Thresholds of biodiversity and ecosystem function in a forest ecosystem undergoing dieback.

Ecological thresholds, which represent points of rapid change in ecological properties, are of major scientific and societal concern. However, very little research has focused on empirically testing the occurrence of thresholds in temperate terrestrial ecosystems. To address this knowledge gap, we tested whether a number of biodiversity, ecosystem functions and ecosystem condition metrics exhibited thresholds in response to a gradient of forest dieback, measured as changes in basal area of living trees relative to areas that lacked recent dieback. The gradient of dieback was sampled using 12 replicate study areas in a temperate forest ecosystem. Our results provide novel evidence of several thresholds in biodiversity (namely species richness of ectomycorrhizal fungi, epiphytic lichen and ground flora); for ecological condition (e.g. sward height, palatable seedling abundance) and a single threshold for ecosystem function (i.e. soil respiration rate). Mechanisms for these thresholds are explored. As climate-induced forest dieback is increasing worldwide, both in scale and speed, these results imply that threshold responses may become increasingly widespread.

Chemical fluxes in time through forest ecosystems in the UK - soil response to pollution recovery.

Long term trend analysis of bulk precipitation, throughfall and soil solution elemental fluxes from 12 years monitoring at 10 ICP Level II forest sites in the UK reveal coherent national chemical trends indicating recovery from sulphur deposition and acidification. Soil solution pH increased and sulphate and aluminium decreased at most sites. Trends in nitrogen were variable and dependant on its form. Dissolved organic nitrogen increased in bulk precipitation, throughfall and soil solution at most sites. Nitrate in soil solution declined at sites receiving high nitrogen deposition. Increase in soil dissolved organic carbon was detected - a response to pollution recovery, changes in soil temperature and/or increased microbial activity. An increase of sodium and chloride was evident - a possible result of more frequent storm events at exposed sites. The intensive and integrated nature of monitoring enables the relationships between climate/pollutant exposure and chemical/biological response in forestry to be explored.

Occurrence and distribution of polycyclic aromatic hydrocarbons in the Egyptian aquatic environment.

Persistent organic pollutants (POPs) such as polycyclic aromatic hydrocarbons (PAHs) are of great concern due to their persistence, bioaccumulation and toxic effects. In this study, water samples were collected during 2007-2008 from two catchment areas that represent two different models of the aquatic environment in Egypt (Rosetta branch as fresh water and El-Moheet drain as untreated/treated waste water). The distribution of 16 PAHs included in the US Environmental Protection Agency's (EPA) priority pollutant list was analyzed by gas chromatography/mass spectrometry (GC/MS). Total PAH concentrations varied from 242 to 732 ng/L in fresh water from the Rosetta branch with a mean value of 408 ng/L; and for waste water the concentrations were in the range 894 to 1979 ng/L with a mean value of 1476 ng/L. The PAH profiles were dominated by low molecular weight PAHs (two- and three-ring components) in all collected water samples. The origin of PAHs in both waste water and fresh water in these study areas may be from oil or sewage contamination. The total PAHs concentrations of untreated waste water decreased along the treatment process by about 30% at the Zenein waste water treatment plant. The levels of PAHs in waste water are relatively high, although lower than locations with known problems.

Cetirizine dihydrochloride interaction with some diclofenac complexes.

IR, 1H NMR and mass spectrometric studies showed that cetirizine dihydrochloride interacted strongly with diclofenac sodium, even when the latter was metal bound, forming high molecular weight stable adducts. These new formations were unaffected by the possible steric constraints that may exist because of coordination yet did not have the power to break the formed coordinate bonds. The formed ionic bond took place between the carbonyl ion of diclofenac and the positively charged piperazine ring of cetirizine, forming a ternary compound in the case of the divalent metal clusters (Ca{(dic)2.2H2O}, Mg{(dic)2.2H2O}, Zn{(dic)2.2H2O}) and a quaternary one with the trivalent iron cluster (Fe{dic}3.3H2O). IR bands assigned to nuNH, deltaNH and nuC-N were shifted to lower frequency values in the spectra of the complexes; thus showing that coordination took place at the NH of the diphenylamine. TG and elemental analysis confirmed these results.

