causal role of HHV-8 has to be considered as well, because this virus was detected in three such ulcers, which were not associated with Kaposi's sarcoma. To conclude, three common members of the herpesvirus family (CMV, EBV, HHV-8) were detected in all but three ulcers in AIDS patients, warranting the inclusion of these viral analyses in the diagnosis of ulcerative lesions of the oral mucosa in all immunosuppressed individuals.

Neurocognitive sequelae of scaphocephaly.

OBJECTIVE: Early cranioplasty for scaphocephaly has become routine in most countries. In addition to normalizing the shape of the skull, it has been found to decrease intracranial hypertension. Whether corrective surgery benefits the child's cognitive outcome has been poorly documented. DESIGN: Eighteen children whose sagittal suture showed premature fusion at birth or soon thereafter were operated on at age 1 week to 7 months. All patients healed without complications and were followed-up at regular intervals. At the age of 7.8 to 16.3 years they were examined to clarify their neurocognitive development and to compare the results with their age- and gender-matched healthy controls. RESULTS: Originally scaphocephalic children, although operated on, had mild deficiencies in auditory short-term memory and language development when examined with the general comprehension, similarities, and digit span subscales of the Wechsler Intelligence Scale for Children-Revised. In all other respects their developmental outcome was equal to that of the controls. CONCLUSIONS: Despite relative early correction of the skull shape, originally scaphocephalic children's neurocognitive performances do not reach the same level in all of the neurocognitive domains as their matched controls at school age. Early operation (

Comparison of the effects of acute and subchronic administration of atipamezole on reaction to novelty and active avoidance learning in rats.

The effects of an alpha2-adrenoceptor antagonist, atipamezole, on exploratory behaviour in a novel environment, spontaneous motor activity and active avoidance learning were studied after acute injection and continuous infusion (0.1 mg/kg h) for 24 h and 6-9 days in rats. The effects of atipamezole on biogenic amines and their main metabolites in brain were studied after an acute injection (0.3 mg/kg s.c.) and continuous infusion (0.1 mg/kg h) for 24 h and 10 days. The level of central alpha2-adrenoceptor antagonism and the drug concentration in blood and in the brain were measured after continuous infusion for 24 h and 10 days. In behavioural tests, atipamezole had no effect on spontaneous motor activity at any of the doses studied. However, after both acute administration and continuous 24-h infusion, atipamezole decreased exploratory behaviour in a staircase test, but no longer after 6 days of continuous infusion. Acute administration of atipamezole impaired performance in active avoidance learning tests causing a learned helplessness-like behaviour. When the training was started after 7 days of continuous infusion, atipamezole significantly improved active avoidance learning. There was a significant increase in the metabolite of noradrenaline (NA), 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO4), after 24 h but not any longer after 10 days of continuous atipamezole infusion, although the extent of central alpha2-adrenoceptor antagonism was unchanged and the atipamezole concentration present in brain was even elevated at 10 days compared to levels after 24-h infusion. In conclusion, these results reveal that acute and subchronic atipamezole treatments have different and even opposite effects on behaviour in novel, stressful situations. After acute treatment, atipamezole potentiates reaction to novelty and stress, causing a decrease in exploratory activity and impairment in shock avoidance learning. After subchronic treatment, there was no longer any effect on exploratory behaviour and, in fact, there was an improvement in the learning of a mildly stressful active avoidance test. The changes in behaviour occurred in parallel with attenuation in the MHPG-SO4-increasing effect, thus the suppressed behaviour in the present test conditions after acute atipamezole injection is associated with a major increase in central NA release. The results support the role of alpha2-adrenoceptors and noradrenergic system in reactions both to novelty and stress and have possible implications in cognitive functions as well as in depression.

The effect of repeated sampling on paraffin-stimulated salivary flow rates in menopausal women.

Paraffin-stimulated whole-saliva samples of 12 post- and perimenopausal women were taken five times over a 7-week period. After 1 min of prestimulation, saliva was collected for 5 min under standardized conditions. Saliva was first collected on three consecutive days, and two additional samples were collected 6 and 7 weeks after the first. Salivary flow rates showed significant variation between samplings. The greatest difference appeared between the first and second collections. The increase in flow rates between these collections was significant (p = 0.003). The third successive collection also gave a significantly (p = 0.005) higher flow rate than the first. The 6-week and baseline samples were similar. The 7-week sample showed a significantly higher flow rate (p = 0.018) compared with the baseline value. These results stress the importance of standardization of sampling intervals when salivary flow rates are studied.

Protean agonism at alpha2A-adrenoceptors.

The coupling of the endogenously expressed alpha2A-adrenoceptors in human erythroleukemia cells (HEL 92.1.7) to Ca2+ mobilization and inhibition of forskolin-stimulated cAMP production was investigated. The two enantiomers of medetomidine [(+/-)-[4-(1-[2, 3-dimethylphenyl]ethyl)-1H-imidazole]HCl] produced opposite responses. Dexmedetomidine behaved as an agonist in both assays (i.e. , it caused Ca2+ mobilization and depressed forskolin-stimulated cAMP production). Levomedetomidine, which is a weak agonist in some test systems, reduced intracellular Ca2+ levels and further increased forskolin-stimulated cAMP production and therefore can be classified as an inverse agonist. A neutral ligand, MPV-2088, antagonized responses to both ligands. Several other, chemically diverse alpha2-adrenergic ligands also were tested. Ligands that could promote increases in Ca2+ levels and inhibition of cAMP production could be classified as full or partial agonists. Their effects could be blocked by the alpha2-adrenoceptor antagonist rauwolscine and by pertussis toxin treatment. Some typical antagonists such as rauwolscine, idazoxan, and atipamezole had inverse agonist activity like levomedetomidine. The results suggest that the alpha2A-adrenoceptors in HEL 92.1.7 cells exist in a precoupled state with pertussis toxin-sensitive G proteins, resulting in a constitutive mobilization of intracellular Ca2+ and inhibition of cAMP production in the absence of agonist. This constitutive activity can be antagonized by inverse agonists such as levomedetomidine and rauwolscine. Levomedetomidine can be termed a "protean agonist" because it is capable of activating uncoupled alpha2-adrenoceptors in other systems and inhibiting the constitutive activity of precoupled alpha2-adrenoceptors in HEL 92.1. 7 cells. With this class of compounds, the inherent receptor "tone" could be adjusted, which should provide a new therapeutic principle in receptor dysfunction.