Egg size and composition in an ageing capital breeder – consequences for offspring performance

1. Egg size is often used as a proxy of egg quality although size and composition may vary, e.g. in insects egg size usually decreases as female ages. Whether this decrease in size reflects reduced concentrations of essential nutrients such as lipids and proteins of eggs laid by ageing females, or does reduced size per se explain often observed lower fitness of later laid eggs is poorly explored. 2. Egg properties were compared with fitness parameters of offspring laid on the first and fourth night during the oviposition period of a capital breeding moth, Cleorodes lichenaria (Hufnagel). The study aim was to explore whether decreased egg size is caused by decreased provisioning into later laid eggs measured as egg protein and lipid concentration, and whether it results in lower fitness of later laid offspring. 3. The fresh and dry weight of eggs decreased over the oviposition period, but the protein and lipid concentration remained constant. Survival of larvae was lower among the fourth night laid offspring on a low quality host Parmelia sulcata Taylor compared to a high quality host Ramalina fraxinea (L.) Ach. No differences were observed in egg fertility or hatchability, neonate survival without food and pupal mass between the offspring produced on different nights. 4. Decreased survival of offspring produced later was rather attributable to absolute provisioning (i.e. lower weight of eggs) than relative provisioning (i.e. decreased concentrations of nutrients in eggs). It is argued that lower survival of later laid smaller eggs on low quality diet is likely attributable to physical and chemical characteristics of host lichens and/or physical properties of tiny neonate larvae.     

Inhibitors of epidermal growth factor receptor tyrosine kinase: optimisation of potency and in vivo pharmacokinetics

The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.     

Indications for admission to a coronary care unit in patients with unstable angina.

One hundred cases with an admission diagnosis of acute coronary insufficiency or unstable angina were reviewed to establish criteria for admission to a coronary care unit. Myocardial infarction was subsequently diagnosed in 20 of the patients. Ventricular tachycardia occurred in 16 patients and ventricular fibrillation in 1 patient. Clinical features found to predict an increased risk of myocardial infarction included chest pain for more than 30 minutes within 24 hours prior to admission, new nonspecific electrocardiographic abnormalities consistent with ischemia, and diaphoresis. All patients with ventricular tachydysrhythmias had presented with both prolonged chest pain prior to admission and new electrocardiographic changes. The sensitivity, specificity and predictive value of various clinical criteria for identifying patients likely to have a myocardial infarction were calculated, and criteria with very high (greater than 90%) sensitivity were identified. These could be used to establish which patients are at increased risk of myocardial infarction and therefore require admission to a coronary care unit.     

Dipetalonema viteae infection in hamsters: enhancement and suppression of microfilaraemia

Mature male Dipetalonema viteae released a substance(s) which caused enhanced microfilaraemia in infected hamsters. In hamsters implanted with female D. viteae, the microfilaraemia of a subsequent infection was suppressed. The microfilaraemia of female worms implanted in hamsters was depressed within 5 days when the animals were given a further infection with infective larvae.     

Calcium metabolism in adult outpatients with epilepsy receiving long-term anticonvulsant therapy

Long-term anticonvulsant drug therapy may lead to abnormalities of calcium metabolism resulting in osteomalacia. The prevalence and severity of altered calcium metabolism was studied in an adult outpatient population of persons with epilepsy receiving anticonvulsant therapy for a minimum of 2 years. Assessment of calcium metabolism was based on serum concentrations of calcium, phosphorus, alkaline phosphatase and 25-hydroxycholecalciferol and of plasma parathyroid hormone, intestinal absorption of isotopic calcium and skeletal bone mineral mass as determined by in vivo neutron activation or x-ray photodensitometry.Thirty-nine patients who had been receiving anticonvulsant therapy for an average of 20 years were studied; none had clinical evidence of metabolic bone disease. Decreased serum calcium concentration was noted in 10%, decreased serum phosphorus concentration in 10% and elevated serum alkaline phosphatase concentration in 44%. The mean serum 25-hydroxycholecalciferol concentration was significantly lower (P < 0.001) than in a control group (11.6 v. 19.6 mg/mL). None of 18 patients studied had an increased plasma concentration of parathyroid hormone, and only 1 of 17 patients had decreased intestinal absorption of isotopic calcium. Bone mineral mass was decreased in 44% of 32 patients studied.It was concluded that long-term treatment with anticonvulsant drugs leads to mild abnormalities of calcium metabolism and decreased bone mineral mass in a substantial percentage of adult outpatients with epilepsy. These abnormalities probably predispose the patients to the development of clinically significant metabolic bone disease.     

