Effectiveness of proprotein convertase subtilisin/kexin‐9 monoclonal antibody treatment on plasma lipoprotein(a) concentrations in patients with elevated lipoprotein(a) attending a clinic

BackgroundLipoprotein(a) (Lp[a]) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Proprotein convertase subtilisin/kexin‐9 monoclonal antibodies (PCSK9mAbs) can lower Lp(a) levels in clinical trials, but their effects in patients with elevated Lp(a) in clinical practice remain unclear.AimsTo investigate the effectiveness and safety of PCSK9mAbs in lowering plasma Lp(a) in patients with elevated Lp(a) concentrations in a lipid clinic.MethodsThis was an open‐label study of 53 adult patients with elevated Lp(a) concentration (≥0.5 g/L). Clinical, biochemical, and safety data were collected before and on treatment with evolocumab or alirocumab over a mean period of 11 months.ResultsTreatment with a PCSK9mAb resulted in a significant reduction of 0.29 g/L (−22%) in plasma Lp(a) concentration (p<.001). There were also significant reductions in low‐density lipoprotein‐cholesterol (LDL‐C) (−53%), remnant‐cholesterol (−12%) and apolipoprotein B (−43%) concentrations. The change in Lp(a) concentration was significantly different from a comparable group of 35 patients with elevated Lp(a) who were not treated with a PCSK9mAb (−22% vs. −2%, p<.001). The reduction in Lp(a) concentration was not associated with the corresponding changes in LDL‐C, remnant‐cholesterol, and apolipoprotein B (p>.05 in all). 7.5% and 47% of the patients attained a target concentration of Lp(a) <0.5 g/L and LDL‐C <1.8 mmol/L, respectively. PCSK9mAbs were well tolerated, the common adverse effects being pharyngitis (9.4%), nasal congestion (7.6%), myalgia (9.4%), diarrhoea (7.6%), arthralgia (9.4%) and injection site reactions (11%).ConclusionPCSK9mAbs can effectively and safely lower plasma Lp(a) concentrations in patients with elevated Lp(a) in clinical practice; the impact of the fall in Lp(a) on ASCVD outcomes requires further investigation.     

Effects of 5-hydroxytryptamine uptake blockers on the concentration in brain of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in male rats, pro-oestrous rats and ovariectomized rats treated with oestrogen and progesterone

The aim of this study was to determine the effect of 5-hydroxytryptamine (5-HT) uptake blockade on 5-HT turnover by measuring the concentrations of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in brain with the aid of high performance liquid chromatography and electrochemical detection. The indoleamines were measured in the anterior hypothalamus (AH), posterior hypothalamus (PH) and raphe nuclei 30 min after the i.v. injection of either alaproclate (30 mg/kg) or zimelidine (20 mg/kg). The effect of alaproclate was studied in male rats, pro-oestrous female rats, rats ovariectomized and injected s.c. with 20 micrograms oestradiol benzoate (OB) on dioestrus and at 12.00 h of the next day (presumptive pro-oestrus) with 2 mg progesterone (model 1) and rats ovariectomized 3-4 weeks before an s.c. injection of 20 micrograms OB followed 72 h later by an s.c. injection of 2 mg progesterone (model 2). Alaproclate caused a significant decrease in the 5-HIAA/5-HT ratio in the AH and PH of the brain of male rats, in the PH and raphe nuclei in pro-oestrous rats and model 1, and in the raphe nuclei alone in model 2. Zimelidine had no effect on the 5-HIAA/5-HT ratio in any area in model 2. In male rats the injection of parachlorophenylalanine produced a marked reduction in the brain concentrations of 5-HT and 5-HIAA, but the 5-HIAA/5-HT ratio was unchanged by a subsequent injection of alaproclate. None of the pharmacological agents affected significantly the brain concentrations of noradrenaline, dopamine or dihydroxyphenylacetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Steroid levels and steroid metabolism in relation to early gonadal development in the tilapia Oreochromis niloticus (Teleostei: cyprinoidei)