Drug-drug interaction between diclofenac, cetirizine and ranitidine.

The interactions between diclofenac (1), cetirizine (2) and ranitidine (3) were investigated by thermal analyses and UV, IR and (1)H NMR spectroscopic studies. In aqueous solution interaction occurred only between 1 and 2, yielding a high molecular weight (1:1), water insoluble ionic salt. Weak charge transfer (CT) interaction exists between the doubly charged piperazine moiety in 2, acting as an electron acceptor and (1). This CT interaction originates from the aromatic groups in 1. The CT band observed at approximately 315 nm exhibits very low absorbance as a result of the partial neutralization of the two positive charges present in the ionic salt. The IR bands of the mixture have wave numbers at nu 3323.1, 1695.3, and delta 1321.1-1210 cm(-1) indicating the presence of the NH group and the neutralized carbonyl group of 1, as well as the carboxylic group of 2. The 1,2,3-substitutions in the benzene ring of 1 in the mixture appear at 1161.1 cm(-1). The (1)H NMR of the mixed drugs shows singlet, triplet and multiplet proton signals due to the same effect.

Struvite urolithiasis in a B6C3F1 mouse.

In a 2 year carcinogenicity bioassay using B6C3F1 mice, one male mouse developed clinical signs near termination of the study, comprising skin sores around the prepuce, penile prolapse and urine scalding. The predominant finding at necropsy was a markedly distended urinary bladder filled with numerous crystallized particles. Microscopically, there was subacute cystitis with marked hyperplasia of the transitional epithelium. X-ray diffraction analysis of the crystals showed a diffraction pattern characteristic of struvite (ammonium magnesium phosphate). The implications of the spontaneous occurrence of bladder stones in rodents on long-term toxicology studies are discussed.

Spontaneous fibro-osseous proliferative lesions in the sternums and femurs of B6C3F1 mice.

Bone morphology associated with fibro-osseous proliferation in the femurs and sternums of 98 female B6C3F1 mice were compared morphologically and quantitatively to femurs and sternums from 100 male B6C3F1 and 79 CF1 mice (48 female and 31 male). In addition, sternal samples from five B6C3F1 mice per sex were collected and processed for electron microscopy. Fibro-osseous proliferation was present in female B6C3F1 mice, but not male B6C3F1 or female CF1 mice. In female B6C3F1 mice at 32 weeks of age, the marrow spaces in the region of the proximal and distal epiphyseal plate were lined by large osteoblasts and had large vascularized centers. At 58 weeks, metaphyseal fibrovascular proliferative areas containing multinucleated cells and new cancellous bone delineating the lesion were seen. At 84 weeks, fibro-osseous tissue occupied the outer third of the sternal marrow cavity and by 110 weeks, more than two thirds of the marrow cavity. Fibro-osseous proliferation was present in 100 and 94% of the examined sternums and femurs, respectively, of female B6C3F1 mice at 110 weeks of age, but not in male B6C3F1 or female CF1 mice. Ultrastructural examination of the sternal changes at 110 weeks showed numerous osteoblasts, irregular bony spicules, and fibrocyte-like cells. By morphometry, the normal marrow cavity in B6C3F1 females occupied 35% of a longitudinal section of the whole sternebra compared with 70% and 75% of the whole sternebra in B6C3F1 males and CF1 female, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Preclinical toxicity studies of an adenosine agonist, N-(2,2-diphenylethyl) adenosine.

