Outbreak of Coxsackievirus A-14 Meningitis among Newborns in a Maternity Hospital Ward

ABSTRACT. During the late winter of 1983, 16 newborns with vague symptoms of failure to thrive, reluctance to feed and a slight rise in body temperature, were found to have meningitis caused by Coxsackievirus A-14. The cerebrospinal fluid showed pleocytosis with polymorphonuclear cells in excess but was otherwise normal. The clinical course was uneventful in all infants, but two of them demonstrated clinical signs of incipient cerebral oedema during the acute phase of the illness. An electroencephalogram (EEG) during the initial course of the disease and at nine months of age was normal in all. During a follow-up period of 21/2 years they all developed normally and no sequelae were noted. The presentation also demonstrates the usefulness of Vero cells for the propagation of the responsible virus.     

Angiotensin-(1–7) stimulates water transport in rat inner medullary collecting duct: evidence for involvement of vasopressin V2 receptors

The peptide angiotensin-(1–7) [Ang-(1–7)] is known to enhance water transport in rat inner medullary collecting duct (IMCD). The aim of this study was to determine the mechanism of the Ang-(1–7) effect on osmotic water permeability (P _f). P _f was measured in the normal rat IMCD perfused in vitro in presence of agonists [Ang-(1–7), arginine vasopressin (AVP) and Ang-(3–8)], and antagonists of the angiotensin and the vasopressin cascade. Ang-(1–7), but not Ang-(3–8), increased P _f significantly. The effect of Ang-(1–7) on P _f was abolished by its selective antagonist, A-779, added before or after Ang-(1–7). Prostaglandin E₂ and the protein kinase A inhibitor H8 also blocked the Ang-(1–7) effect. Blockade of vasopressin V₁ receptors by antagonists did not change the Ang-(1–7) effect, but pre-treatment with a V₂ antagonist abolished the effect of Ang-(1–7) on P _f. Similarly, pre-treatment with A-779 inhibited AVPs effect on P _f. Forskolin-stimulated P _f was blocked both by A-779 and by the V₂ antagonist. Finally, Ang-(1–7) increased cAMP levels in fresh IMCD cell suspensions whilst the forskolin-stimulated cAMP synthesis was decreased by A-779 and the V₂ antagonist. These data provide evidence that Ang-(1–7) interacts via its receptor with the AVP V₂ system through a mechanism involving adenylate-cyclase activation.     

Presence of autoantibodies to apolipoprotein A-1 in patients with acute coronary syndrome further links autoimmunity to cardiovascular disease

Anti-apolipoprotein A-1 (Apo A-1) autoantibodies were described in autoimmune disorders such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) and might be involved in the genesis of arterial and venous thrombotic events. To investigate the presence of these autoantibodies in patients with acute coronary syndrome (ACS) without other features of autoimmunity, we set up an enzyme-linked immunosorbent assay (ELISA) for anti-Apo A-1 antibodies. We used it to investigate their prevalence in ACS as compared to SLE and APS and correlated them to plasma Apo A-1 and serum amyloid A protein (SAA) concentrations. The prevalence of anti-Apo A-1 autoantibodies in the healthy control group was 1% (1/92), but was significantly higher in other groups: 21% (11/53) in ACS group (P=0.001), 13% (12/92) in SLE and/or APS group (P=0.005). Multiple linear regression revealed a significant correlation between plasma Apo A-1 (r=-0.72, P=0.013), plasma SAA concentration (r=0.76, P=0.0066) and anti-Apo A-1 IgG titre in ACS patients. The presence of anti-Apo A-1 autoantibodies in patients with ACS highlights an additional link between autoimmunity, inflammation and atherosclerosis.     

Chromosomal changes in bovine papillomavirus type 1-induced Syrian hamster tumors

Bovine papillomavirus type 1 (BPV-1) induced fibrosarcomas in the Syrian hamster were studied cytogenetically by G- and C-banding techniques. All tumor derived cells showed chromosome abnormalities that remained stable during serial tumor transplantations. Cells without chromosome abnormalities found in two cultures were derived from the host animals on account of heterochromatin polymorphisms. In most tumors pseudodiploid cells prevailed, some cells were hypodiploid lacking one or two chromosomes, and one tumor showed two hyperdiploid cell clones with one and three additional chromosomes, respectively. Some of the chromosome abnormalities apparently are nonrandom. Three chromosomes (#1, #4, and #15) were most frequently involved in aberrations.     

Additive cytotoxicity of adriamycin and a naturally occurring growth inhibitor extracted from bovine aorta

A factor of nominal molecular weight 6K–10K Daltons, isolated from bovine aorta, has previously been shown to inhibit neovascularization and tumor growth in vivo and the growth of some tumor cells as well as endothelial cells in culture. This factor, termed A-10, was tested alone and in combination with Adriamycin against TA3Ha mammary adenocarcinoma cells in tissue culture. It was found to have cytotoxicity additive to that of Adriamycin in inhibiting the growth of these cells. In vitro and animal studies show that the sequence of Adriamycin A-10 is superior to either agent alone in delaying the appearance of palpable tumors after subcutaneous injection of 10⁵ pre-treated tumor cells in the tail of strain A mice. While the growth rate of the primary tumor was not affected by such treatment, survival was prolonged to a greater degree by the this sequence than by either of these agents used alone. A-10 treatment reduced the number of metastases to the adrenal gland but not to lung, liver, or lymph nodes. It did, however, reduce the size of metastases to para-aortic lymph nodes.     