Sex steroid levels and steroid metabolism were investigated in relation to early gonadal development in a mixed sex population of the tilapia Oreochromis niloticus. Androstenedione (AD), testosterone (T), 11-ketotestosterone (KT), and estradiol (E2) were quantified by radioimmunoassay (RIA) of whole body extracts. Androstenedione metabolism was assessed by incubations in vitro with 3H-AD and metabolites were identified by thin-layer chromatography coupled with radioisotope image analysis. Histology revealed the presence of gonadal structures at 15 days postfertilization (dpf) and ovaries at 36 dpf, with other individuals exhibiting undifferentiated gonads containing germinal cells, presumably eventual testes. Androgen levels were initially high in eggs then decreased severalfold prior to the emergence of gonads. A transient increase in the levels of T and KT occurred at 22 dpf. Levels of E2 were either low or undetectable except for a transient increase (43 dpf) after ovaries were present. Levels of T approached bimodality from 57 to 64 dpf. Steroid metabolism generally increased throughout development. Metabolites were generally similar, consisting of T predominantly as well as 5beta-reduced androgen derivatives and 11-oyxgenated derivatives. Estriol was tentatively identified. Conjugated steroids were not formed. Two types of steroid metabolic profiles occurred at 50 dpf. These results demonstrate that changes in the steroidogenic profile occur during early transitions of gonadal development. Notably, (1) steroid biosynthetic capacity preceeds gonadal differentiation, (2) evidence for estrogens occurs after ovarian development has begun, and (3) bimodality of levels of T and differential steroid metabolism later in development may reflect the onset of sexual divergence.     

Regional differences in cardiovascular risk factor prevalence in Tasmania: are they consistent with the increased cardiovascular mortality?

Background: The death rate from cardiovascular disease in Tasmania has been among the highest in Australian States for a number of years. The North-West (NW) and Northern regions of Tasmania account for most of the increased mortality.
Aims: To determine the prevalence of cardiovascular risk factors in the North and NW regions of Tasmania and to ascertain whether any differences are consistent with the regional patterns of mortality for ischaemic heart disease (IHD) within the State.
Methods: The design of the study was almost identical to the previous National Heart Foundation (NHF) Risk Factor Prevalence Survey conducted in 1989. The subjects, aged 20–69 years, were randomly selected from the Electoral Roll with 1146 subjects participating in the North and 1219 in the NW. Subjects answered a detailed questionnaire and then underwent a brief physical examination with venipuncture for blood lipids. Hobart data from the NHF Risk Factor Prevalence Survey in 1989 were used as an estimate of risk factor prevalence in the Southern region.
Results: In both males and females, mean systolic blood pressure was significantly higher in the NW than the South which was in turn higher than the North. Mean serum cholesterol levels in males were higher in the NW than the North. Smoking behaviour was similar in males and females in all regions. Males and females in the NW and North were more inactive than those in the South. Similar proportions in all regions were on either 'no specific' or 'fat modified' diets. Body mass index in males and females was higher in the NW and North but waist to hip ratios failed to show a consistent trend.
Conclusions: While the NW has an unfavourable risk factor profile compared with the South, the North does not. The risk factor data are broadly consistent with, but unlikely to be sufficient to explain fully, the regional differences in mortality from IHD. (Aust NZ J Med 1995; 25: 290–296.)     

Pragmatic language interpretation after closed head injury: Relationship to executive functioning

Introduction: Closed head injury is associated with impairment in a range of executive skills, and with everyday difficulties in social interactions. Comprehension of pragmatic language plays an important role in social interactions. The present study was designed to examine performance on a task involving pragmatic judgement in people who had suffered closed head injury (CHI), and the relationship between this and any impairments in executive skills. Methods: Participants with CHI were compared to a matched healthy control group on a pragmatic inference task consisting of a series of brief vignettes. Participants made judgements about alternative responses in relation to social appropriateness/skill, and carried out several nonsocial executive tasks thought to play a role in pragmatic judgement. Results: The CHI group was poorer than the control group on the pragmatic measure, showing less discrimination than the control group between direct, literal interpretations and correct, indirect interpretations. They also performed more poorly on the nonsocial executive measures. Regression analysis showed an association between pragmatic performance and one of the executive tasks, a measure of inhibition. Conclusions: More work is needed to explore further the nature of any relationship between pragmatic judgement and executive skills.