N-(2,2-Diphenylethyl)adenosine (DPEA) has been identified as a potential antipsychotic agent acting via stimulation of adenosine receptors. The projected human therapeutic dose, based on animal studies, is 2-3 mg/kg. DPEA has been tested for potential toxicity in mice, rats, dogs and monkeys. Following single oral doses, median lethal dose values were approximately 10-fold greater in rats than in mice, although similar clinical signs including reduced activity, prostration, and necrosis of the tail were seen in both species. DPEA was well tolerated at daily doses up to 40 mg/kg in rats for 2 weeks. A no observed effect level (NOEL) was not identified in the dog or monkey studies. Reduced activity, dacryorrhea, ptosis, hypothermia, necrosis of the tail, and death occurred in rats given 120 and 160 mg/kg. Pathologic changes consisted of pancreatitis, gastric erosion/ulceration, lymphocyte depletion of the thymus, and pulmonary congestion and hemorrhage at 80 mg/kg or greater. In dogs, sporadic emesis was noted at 12.5 mg/kg and greater, and significant pathologic changes consisted of coronary arteritis associated with myocardial lesions and lymphocyte depletion at 25 and 50 mg/kg, pancreatic acinar necrosis at 50 mg/kg, and renal tubular degeneration at 12.5 mg/kg and greater. Emesis and depression were noted at 25 and 50 mg/kg in monkeys. Renal tubular dilatation and degeneration at 25 and 50 mg/kg were noted in the monkeys. These studies demonstrated that DPEA produced a range of adverse effects in common laboratory animal species.

Preclinical toxicology of the anticonvulsant calcium valproate.

The oral toxicity of the anticonvulsant calcium valproate with selected comparisons to valproic acid and sodium valproate was evaluated in mice, rats and Beagle dogs. Median lethal doses of the three forms of valproate in rodents ranged from 1100 to 3900 mg/kg. Clinical signs in acute studies and reductions in body weight or body weight gain and food consumption at high doses in rats and dogs during 2-, 13- and 52-week studies were considered to be central nervous system related. In the 13-week study in rats (calcium valproate at 200, 400, 800, 1200 and 1600 mg/kg and sodium valproate at 1200 mg/kg), reduced plasma globulin levels and low white blood cell counts due to suppressed neutrophil maturation were noted at doses of 800 mg/kg and higher. Platelet counts were reduced at 1200 and 1600 mg/kg. Testicular atrophy occurred at 1200 and 1600 mg/kg. In dogs given calcium valproate at 100, 200 and 400 mg/kg for 13 weeks, testicular atrophy was seen at 400 mg/kg and mild hepatocellular changes at all doses. In rats given calcium valproate at 125, 250 and 500 mg/kg for 1 year, reduced plasma protein and globulin levels and a dose-dependent increased incidence and severity of atrophic pancreatitis were noted at 250 and 500 mg/kg. Calcium valproate, given for 1 year to dogs at doses of 50, 100 and 200 mg/kg, was well tolerated. These studies indicated that calcium valproate has a toxicity profile similar to other forms of valproate.

Auricular chondritis in Wistar rats.

The macroscopic and microscopic features of auricular chondritis in Wistar rats are described. Histologic lesions are characterized by granulomatous inflammation, chondrolysis, and multinodular proliferative foci. The condition in Wistar rats is compared to auricular chondritis in other strains of rats.

Renal and hepatic toxicity of a benzopyran-4-one in the Cynomolgus monkey.

The administration of PD 119819, a novel benzopyran-4-one brain dopamine autoreceptor agonist, to Cynomolgus monkeys was followed by deposition of needle-like drug crystals in the bile canaliculi, hepatocytes, proximal renal tubules and renal parenchyma. The crystals were associated with a granulomatous inflammation, and histological and biochemical evidence of hepatic and renal cell damage. Although metabolism differences may be the reason why primates, but not rodents, developed these changes, this form of crystallization appeared to be primarily a result of the insolubility of PD 119189 at alkaline pH.

Polyarteritis in a beagle.

