Is It Time To Review The Vaccination Strategy To Protect Adults Against Invasive Pneumococcal Disease?

Pneumococcal conjugate vaccines (PCVs) have reduced the predominant serotypes causing invasive pneumococcal disease (IPD). We assessed the impact of the paediatric 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) among older adults. We compared serotype-specific incidence rates from 2007/08 to 2016/17, expressed as incidence rate ratios (IRR). Introducing PCV7 and PCV13 into the childhood immunisation programme resulted in a decline in these serotypes in adults ≥65 years of age, with PCV7 serotypes decreasing by 85% (IRR=0.11, 95%CI: 0.05-0.22, p<0.0001) and PCV13 serotypes not included in PCV7 (PCV13-7), decreasing by 9% (IRR=0.68, 95%CI: 0.40-1.16, p=0.134). However, there was a significant increase in serotypes only found in the 23-valent polysaccharide vaccine, PPV23-PCV13: IRR=2.57, 95%CI: 1.68-4.03, p<0.0001, and non-vaccine types (NVTs), IRR=3.33, 95%CI: 1.75-6.84, p=0.0001. The decline of IPD associated with PCV7/13 serotypes and the increase in PPV23-PCV13 serotypes indicates clear serotype replacement. Increasing PPV23 uptake could still reduce the burden of disease for this population.

The epidemiology of invasive pneumococcal disease in older adults in the post-PCV era. Has there been a herd effect?

The 7 and 13-valent pneumococcal conjugate vaccines (PCVs) have reduced the incidence of invasive pneumococcal disease (IPD) in children in many countries. The objective of this work was to assess the impact of PCVs and potential herd-protection in older adults in Ireland. IPD notification and typing data from adults ⩾65 years of age from July 2007 to June 2016 was assessed using national surveillance data. There was a 94% reduction in PCV7 serotypes from 2007-2008 to 2015-2016, incidence rate ratio (IRR 0·05, P < 0·0001). However, there was no decline in the additional PCV13 (PCV13-7) serotypes over the same period (IRR 0·90) nor in comparison with the pre-PCV13 period 2009-2010 (IRR 0·92). The incidence of serotypes in the 23-valent pneumococcal polysaccharide vaccine only (PPV23-PCV13) and non-vaccine types (NVTs) increased significantly (IRR 2·17, P = 0·0002 and IRR 3·43, P = 0·0001 respectively). Consequently, the overall IPD incidence rate in adults has remained relatively unchanged (from 28·66/100 000 to 28·88/100 000, IRR 1·01, P = 0·9477). Serotype 19A and NVTs were mainly responsible for penicillin resistance in recent years. The decline of PCV7 serotypes indicate that the introduction of PCV7 resulted in herd-protection for adults. However, increases in PPV23-PCV13 and NVTs suggest that changes in vaccination strategy amongst older adults are needed to build on the success of PCVs in children.

Exercise training effect on obstructive sleep apnea syndrome.

The role, if any, of exercise training in the management of individuals with obstructive sleep apnea syndrome (OSAS) is unclear. Anecdotally, patients have reported improvement in symptoms with regular participation in an exercise regime. In this study, we evaluated the effects of an exercise training program and weight loss on physical and subjective measures associated with OSAS. Nine subjects with mild to moderate OSAS completed a six month supervised exercise program. Pre and post-training measures on polysomnographic testing, physical training, anthropometric measures, quality of life (QOL), daytime somnolence and mood states were assessed. A significant decrease in the AHI (p=0.002) was noted along with improvements (p<0.05) in total sleep time, sleep efficiency, number of awakenings/hour, arousals/hour, apnea index and mean exercise training workloads. Significant decreases (p<.001) in weight (-6.2 kg) and body mass index (-1.6) were observed. Evaluation of QOL measures by the Health Status Questionnaire, Profile of Mood States and Epworth Sleepiness Scale showed significant changes in health status, affective state, and a decrease in daytime somnolence. Regular exercise training had a positive impact on the AHI, aerobic capacity, body mass index and QOL. However, exercise training alone was not an adequate intervention strategy for most individuals with OSAS but may serve well as an adjunct treatment strategy in the conservative management of individuals with mild to moderate OSAS.

