The pre-vaccination epidemiology of measles, mumps and rubella in Europe: implications for modelling studies

Data on the pre-vaccination patterns of infection for measles, mumps and rubella are collated from a number of European countries in order to compare the epidemiology of the three viruses. Key epidemiological parameters, such as the age-specific force of infection and the basic reproduction number (R0) are estimated from case notification or serological data using standard techniques. A method is described to compare force of infection estimates derived from serological data. Analysis suggests that the pre-vaccination patterns of measles and mumps infection in the different countries were similar. In contrast, the epidemiology of rubella was highly variable between countries. This suggests that it may be acceptable to use parameter values estimated from other countries to model measles and mumps transmission, but that this approach to modelling rubella transmission requires more caution. Estimates of R0 depend on underlying mixing assumptions. Constraints were placed on R0 estimates by utilising knowledge of likely mixing patterns. The estimates for R0 were highest for measles, intermediate for mumps, and generally lowest for rubella. Analysis of within- and between-age-group transmission rates suggested that mumps transmission tends to be more concentrated within young children than the other two viruses. The implications for the design of immunization programmes are that mumps may be the easiest to control via infant immunization since it is predominantly transmitted between the very young and the variability in rubella epidemiology requires that careful consideration of the possible effects of vaccination options should be made using local data when planning rubella immunization programmes.     

Modelling the impact of immunization on the epidemiology of varicella zoster virus

The objective of this study was to develop and apply a dynamic mathematical model of VZV transmission to predict the effect of different vaccination strategies on the age-specific incidence and outcome of infection. To do so a deterministic realistic age-structured model (RAS) was used which takes account of the increased potential for transmission within school aged groups. Various vaccine efficacy scenarios, vaccine coverages and vaccination strategies were investigated and a sensitivity analysis of varicella incidence predictions to important parameters was performed. The model predicts that the overall (natural and breakthrough) incidence and morbidity of varicella would likely be reduced by mass vaccination of 12-month-old children. Furthermore, adding a catch-up campaign in the first year for 1-11 year olds seems to be the most effective strategy to reduce both varicella incidence and morbidity (in the short and long term), though with the possible detrimental effect of increasing the incidence of zoster.     

Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanding CAG repeat coding for polyglutamine in the huntingtin protein. Recent data have suggested the possibility that an N-terminal fragment of huntingtin may aggregate in neurons of patients with HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus, forming intranuclear neuronal inclusion bodies. An animal model of HD using the short N-terminal fragment of huntingtin has also been found to have intranuclear inclusions and this same fragment can aggregate in vitro . We have now developed a cell culture model demonstrating that N-terminal fragments of huntingtin with expanded glutamine repeats aggregate both in the cytoplasm and in the nucleus. Neuroblastoma cells transiently transfected with full-length huntingtin constructs with either a normal or expanded repeat had diffuse cytoplasmic localization of the protein. In contrast, cells transfected with truncated N-terminal fragments showed aggregation only if the glutamine repeat was expanded. The aggregates were often ubiquitinated. The shorter truncated product appeared to form more aggregates in the nucleus. Cells transfected with the expanded repeat construct but not the normal repeat construct showed enhanced toxicity to the apoptosis- inducing agent staurosporine. These data indicate that N-terminal truncated fragments of huntingtin with expanded glutamine repeats can aggregate in cells in culture and that this aggregation can be toxic to cells. This model will be useful for future experiments to test mechanisms of aggregation and toxicity and potentially for testing experimental therapeutic interventions.      

Effect of octreotide on gastric and small bowel motility in patients with gastroparesis

Background:

Octreotide has been shown to have effects on gastric and small bowel motility with implications for its role in treating patients with upper gastrointestinal dysmotility syndromes. Our aim was to investigate the effect of octreotide on antral and small bowel motility in patients with gastroparesis.

Methods:

Upper gastrointestinal manometry was carried out continuously for a period of 30 h in 11 patients with gastroparesis. The spontaneous migrating motor complex (MMC) in the fasting state and octreotide-induced MMCs were characterized and compared with regard to site of origin, duration of phase III, amplitude of phase III and propagation velocity of the MMC along the gut. The 2-h postprandial motility index was compared after a control meal as well as after a 100 μg octreotide administration.