A 13-month-old Beagle became anorectic and had fever, stiff gait, and tenderness in the inguinal region. Clinical signs of disease were associated with neutrophilia and a decrease in the albumin-to-globulin ratio. The dog became clinically normal for 5 days after 3 days of treatment with penicillin G and dihydrostreptomycin. Clinical signs of disease recurred, and the dog was euthanatized after failing to respond to administration of a trimethoprim-sulfamethoxazole combination for 9 days. Disseminated arteritis was seen in the testes, epididymides, mesentery, coronary arteries, aorta, and thyroid gland. Lesions were seen in large and medium-sized arteries and varied from acute necrotizing arteries to a chronic lesion with organization and recanalization of thrombi. The clinical signs of disease resembled those of Beagle pain syndrome, described in laboratory Beagles.

Chronic toxicity of the anticonvulsant zonisamide in beagle dogs.

The chronic toxicity of the new anticonvulsant drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was evaluated in a detailed 52-week study in which dose levels of 0, 10, 30 and 75 mg/kg/day were administered orally in gelatin capsules to groups of five Beagle dogs per sex. Potential toxicity was based on the effects of zonisamide on body weight and food consumption; clinical and ophthalmic examinations; electrocardiography and heart rates; clinical biochemistry, hematology and urinalysis determinations; organ weights and gross and histopathologic evaluations; electron microscopy of high dose and control male dogs; and plasma zonisamide concentrations. Zonisamide was relatively well tolerated during the study. In animals given 75 mg/kg/day, early body weight losses occurred and therefore, from Weeks 2 and 3 until study termination, for males and females respectively, the high dose was given as two equal portions (i.e., 37.5 mg/kg each) approximately 3-4 hr apart. Clinical laboratory analyses in the dogs given 75 mg/kg revealed a small but statistically significant decrease in plasma albumin concentration and a small increase in alkaline phosphatase activity. In animals given 75 mg/kg, liver weights were increased and a brownish discoloration of the liver was noted grossly at necropsy. No significant light microscopic changes were evident; however, electron microscopic evaluation of the liver tissue from the 5 male dogs given 75 mg/kg revealed the presence of concentric lamellae of paired smooth membranes which were not seen in control animals. At the 10 and 30 mg/kg dose levels, plasma zonisamide concentrations reached steady-state and were proportional to dose, but at 75 mg/kg, plasma levels were disproportionately higher and never achieved steady-state. The results of this study indicated that at the high dose level of 75 mg/kg, chronic administration of zonisamide had a mild effect on the liver, particularly the endoplasmic reticulum.

Parkinson-like syndrome in nonhuman primates receiving a tetrahydropyridine derivative.

Antipsychotic drugs, while ameliorating symptoms in schizophrenia, evoke extrapyramidal effects which resemble parkinsonism. We studied the potential of 1- (4,4-bis(4-fluorophenyl)butyl)-4-(4-fluorophenoxy)-1,2,3,6-tetrahydropyr idine d-tartrate to induce extrapyramidal side effects in Rhesus monkeys. This agent shares neurochemical effects of known antipsychotic agents in its ability to antagonize cerebral dopamine action by competing for (3H)-Haloperidol binding of the dopamine receptors and inhibiting limbic and striatal adenylate cyclase in rat brain. The compound was administered orally to monkeys for 18 days, starting at 2 mg/kg and increasing to 20 mg/kg. Additional groups of monkeys received the drug for 29 consecutive days at 5 and 7.5 mg/kg/day. In both studies, extrapyramidal signs were associated with neuropathological changes in the brains of treated monkeys. The findings resemble those reported in Rhesus monkeys and in drug addicts after repeated intravenous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The findings also suggest a structure/activity relationship of tetrahydropyridine analogs with neurologic and associated neuropathologic manifestations produced in monkeys. The experimental model is useful to study the pathogenesis and possibly therapeutic approaches for Parkinson's disease.

Morphologic and immunohistochemical features of two spontaneous peripheral nerve tumors in Wistar rats.