A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension.

OBJECTIVE: To determine the best therapeutic strategy for the use of midodrine in patients with neurogenic orthostatic hypotension (NOH). BACKGROUND: Midodrine is a peripherally acting alpha-adrenergic agonist useful in the treatment of NOH. However, neither the most effective dosage of midodrine nor the required frequency of administration is established. DESIGN/METHODS: Midodrine dose-blood pressure response, pharmacokinetics, and duration of action were examined in a double-blind, placebo-controlled, four-way crossover trial. Twenty-five patients with NOH were randomized to receive on successive days placebo or midodrine 2.5, 10, or 20 mg. Blood pressures of patients in the supine and standing positions were measured sequentially. A global assessment of the patient's overall symptom improvement after each leg of the study was performed. Blood levels of midodrine and its active metabolite, desglymidodrine, were assayed. RESULTS: Midodrine significantly increased standing systolic blood pressure, with the increase peaking at 1 hour. There was a significant linear relation between midodrine dosage and mean systolic blood pressure. The mean score for global improvement of symptoms was significantly higher for midodrine (10 and 20 mg) compared with placebo. The half-life of desglymidodrine was approximately 4 hours. CONCLUSION: A 10-mg dose of midodrine prescribed two to three times daily is effective in increasing orthostatic blood pressure and ameliorating symptoms in patients with NOH.

Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group.

OBJECTIVE: To evaluate the efficacy of a 10-mg dose of midodrine 3 times per day in improving blood pressure (BP) and ameliorating symptoms of orthostatic hypotension in patients with neurogenic orthostatic hypotension. Midodrine hydrochloride, an alpha-agonist, could improve orthostatic BP by increasing vasomotor and venomotor tone. DESIGN/METHODS: A total of 171 patients with orthostatic hypotension participated in a multicenter, randomized, placebo-controlled study. They were randomized to a 10-mg dose of midodrine or placebo 3 times per day in a 6-week study, comprising single-blind run-in (at week 1) and washout at weeks 5 and 6, with an intervening double-blind period (weeks 2 to 4). SETTING: Twenty-five centers, with most patients evaluated in referral centers. MAIN OUTCOME MEASURES: The primary end points were improvement in standing systolic BP, symptoms of lightheadedness, and a global symptom relief score (by the investigator and patient separately). RESULTS: Nine patients were not evaluable because of noncompliance or taking concomitant vasoactive medications (3 in the midodrine group, 6 in the placebo group). In the evaluable patients, midodrine resulted in improvements in standing systolic BP at all time points (P<.001 at visits 2, 3, 4, and 5), in reported symptoms by the end of the second week of treatment (P=.001), and in the global symptom relief score rated by both the patient (P=.03) and the investigator (P<.001). There was no effect by center, severity of orthostatic hypotension, use of fludrocortisone or compression garments, or diagnosis. The main adverse effects were those of pilomotor reactions, urinary retention, and supine hypertension. CONCLUSIONS: Midodrine is efficacious and safe in the treatment of neurogenic orthostatic hypotension.

Diet after pancreas transplantation.

OBJECTIVE: To determine whether discontinuation of insulin therapy and glucose monitoring and instructions to increase dietary salt and water intake after pancreas transplantation (PTX) resulted in changes in food choices. RESEARCH DESIGN AND METHODS: All PTX recipients who had completed a preoperative diet record, had received their PTX > 6 months before, had stable pancreas and kidney function, and were on a stable diet were invited to submit a 3-day post-PTX diet record. Of the 14 eligible, 11 agreed to participate and completed the study (2 women and 9 men). Their pre- and post-PTX diet records were analyzed by computer program. Weight, glycohemoglobin, blood pressure, medications, and fasting lipids both before and after PTX were also analyzed. RESULTS: The recipients were studied 576 +/- 60 days post-PTX, on average. Total calories and BMI were unchanged after PTX. Before PTX, 34% of calories were in fats, 49% in carbohydrate, and 17% in protein with no change in distribution of calories after PTX, although there was a trend toward greater saturated fat intake. Total salt intake was increased after PTX (P < 0.01) because of sodium bicarbonate administration, although dietary salt intake did not change. The HDL cholesterol concentration increased and cholesterol-to-HDL ratio decreased after PTX (P < 0.05), while the remaining lipids were unchanged. CONCLUSION: Weight, total calories and distribution of calories, and dietary salt were unchanged after PTX, and diet did not explain the changes in HDL cholesterol or cholesterol-to-HDL ratio. These preliminary diet results suggest that greater emphasis on dietary instruction may be needed after PTX.

Midodrine treatment for patients with hemodialysis hypotension.

Hypotension is the principal complication of chronic hemodialysis. Autonomic insufficiency is thought to be a primary contributing cause of hemodialysis hypotension. We treated patients who experience hemodialysis hypotension with midodrine, a selective alpha-1 adrenergic pressor agent in an initial effort to assess potential efficacy. Twenty-one patients who experienced severe hypotension during hemodialysis participated in this study. To qualify, patients had to exhibit a fall of > or = 30 mmHg in systolic blood pressure with associated clinical symptoms during hemodialysis. The lowest intra- and post-dialysis blood pressures were monitored for five consecutive hemodialysis treatment periods before receiving midodrine, as a baseline. After the patients were titrated to a maintenance midodrine dose, the lowest intra- and post-dialysis blood pressure data were again collected for five consecutive dialysis treatments. Hemodialysis blood pressures on midodrine treatment were compared to baseline to evaluate the effect of midodrine. Midodrine given at a mean treatment dose of 8 mg (range 2.5-25) significantly increased the mean (+ or - SE) minimal systolic pressure from 93.1 "+ or - " 3.8 to 107.1 + or - 3.2 mmHg (p <0.01) and elevated the mean diastolic pressure from 52.3 + or - 2.9 to 57.9 + or - 2.3 mmHg during hemodialysis. Also, the post-dialysis blood pressures (systolic/diastolic) were significantly increased from 115.6 + or - 3.1/62.3 + or - 2.1 to 129.9 + or - 3.9/68.1 + or - 1.7 mmHg (p <0.01 and 0.05, respectively). No apparent clinical or laboratory abnormalities were observed. Oral midodrine appears to be a safe and effective therapy for the treatment of hemodialysis hypotension.

A comparison of postspace-flight orthostatic intolerance to vasovagal syncope and autonomic failure and the potential use of the alpha agonist midodrine for these conditions.

After space-flights of less than ten days, orthostatic hypotension upon reentry is characterized by plasma volume depletion that may lead to activation of the Bezold-Jarisch reflex which is also considered to be the mechanism of vasovagal (neurocardiogenic) syncope. For space-flight of longer duration, loss of cardiovascular reflex control may take precedence over volume depletion and thus may have similarities to the orthostatic hypotension seen in patients with autonomic failure secondary to basal ganglial disease and peripheral neuropathies. Midodrine is an alpha-one agonist that produces arterial and venous constriction and leads to a decrease in heart rate by baroreceptor reflexes. The efficacy of Midodrine in successfully treating orthostatic hypotension secondary to autonomic failure has been shown in clinical trials. Midodrine's ability to vasoconstrict without increasing heart rate suggests that it might be a useful treatment for vasovagal syncope since stimulation of the Bezold-Jarisch reflex would be less likely. For post-space flight orthostatic hypotension, midodrine may be a useful adjunctive treatment to the measures currently being used.