Results:

In all 11 gastroparetic patients, octreotide induced a phase III-like activity front within minutes after administration and this primarily originated in the small bowel (86% of activity fronts compared with 32% of fronts originating in the small bowel prior to octreotide administration (P < 0.004)). Gastric initiation of these activity fronts dramatically decreased after octreotide administration, occurring in 68% of activity fronts prior to octreotide administration and 14% of occasions after octreotide injection (P < 0.05). The postprandial antral motility index was markedly reduced after octreotide administration (11.33 ± 0.39 vs. 7.96 ± 0.76, P < 0.0003) and octreotide re-established a motility pattern during the postprandial period that was similar to that normally seen in the interdigestive state. The octreotide-induced phase III activity fronts appeared at a higher frequency and had a higher propagative velocity compared to the spontaneous phase III fronts in the fasting state (9.27 ± 0.82 vs. 5.56 ± 0.81 cm/min, P < 0.05).

Conclusions:

We conclude that octreotide’s marked inhibitory effect on antral contractility may serve to worsen clinical symptoms in patients with gastroparesis and therefore this agent should not be given in the peri-prandial period. Those gastroparetic patients with associated small bowel dysmotility and diarrhoea from bacterial overgrowth may benefit from the nocturnal administration of octreotide because of its stimulatory effect of phase III MMC activity as well as its known inhibitory effect on small bowel secretions.

     

Effects of tumour necrosis factor-α on the coronary circulation of the rat isolated perfused heart: a potential role for thromboxane A2 and sphingosine

1. The actions of tumour necrosis factor-α (TNF-α) on the coronary circulation were investigated in the rat isolated heart, perfused under constant flow, recirculating conditions.
2. An early increase in coronary perfusion pressure (CPP) was observed upon treatment with TNF-α (increase in CPP 10 min after TNF-α treatment: 45±12 mmHg vs control: 15±4 mmHg, P<0.05). The role of sphingosine, prostanoids and endothelins, in this coronary constrictor action, was investigated with the use of pharmacological inhibitors and antagonists.
3. The TNF-α induced increase in coronary tone was blocked by indomethacin, 10 μM (increase in CPP after 10 min: 13±4 mmHg vs TNF-α alone, P<0.05).
4. The thromboxane receptor antagonist GR32191, 10 μM, attenuated the TNF-α induced coronary constriction (12±2 mmHg vs TNF-α alone, P<0.05), as did the joint thromboxane A₂ synthesis inhibitor and receptor antagonist ZD1542, 10 μM (8±1 mmHg vs TNF-α alone, P<0.05).
5. The ceramidase inhibitor N-oleoylethanolamine (NOE), 1 μM, also blocked the TNF-α induced response (8±4 mmHg vs TNF-α alone, P<0.05).
6. In contrast, the coronary constrictor action of TNF-α was not inhibited by the endothelin_A/B receptor antagonist bosentan, 3 μM (38±9 mmHg vs TNF-α, P=NS).
7. These data indicated that the early coronary vasoconstriction induced by TNF-α was mediated by both thromboxane A₂ and sphingosine, suggesting an interaction between both the sphingomyelinase and phospholipase A₂ metabolic pathways.

     

Low dose of cyproterone acetate and testosterone enanthate for contraception in men