Morphologic features and S-100 protein immunoreactivity of a benign and malignant peripheral nerve sheath tumor were studied in two Wistar rats. Neoplasms that developed in untreated control rats from tumor bioassays were S-100 protein positive and had similar histopathologic features. Each peripheral nerve sheath tumor was encapsulated and composed of spindle cells arranged around small thin-walled blood vessels. Palisaded tumor cells were in the benign peripheral nerve sheath tumor while cells of the malignant peripheral nerve sheath tumor had cellular atypia and moderate numbers of mitoses. Ultrastructural examination of the malignant peripheral nerve sheath tumor revealed cells with external lamina and interdigitation of cytoplasmic processes. Intracytoplasmic concentric lamellae were seen; they were regularly spaced with a periodicity of about 15 nm. Such structures, indistinguishable from myelin sheaths, have not been commonly associated with peripheral nerve sheath tumors in man. Electron microscopy and immunohistochemistry were useful in the diagnosis of these tumors as Schwannomas and in differentiation from other spindle cell tumors.

Leukocyte and bone marrow effects of a thiomorpholine quinazosin antihypertensive agent.

PD-88823, a thiomorpholine analog of prazosin, induced a consistent dose-related suppression of granulopoiesis with subsequent neutropenia and leukopenia in rats and dogs. Rats treated at 600 mg kg-1 day-1 had neutrophil counts reduced by 44% in males and 30% in females after 13 weeks. A 4-week observation period after drug treatment resulted in a rebound in neutrophil counts to 123 and 215% of control values in males and females, respectively. White blood cell count reductions were less evident in dogs, probably because of the lower doses. In both species, the extent of bone marrow suppression was related to duration of treatment. No other hematologic changes were manifest in either species. The mechanism for bone marrow depression and subsequent granulocytopenia was not established. The lack of reported bone marrow effects by quinazosin analogs suggests that the thiomorpholine group of PD-88823 is involved in toxicity. This correlation may be important to safety considerations for future drug design.

Morphofunctional investigations on spontaneous pituitary tumors in Wistar rats.

Adenoma of the pituitary gland represents one of the commonest spontaneous tumors in strains of laboratory rats. In a retrospective survey of pituitary glands from 2165 albino Wistar rats, the total number of pituitary adenomas was 501, representing an overall incidence of 23% with females showing a higher incidence (32%) than males (13%). Pituitary adenoma was rare from 6-52 weeks of age and accounted for only 0.2% of the total incidence. The first pituitary tumors in this series were observed at 32 weeks in 2 female rats and at 40 weeks in a male rat. From 52-85 weeks of age, incidence remained low, and then increased progressively in animals that died from 85-110 weeks of age. In a series of 200 Wistar rats, detailed evaluation was completed for neoplastic and hyperplastic lesions of the pituitary gland. The immunocytochemical characteristics of the pituitary adenoma were investigated using markers for prolactin, growth hormone, and thyrotropic hormone. Positive immunoperoxidase staining revealed an incidence of 59% prolactinomas in both male and female rats. Forty-one percent of pituitary adenomas did not stain for prolactin, thyrotropic, or growth hormone and showed no specific morphologic differences from prolactinomas. The application of immunoperoxidase-staining techniques offers a useful tool for characterizing secretory activity of pituitary adenomas and evaluating histopathologic changes of the pituitary gland.

Histiocytic sarcoma in Wistar rats. A light microscopic, immunohistochemical, and ultrastructural study.

Histiocytic sarcoma, a recently described tumor entity in rats, was studied by light microscopy in 20 male and female Wistar rats. The tumors originated from subcutaneous tissues; metastasis involved primarily the liver with sinusoidal spread and the lungs with peribronchiolar distribution. The characteristic features of this tumor were the uniform population of tumor cells, palisading necrosis, and abundant multinucleated giant cells. Immunocytochemical and ultrastructural findings confirmed the histiocytic nature of the tumor cells.