Combined modality treatment with ternary Cu(II) complexes and X rays.

Ternary Cu(II) complexes with bidentate malonato- and heterocyclic amine ligands were tested with regard to cytotoxicity and potentiation of x-ray induced cell killing in V79 cells. Two lead complexes were also tested in a tumor assay using the MTG-B murine adenocarcinoma model growing in the flanks of female C3H/HeJ mice. One complex, [2,2'-bipyridyl malonatoCu(II)] (RL-5077), produced sensitizer enhancement ratios (SER's) of 1.8 (hypoxic conditions) and 1.0 (oxic conditions) in vitro when irradiation followed 1 hr exposure to the drug at 100 microM. When RL-5077 was administered at doses of 1/2 (11.65 mg/kg) or 1/4 (5.25 mg/kg) the maximum tolerated dose (MTD), 15 min prior to a locally delivered dose of 20 Gy, enhancement ratios (ER's) of 1.6 and 2, respectively, resulted. The second lead complex, [1,10 phenanthroline (malonato)Cu(II)hydrate] (RL-5027), produced SER's of 1.8 and 1.2 under hypoxic and oxic conditions, respectively, at a concentration of 25 microM. Injection of RL-5027 (5 mg/kg) resulted in toxicity without enhancement in combination with radiation. Analogues of these two complexes have been synthesized in an effort to optimize the potentiation of radiation effects while minimizing toxicity to drug alone and increasing water solubility of the drug. Further studies of the structure-activity relationship of Cu(II) ternary complexes using in vitro radiosensitization as the endpoint have identified four classes of ligands with varying biological activity and have supplied information about the effects of group substitution on solubility, toxicity, and radiation potentiation. This group of complexes represents a new class of radiopotentiators that deserves further investigation into its potential for clinical use.

Effects of a beta-adrenergic agonist on protein turnover in muscle cells in culture.

beta-Adrenergic agents powerfully stimulate muscle growth in animals. Whether the mechanism of action involves a direct effect on muscle cell beta-receptors or is secondarily due to a beta-induced alteration in the hormonal environment is not known. To assess whether direct beta-receptor activation results in muscle protein accretion, we examined the effect of the beta-agonist zinterol on several anabolic processes in L8 muscle cells in culture. In vivo feeding of zinterol (26.5 ppm) to rats significantly increased muscle weight by 15%. In vitro, zinterol stimulated lactate release from L8 cells whereas propranolol inhibited this process, demonstrating that these cells have functional beta-receptors both before and after fusion. We measured several anabolic processes, in both serum-stimulated and quiescent cells, over a wide range of zinterol concentrations. Zinterol had no effect on protein or DNA synthesis, protein degradation, or rates of amino acid uptake. These data suggest that the in vivo muscle growth stimulation is either indirect or some in vivo requirements (e.g. tension and nerve interactions) are necessary for expression of the effect.

Histidine and proline are important sites of free radical damage to proteins.

Our hypothesis that proline and histidine are major sites of damage during radical attack upon proteins, becoming respectively glutamate and aspartate, was investigated using proteins biosynthetically labelled with radioactive proline or histidine as targets. Free radicals were generated by copper and H2O2, or by gamma radiolysis. Protein-bound histidine was substantially converted into aspartate. Much proline was modified during radical attack, but it was not converted into glutamate. We conclude that histidine and proline are important sites of protein attack by radicals; protein cleavage may result from these reactions.

Effect of continuous and intermittent clenbuterol feeding on rat growth rate and muscle.

1. The growth response to clenbuterol is a dynamic process. 2. Body weight gain is stimulated within two days of treatment and the effect attenuates by two weeks of treatment. 3. Intermittent feeding prevents the attenuation of the growth response. 4. Muscle weight increased 14-22% by both feeding regimens. 5. Clenbuterol decreased cathepsin B activity in the EDL and gastrocnemius and increased the activity in the soleus after two weeks of continuous clenbuterol treatment.

Prostaglandin production in myotube cultures. Influence on protein turnover.

The production of prostaglandins (PG) E2 and F2 alpha and their possible role in regulation of protein turnover in cultured skeletal-muscle cells were examined. Primary chick myoblasts and myotubes, and L8 myotubes, produced PGE2 and PGF2 alpha from endogenous arachidonic acid. PG production by all three cell types was increased manyfold by the addition of exogenous arachidonic acid. Arachidonate-stimulated PG production was inhibited by the addition of indomethacin (0.1 mM). When L8 and chick myotubes were treated with PGE2, PGF2 alpha, arachidonic acid (0.01 mM) or indomethacin (0.1 mM), no significant alterations in rates of protein synthesis or degradation were observed. Rates of protein synthesis and degradation in these cells were responsive to the addition of 10% fetal-bovine serum under identical experimental conditions. Thus, in contrast with incubated adult skeletal muscle, it appears that the production of prostaglandin metabolites from arachidonic acid is unrelated to regulation of protein turnover in cultured muscle cells.

Protein turnover and growth of L8 muscle cultures in serum from rats fed clenbuterol.

Beta-adrenergic agonists stimulate muscle growth in chronically treated animals. The response may be primary (receptor binding directly stimulates anabolism) or secondary (circulating levels of hormones or other factors regulate muscle mass). Although B-receptors are functional in L8 muscle cells in culture, a direct effect of B-agonists on protein turnover in culture has not been demonstrated. To determine whether the stimulation of muscle growth is a secondary effect, we assessed the anabolic activity of sera from both clenbuterol-treated rats and normal rats in L8 cultured muscle cells. Rats were fed either normal diet or diet containing ten parts per million clenbuterol for seven days. Blood was collected from the inferior vena cava of rats under metofane anaesthesia and serum prepared. The anabolic activities of serum were measured in cultures of either myoblasts (still dividing) or fused myotubes (non-dividing) to distinguish mitogenic action from alteration in rates of protein turnover. Sera from both normal and clenbuterol-treated rats gave the same stimulation of protein synthesis in myotube cultures. Sera from both groups of rats contained factors which inhibited protein degradation, stimulated amino isobutyric acid (AIB) and thymidine uptake (myoblasts only). These processes were not augmented by sera from rats treated with clenbuterol. Protein accumulation was equivalent after 48 hours of exposure to either test sera. In conclusion, adult rat serum contained anabolic factors but there was no evidence for an increase in activity in serum from clenbuterol-treated rats.

Clenbuterol-induced muscle growth: investigation of possible mediation by insulin.

The role of insulin as a possible mediator of the beta-adrenergic agonist stimulation of muscle growth was investigated. To exclude possible action of the beta-agonist on the pancreatic release of insulin, diabetes was induced in rats by a streptozotocin injection (100 mg/kg). Insulin levels were almost not detectable in these rats. Feeding either normal diet or diet containing the beta-adrenergic agonist clenbuterol (10 parts/million) did not alter plasma insulin concentrations. The effects of clenbuterol on muscle and weight gain were determined in diabetic rats given daily insulin replacement (D + I) and fed either a normal diet or clenbuterol-treated diet. Clenbuterol, fed for 1 wk, increased the wet weight of the gastrocnemius, soleus, and extensor digitorum longus muscles (15-23%) in both normal and D + I rats. Although clenbuterol increased body weight gain, it did not alter feed consumption and, therefore, feed efficiency (g gain/g food) was improved. Activities of cathepsin B and N-acetyl-beta-glucosaminidase, but not cathepsin D, were elevated in the soleus muscles of clenbuterol-treated rats. The clenbuterol-induced increase in muscle growth in the insulin-replaced diabetic rats indicated that this beta-adrenergic agonist effect was not mediated by an alteration of circulating levels of insulin, secondary to beta-agonist action on pancreatic insulin release.