After a control phase, 10 normal men received cyproterone acetate (CPA) at a dose of 25 mg/day (CPA-25; n=5) or 12.5 mg/day (CPA-12.5; n=5) plus testosterone enanthate (TE) 100 mg/week, for 16 weeks. Throughout the study sperm counts were performed every 2 weeks, and luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone, biochemical and haematological tests were performed every 4 weeks. All five men in group CPA-25 and three men in group CPA-12.5 achieved azoospermia. One man in group CPA-25 was azoospermic by week 12 of hormone administration, but had a sperm count of 0.1 x 10(6)/ml at week 16. Time to azoospermia was 9.0+/-1.3 and 8.7+/-0.7 weeks in groups CPA- 25 and CPA-12.5 respectively. Gonadotrophins were decreased by week 4 of hormone administration, remained around the minimum detectability of the assay for the duration of hormone administration and returned to baseline after stopping hormone administration. Testosterone values did not change. No change in any biochemical parameters was found. Haematological parameters were decreased at week 16 of hormone administration and returned to baseline after stopping hormone administration. In conclusion, these results suggest that an hormonal regimen consisting of testosterone plus a progestin with anti- androgenic properties holds promise as an effective, safe and reversible male contraceptive.      

Does nitric oxide allow endothelial cells to sense hypoxia and mediate hypoxic vasodilatation?in vivo and in vitro studies

Hypoxia-evoked vasodilatation is a fundamental regulatory mechanism that is often attributed to adenosine. The identity of the O₂ sensor is unknown. Nitric oxide (NO) inhibits endothelial mitochondrial respiration and ATP generation by competing with O₂ for its binding site on cytochrome oxidase. We proposed that in vivo this interaction allows endothelial cells to release adenosine when O₂ tension falls or NO concentration increases. Using anaesthetised rats, we confirmed that the increase in femoral vascular conductance (FVC, hindlimb vasodilatation) evoked by systemic hypoxia is attenuated by NO synthesis blockade with l -NAME, but restored when baseline FVC is restored by infusion of NO donor. This 'restored' hypoxic response, like the control hypoxic response, is inhibited by the adenosine A₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Similarly, the FVC increase evoked by adenosine infusion was attenuated by l -NAME but restored by infusion of NO donor. However, when baseline FVC was restored after l -NAME with 8-bromo-cGMP, the FVC increase evoked by adenosine infusion was restored, but not in response to systemic hypoxia, suggesting that adenosine was no longer released by hypoxia. Infusion of NO donor at a given rate after treatment with l -NAME evoked a greater FVC increase during systemic hypoxia than during normoxia, both responses being reduced by 8-cyclopentyl-1,3-dipropylxanthine. Finally, both bradykinin and NO donor released adenosine from superfused endothelial cells in vitro ; l -NAME attenuated only the former response. We propose that in vivo , shear-released NO increases the apparent K _m of endothelial cytochrome oxidase for O₂, allowing the endothelium to act as an O₂ sensor, releasing adenosine in response to moderate falls in O₂.     

The cost of integrating hepatitis B virus vaccine into national immunization programmes: a case study from Addis Ababa

National programmes of hepatitis B virus (HBV) vaccination are recommended by the World Health Organization for all countries. Countries suffering the highest burden of HBV disease are those most needy of universal vaccination, but are frequently of very low income and resources for health care are scarce. The introduction of HBV vaccination would inevitably stretch these resources further even with support of donor agencies. Thus an assessment of the cost-effectiveness of HBV vaccination is desirable to assist in decision making about resource allocation. We describe here a method for estimating the additional costs of introducing HBV vaccination into the Expanded Programme on Immunization (EPI) at a national level. Of fundamental importance is that this method enables costs to be assessed prior to the introduction of vaccination. We illustrate the method using a study carried out at the sub-national level, in the city of Addis Ababa, Ethiopia, but which can be expanded countrywide. The method, in brief, involved the use of a number of questionnaires which could be used to estimate the costs associated with the EPI programme from a large sample of the static clinics as well as from central sources. Since unit costs were collected along with the quantities of resources used and estimates of the capacity used for certain facilities (such as refrigerators), the additional cost of introducing HBV vaccine could be estimated largely by extrapolation of the resources used in vaccinating against diphtheria/pertussis/tetanus vaccine (which, similar to HBV vaccine, requires three doses). The estimation of costs is only part of the information required to make decisions on resource allocation, and should be used in association with measures of the burden of disease due to the infection in the community and effectiveness of the control programme at reducing this burden. The prediction of the latter, based upon a sound epidemiological understanding of the infection, is the subject of a forthcoming paper.