The relationship between plasma apolipoprotein A-Ⅳ levels and coronary heart disease

Objective To evaluate the relationship between plasma apoA-Ⅳ levels and coronary atheros clerosis and to explore its relation to other risk factors.Methods Using ELISA techniques, plasma apoA-Ⅳ levels were quantified in 181 patients w ho underwent coronary angiography (CAG).Patients were divided according to the ir coronary status into a coronary heart disease (CHD) group (stenotic lesion on CAG, n=118) and a control group (normal CAG, n=63).The severity of athero sclerosis was assessed by stenosis scoring of the different lesions.Other para meters, including apoA-Ⅰ,apoB, Lp(a), HDL-C, LDL-C, TG, and T C, were measured as well.Univariate, logistic regression analyses were used to define the relationship between coronary atherosclerosis and plasma apoA-Ⅳ levels.Results When compared with the control group, plasma apoA-Ⅳ levels were found to be lo wer in the CHD group.There was a weak negative correlation between plasma apoA -Ⅳ levels and the severity of coronary atherosclerosis.ApoA-Ⅳ was found to be a relatively independent risk factor for CHD.We also found a positive corr elation between apoA-Ⅳ and triglyceride levels.Conclusions ApoA-Ⅳ may be important in the prediction of CHD and coronary atherosclerosis severity.It may also play an important role in the metabolism of triglycerides .     

Pharmacological characterization of an α1A-adrenoceptor mediating contractile responses to noradrenaline in isolated caudal artery of rat

1. The α₁-adrenoceptor population mediating contraction of caudal artery of rat has been characterized by using quantitative receptor pharmacology.
2. Cumulative concentration-effect (E/[A]) curves to noradrenaline (NA) yielded a p[A]₅₀ of 5.56±0.05 (n=16). Prazosin caused concentration-dependent, parallel, dextral shifts of E/[A] curves to NA yielding a pK_b of 8.9 (Schild regression slope=1.0). RS-17053 (N-[2-(2-cyclopropyl methoxy phenoxy) ethyl]-5-chloro-α ,α-dimethyl -1H-indole- 3-ethanamine hydrochloride; 10–100 nM), a selective α_1A-adrenoceptor antagonist, produced non-parallel, biphasic, dextral shifts of E/[A] curves to NA, suggesting the involvement of more than one α₁-adrenoceptor subtype. Analysis of the high affinity component yielded an apparent pA₂ value of 9.2±0.3.
3. A-61603, a selective agonist at α_1A adrenoceptors behaved as a full agonist relative to NA and yielded monophasic E/[A] curves with a p[A₅₀] of 7.59±0.04 (n=15). Pretreatment of tissues with chloroethylclonidine (CEC; 100 μM for 20 min, followed by 40 min washout), which preferentially alkylates α_1B- and α_1D-adrenoceptors, did not alter E/[A] curves to A-61603. Prazosin (3–300 nM) caused concentration-dependent, parallel, dextral shifts of E/[A] curves to A-61603 yielding a pA₂ estimate of 9.2±0.2.
4. Experiments with α₁-adrenoceptor antagonists of varying subtype selectivities (RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739) revealed parallel dextral shifts of E/[A] curves to A-61603. Schild regression analyses yielded pA₂ estimates of 9.2, 9.3, 11.2, 9.0, 6.3, 8.7 and 10.0 for RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739, respectively, although deviations from unit slope (possibly reflecting a secondary involvement of another α₁-adrenoceptor) hindered estimations of pK_b for some antagonists. The antagonist affinity profile obtained reflects best that described for the α_1A-adrenoceptor.
5. In conclusion, caudal artery of rat contracts in response to NA via activation of at least two α₁-adrenoceptor subtypes. One of these subtypes displays the pharmacology of the α_1A-adrenoceptor, while the other remains to be defined. Use of the novel selective agonist, A-61603, allows for limited pharmacological isolation of the α_1A-adrenoceptor permitting characterization of the properties of selective antagonists.

     

Overactive bladder treatments in early phase clinical trials

‘Overactive bladder’ (OAB) is a syndrome that is characterised by symptoms of urgency, with or without urge urinary incontinence, usually with frequency and nocturia . It is a highly prevalent condition affecting 17% of the general population, with a significant negative effect on quality of life, impairing several areas with physical, social, emotional and sexual limitations. The prevalence of OAB increases with age in both men and women . The pathophysiology is multifactorial and not yet fully understood. Non-surgical treatment is the mainstay of therapy for OAB. The available options include biofeedback, electrical stimulation, bladder training, pharmacotherapy or a combination of these options. Nevertheless pharmacotherapy is still the treatment of choice for OAB symptoms . The pharmacological treatment of OAB is generally directed towards the central or the peripheral neural control pathways or the detrusor muscle . The antimuscarinic drugs are the most commonly used. In the US, approved antimuscarinics include oxybutynin, tolterodine, trospium chloride, solifenacin and darifenacin. Although this class of drugs has been shown to be more effective than placebo in specific meta-analyses , it has been reported that ≤ 80% of the patients discontinue the treatment within 6 months, mainly for the low drug compliance due to the high incidence of side effects . Therefore, there is a strong need to identify drugs with novel mechanisms of action, which could provide equal or even better efficacy and overall greater acceptability than antimuscarinic drugs. At present, several other specific molecular targets identified within detrusor muscle and/or neural systems are under investigation for the development of more specific treatments of OAB. This article provides an up-to date review of drugs that are in investigational preclinical and early stage (Phase I and II) clinical trials for the treatment of OAB.