Demonstration of a novel ecto-enzyme on human erythrocytes, capable of degrading ADP and of inhibiting ADP-induced platelet aggregation

The role of ADP as an important inducer of platelet aggregation is generally accepted. Therefore it has been postulated by many authors that the enzymatic removal of extracellular ADP from the circulation is essential to avoid platelet aggregation and thrombus formation. Here we show that erythrocytes essentially contribute to the clearance of ADP. The removal of ADP from suspensions of washed human erythrocytes was due to at least two different activities. One activity, which had already been observed by earlier workers, was identified as adenylate kinase, on the basis of the reaction products and the inhibition by adenosine(5')pentaphospho(5')adenosine (Ap5A). This enzyme was not associated with the cells and was always detectable in cell-free supernatants, indicating that the enzyme had leaked from the cells into the extracellular medium. In contrast, the second activity, which is described here for the first time, was tightly bound to the cells. The activity was not inhibited by Ap5A. The main product of the reaction was AMP, and enzyme activity depended on the presence of divalent cations. The Michaelis constant was about 28 mumol/l. This activity seemed to be an ecto-ADPase. Studies with various inhibitors revealed that degradation of ADP was not due to a non-specific phosphatase. Besides the well known ADPase on the endothelium, the ecto-activity on erythrocytes may play an important part in destroying pro-aggregatory ADP.     

Approach to drug therapy for hypertension.

Prevention of complications of hypertension requires the lowering of blood pressure. The therapeutic goal is to achieve and maintain a diastolic pressure of less than 90 mm Hg with minimal adverse effects. The treatment of patients with established diastolic blood pressures between 90 and 104 mm Hg (determined from three separate readings) should be individualized; general measures such as weight loss and salt restriction should be tried first as an alternative to drug therapy. Patients with diastolic pressure in excess of 104 mm Hg should be treated with antihypertensive drugs; the first step should be the use of a thiazide diuretic in addition to general measures. Patients with diastolic pressures of 90 to 115 mm Hg may require the addition of a beta-adrenergic-receptor antagonist, methyldopa or clonidine if the therapeutic goal is not achieved; rarely they require the further addition of hydralazine or prazosin. Patients with diastolic pressures of 116 to 129 mm Hg usually require initially both a thiazide diuretic and a beta-blocker, methyldopa or clonidine; if the therapeutic goal is not achieved, hydralazine or prazosin is added, and if a further hypotensive effect is required guanethidine can be added. Patients with severe hypertension (diastolic pressures greater than 130 mm Hg) may require urgent treatment with combinations of drugs of all three levels. Emphasis should be placed on individualized therapy and patient compliance in the assessment of therapeutic failures. These "step-care" guidlines represent a framework for antihypertensive therapy devised from information available in 1977. It is not a rigid scheme and should be adjusted to the individual patient to ensure as normal a life as possible.     

Aberrant post‐translational modifications compromise human myosin motor function in old age

Novel experimental methods, including a modified single fiber in vitro motility assay, X‐ray diffraction experiments, and mass spectrometry analyses, have been performed to unravel the molecular events underlying the aging‐related impairment in human skeletal muscle function at the motor protein level. The effects of old age on the function of specific myosin isoforms extracted from single human muscle fiber segments, demonstrated a significant slowing of motility speed (P < 0.001) in old age in both type I and IIa myosin heavy chain (MyHC) isoforms. The force‐generating capacity of the type I and IIa MyHC isoforms was, on the other hand, not affected by old age. Similar effects were also observed when the myosin molecules extracted from muscle fibers were exposed to oxidative stress. X‐ray diffraction experiments did not show any myofilament lattice spacing changes, but unraveled a more disordered filament organization in old age as shown by the greater widths of the 1, 0 equatorial reflections. Mass spectrometry (MS) analyses revealed eight age‐specific myosin post‐translational modifications (PTMs), in which two were located in the motor domain (carbonylation of Pro79 and Asn81) and six in the tail region (carbonylation of Asp900, Asp904, and Arg908; methylation of Glu1166; deamidation of Gln1164 and Asn1168). However, PTMs in the motor domain were only observed in the IIx MyHC isoform, suggesting PTMs in the rod region contributed to the observed disordering of myosin filaments and the slowing of motility speed. Hence, interventions that would specifically target these PTMs are warranted to reverse myosin dysfunction in old age.     

Human monocyte derived dendritic cells express functional P2X and P2Y receptors as well as ecto-nucleotidases

We investigated the expression and function of P2 receptors and ecto-nucleotidases on human monocyte derived dendritic cells (DC). In addition we analyzed the effect of extracellular ATP on the maturation of DC. By RT-PCR, DC were found to express mRNA for several P2X (P2X1, P2X4, P2X5, P2X7) and P2Y (P2Y1, P2Y2, P2Y4, P2Y5, P2Y6, P2Y10, P2Y11) receptors. As shown by FURA-2 measurement, triggering of P2 receptors resulted in an increase in free intracellular Ca2+. In combination with Tumor necrosis factor-alpha, ATP increased the expression of the DC surface markers CD80, CD83 and CD86 indicating a maturation promoting effect. DC expressed the ecto-apyrase CD39 and the ecto-5'-nucleotidase CD73 as demonstrated by RT-PCR. Extracellular ATP was rapidly hydrolyzed by these ecto-enzymes as shown by separation of 3H-labeled ATP metabolites using a thin layer technique. These data suggest that ATP acts as a costimulatory factor on DC maturation.     

Novel nevirapine-like inhibitors with improved activity against NNRTI-resistant HIV: 8-heteroarylthiomethyldipyridodiazepinone derivatives

A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes.