In vivo model to study the impact of genetic variation on clinical outcome of mastitis in uniparous dairy cows.

BACKGROUND: In dairy herds, mastitis causes detrimental economic losses. Genetic selection offers a sustainable tool to select animals with reduced susceptibility towards postpartum diseases. Studying underlying mechanisms is important to assess the physiological processes that cause differences between selected haplotypes. Therefore, the objective of this study was to establish an in vivo infection model to study the impact of selecting for alternative paternal haplotypes in a particular genomic region on cattle chromosome 18 for mastitis susceptibility under defined conditions in uniparous dairy cows. RESULTS: At the start of pathogen challenge, no significant differences between the favorable (Q) and unfavorable (q) haplotypes were detected. Intramammary infection (IMI) with Staphylococcus aureus 1027 (S. aureus, n = 24, 96 h) or Escherichia coli 1303 (E. coli, n = 12, 24 h) was successfully induced in all uniparous cows. This finding was confirmed by clinical signs of mastitis and repeated recovery of the respective pathogen from milk samples of challenged quarters in each animal. After S. aureus challenge, Q-uniparous cows showed lower somatic cell counts 24 h and 36 h after challenge (P < 0.05), lower bacterial shedding in milk 12 h after challenge (P < 0.01) and a minor decrease in total milk yield 12 h and 24 h after challenge (P < 0.01) compared to q-uniparous cows. CONCLUSION: An in vivo infection model to study the impact of genetic selection for mastitis susceptibility under defined conditions in uniparous dairy cows was successfully established and revealed significant differences between the two genetically selected haplotype groups. This result might explain their differences in susceptibility towards IMI. These clinical findings form the basis for further in-depth molecular analysis to clarify the underlying genetic mechanisms for mastitis resistance.

Genetic selection for bovine chromosome 18 haplotypes associated with divergent somatic cell score affects postpartum reproductive and metabolic performance.

The susceptibility of animals to periparturient diseases has a great effect on the economic efficiency of dairy industries, on the frequency of antibiotic treatment, and on animal welfare. The use of selection for breeding cows with reduced susceptibility to diseases offers a sustainable tool to improve dairy cattle farming. Several studies have focused on the association of distinct bovine chromosome 18 genotypes or haplotypes with performance traits. The aim of this study was to test whether selection of Holstein Friesian heifers via SNP genotyping for alternative paternal chromosome 18 haplotypes associated with favorable (Q) or unfavorable (q) somatic cell scores influences postpartum reproductive and metabolic diseases. Thirty-six heifers (18 Q and 18 q) were monitored from 3 wk before calving until necropsy on d 39 (± 4 d) after calving. Health status and rectal temperature were measured daily, and body condition score and body weight were assessed once per week. Blood samples were drawn twice weekly, and levels of insulin, nonesterified fatty acids, insulin-like growth factor-I, growth hormone, and ß-hydroxybutyrate were measured. Comparisons between the groups were performed using Fisher's exact test, chi-squared test, and the GLIMMIX procedure in SAS. Results showed that Q-heifers had reduced incidence of metritis compared with q-heifers and were less likely to develop fever. Serum concentrations of ß-hydroxybutyrate were lower and insulin-like growth factor-I plasma concentrations were higher in Q- compared with q-heifers. However, the body condition score and withers height were comparable between haplotypes, but weight loss tended to be lower in Q-heifers compared with q-heifers. No differences between the groups were detected concerning retained fetal membranes, uterine involution, or onset of cyclicity. In conclusion, selection of chromosome 18 haplotypes associated with a reduced somatic cell score resulted in a decreased incidence of postpartum reproductive and metabolic diseases in this study. The presented data add to the existing knowledge aimed at avoiding negative consequences of genetic selection strategies in dairy cattle farming. The underlying causal mechanisms modulated by haplotypes in the targeted genomic region and immune competence necessitate further investigation.

Quadrupolar transitions evidenced by resonant auger spectroscopy.

From absorption spectra, the only way to bring to the fore the occurrence of quadrupolar transitions is to study their angular dependence. Resonant spectroscopies offer a new opportunity to obtain more insight into excited electronic states by studying lineshape and intensity of decay processes. We show here that resonantly excited Ti KL(2,3)L(2,3) Auger spectra of TiO2(110) carry a clear signature of quadrupolar transitions to localized e(g) and t(2g) d-like states, giving access to a direct measurement of crystal field splitting.

Lessons learned from a review of the development of selected vaccines. National Vaccine Advisory Committee.

BACKGROUND: Although the vaccine research and development network in the United States remains vibrant, its continued success requires maintaining harmonious interaction among its many components. Changing one component is likely to affect the system overall. An examination of case studies of the development of selected vaccines would allow an examination of the network as a whole. This article presents conclusions drawn from the case study review undertaken. OBJECTIVE: Successful development of vaccines is a time-intensive process requiring years of commitment from a network of scientists and a continuum of regulatory and manufacturing entities. We undertook this work to shed light on how well the vaccine development system in the United States performs. METHOD: The National Vaccine Advisory Committee examined the research and development pathways of several vaccines that reached licensure expeditiously (hepatitis B vaccine, Haemophilus influenzae type b conjugate vaccines); some that became licensed only after considerable delay (oral typhoid Ty21a vaccine, varicella vaccine); some that are at the point of imminent or recent licensure (reassortant Rhesus rotavirus vaccine, which was licensed by the Food and Drug Administration on August 30, 1998) or near submission for licensure (intranasal cold adapted influenza vaccine); and one for which clinical development is slow because of hurdles that must be overcome (respiratory syncytial virus vaccines). RESULTS: Some common themes emerged from the reviews of these vaccine "case histories": the expediting influence of a strong scientific base and rationale; the need for firm quantitation of disease burden and clear identification of target populations; the critical role played by individuals or teams who act as "champions" to overcome the inevitable obstacles; availability of relevant animal models, high-quality reagents and standardized assays to measure immune response; the absolute requirement for well designed, meticulously executed clinical trials of vaccine safety, immunogenicity, and efficacy; postlicensure measurements of the public health impact of the vaccine and a track record of the vaccine's safety and acceptance with large-scale use; and the critical need for international collaborations to evaluate vaccines against diseases of global importance that are rare in the United States (eg, typhoid fever). It was clear that the critical step-up from bench scale to pilot lots and then to large-scale production, which depends on a small group of highly trained individuals, is often a particularly vulnerable point in the development process. CONCLUSIONS: One fundamental lesson learned is that within the varied and comprehensive US vaccine development infrastructure, multiple and rather distinct paths can be followed to reach vaccine licensure. The National Vaccine Advisory Committee review process should be conducted periodically in the future to ascertain that the US vaccine development network, which has been enormously productive heretofore and has played a leadership role globally, is adapting appropriately to ensure that new, safe, and efficacious vaccines become available in a timely manner.

Reduced leg blood flow during dynamic exercise in older endurance-trained men.

It is currently unclear whether aging alters the perfusion of active muscles during large-muscle dynamic exercise in humans. To study this issue, direct measurements of leg blood flow (femoral vein thermodilution) and systemic arterial pressure during submaximal cycle ergometry (70, 140, and 210 W) were compared between six younger (Y; 22-30 yr) and six older (O; 55-68 yr) chronically endurance-trained men. Whole body O2 uptake, ventilation, and arterial and femoral venous samples for blood-gas, catecholamine, and lactate determinations were also obtained. Training duration (min/day), estimated leg muscle mass (dual-energy X-ray absorptiometry; Y, 21.5 +/- 1.2 vs. O, 19.9 +/- 0.9 kg), and blood hemoglobin concentration (Y, 14.9 +/- 0.4 vs. O, 14.7 +/- 0.2 g/dl) did not significantly differ (P > 0.05) between groups. Leg blood flow, leg vascular conductance, and femoral venous O2 saturation were approximately 20-30% lower in the older men at each work rate (all P < 0.05), despite similar levels of whole body O2 uptake. At 210 W, leg norepinephrine spillover rates and femoral venous lactate concentrations were more than twofold higher in the older men. Pulmonary ventilation was also higher in the older men at 140 (+24%) and 210 (+39%) W. These results indicate that leg blood flow and vascular conductance during cycle ergometer exercise are significantly lower in older endurance-trained men in comparison to their younger counterparts. The mechanisms responsible for this phenomenon and the extent to which they operate in other groups of older subjects deserve further attention.

Reflex responses to regional venous pooling during lower body negative pressure in humans.

Lower body negative pressure is frequently used to simulate orthostasis. Prior data suggest that venous pooling in abdominal or pelvic regions may have major hemodynamic consequences. Therefore, we developed a simple paradigm for assessing regional contributions to venous pooling during lower body negative pressure. Sixteen healthy men and women underwent graded lower body negative pressure protocols to 60 mmHg while wearing medical anti-shock trousers to prevent venous pooling under three randomized conditions: 1) no trouser inflation (control), 2) only the trouser legs inflated, and 3) the trouser legs and abdominopelvic region inflated. Without trouser inflation, heart rate increased 28 +/- 4 beats/min, mean arterial pressure fell -3 +/- 2 mmHg, and forearm vascular resistance increased 51 +/- 9 units at 60 mmHg lower body negative pressure. With inflation of either the trouser legs or the trouser legs and abdominopelvic region, heart rate and mean arterial pressure did not change during lower body negative pressure. By contrast, although the forearm vasoconstrictor response to lower body negative pressure was attenuated by inflation of the trouser legs (delta forearm vascular resistance 33 +/- 10 units, P < 0.05 vs. control), attenuation was greater with the inflation of the trouser legs and abdominopelvic region (delta forearm vascular resistance 16 +/- 5 units, P < 0.05 vs. control and trouser legs-only inflation). Thus the hemodynamic consequences of pooling in the abdominal and pelvic regions during lower body negative pressure appear to be less than in the legs in healthy individuals.

Influence of age and gender on cardiac output-VO2 relationships during submaximal cycle ergometry.

It is presently unclear how gender, aging, and physical activity status interact to determine the magnitude of the rise in cardiac output (Qc) during dynamic exercise. To clarify this issue, the present study examined the Qc-O2 uptake (Vo2) relationship during graded leg cycle ergometry in 30 chronically endurance-trained subjects from four groups (n = 6-8/group): younger men (20-30 yr), older men (56-72 yr), younger women (24-31 yr), and older women (51-72 yr). Qc (acetylene rebreathing), stroke volume (Qc/heart rate), and whole body Vo2 were measured at rest and during submaximal exercise intensities (40, 70, and approximately 90% of peak Vo2). Baseline resting levels of Qc were 0.6-1.2 l/min less in the older groups. However, the slopes of the Qc-Vo2 relationship across submaximal levels of cycling were similar among all four groups (5.4-5.9 l/l). The absolute Qc associated with a given Vo2 (1.0-2.0 l/min) was also similar among groups. Resting and exercise stroke volumes (ml/beat) were lower in women than in men but did not differ among age groups. However, older men and women showed a reduced ability, relative to their younger counterparts, to maintain stroke volume at exercise intensities above 70% of peak Vo2. This latter effect was most prominent in the oldest women. These findings suggest that neither age nor gender has a significant impact on the Qc-Vo2 relationships during submaximal cycle ergometry among chronically endurance-trained individuals.

Forearm sympathetic withdrawal and vasodilatation during mental stress in humans.

1. In humans, mental stress elicits vasodilatation in the muscle vascular beds of the forearm that may be neurally mediated. We sought to determine the extent to which this vasodilatation is due to sympathetic withdrawal, active neurogenic vasodilatation, or beta-adrenergically mediated vasodilatation. 2. We simultaneously measured forearm blood flow and muscle sympathetic nerve traffic to the forearm during mental stress in humans. In a second study, we measured forearm blood flow responses to mental stress after selective blockade of alpha-adrenergic neurotransmission in one forearm. In a final study, we measured forearm blood flow responses to mental stress after unilateral anaesthetic blockade of the stellate ganglion, alone or in combination with selective beta-adrenergic receptor blockade of the forearm. 3. During mental stress, muscle sympathetic nerve activity decreased from 5113 +/- 788 to 1509 +/- 494 total integrated activity min-1 (P < 0.05) and forearm vascular resistance decreased from 96 +/- 29 to 33 +/- 7 mmHg (dl of tissue) min ml-1 (P < 0.05). Considerable vasodilation was still elicited by mental stress after selective blockade of alpha-adrenergic neurotransmission. Vasodilatation also occurred during mental stress after stellate ganglion blockade. This dilatation was reduced by selective blockade of beta-adrenergic receptors in the forearm. 4. Our results support a role for both sympathetic withdrawal and beta-adrenergic vasodilatation as the major causes of the forearm vasodilatation during mental stress in humans.

Sympathetic withdrawal and forearm vasodilation during vasovagal syncope in humans.

Our aim was to determine whether sympathetic withdrawal alone can account for the profound forearm vasodilation that occurs during syncope in humans. We also determined whether either vasodilating beta 2-adrenergic receptor or nitric oxide (NO) contributes to this dilation. Forearm blood flow was measured bilaterally in healthy volunteers (n = 10) by using plethysmography during two bouts of graded lower body negative pressure (LBNP) to syncope. In one forearm, drugs were infused via a brachial artery catheter while the other forearm served as a control. In the control arm, forearm vascular resistance (FVR) increased from 77 +/- 7 units at baseline to 191 +/- 36 units with -40 mmHg of LBNP (P < 0.05). Mean arterial pressure fell from 94 +/- 2 to 47 +/- 4 mmHg just before syncope, and all subjects demonstrated sudden bradycardia at the time of syncope. At the onset of syncope, there was sudden vasodilation and FVR fell to 26 +/- 6 units (P < 0.05 vs. baseline). When the experimental forearm was treated with bretylium, phentolamine, and propranolol, baseline FVR fell to 26 +/- 2 units, the vasoconstriction during LBNP was absent, and FVR fell further to 16 +/- 1 units at syncope (P < 0.05 vs. baseline). During the second trial of LBNP, mean arterial pressure again fell to 47 +/- 4 mmHg and bradycardia was again observed. Treatment of the experimental forearm with the NO synthase inhibitor NG-monomethyl-L-arginine in addition to bretylium, phentolamine, and propranolol significantly increased baseline FVR to 65 +/- 5 units but did not prevent the marked forearm vasodilation during syncope (FVR = 24 +/- 4 vs. 29 +/- 8 units in the control forearm). These data suggest that the profound vasodilation observed in the human forearm during syncope is not mediated solely by sympathetic withdrawal and also suggest that neither beta 2-adrenergic-receptor-mediated vasodilation nor NO is essential to observe this response.

Adult immunizations: how are we doing?

Physicians seldom ask adult patients about basic immunizations or seek to determine whether the patient's occupation, lifestyle, or travel may warrant additional vaccine coverage. Yet more than 30,000 lives could be saved every year in the United States if adult immunization recommendations were implemented. Strategies for improving delivery are reviewed and information on specific vaccines is updated.

Adult immunizations.

New vaccines have been licensed for hepatitis A, varicella, and typhoid. This paper reviews these vaccines and their recommended uses in adults. Special attention is given to a new national policy establishing age 50 years as a time for review of preventive health measures with emphasis on evaluating risk factors that indicate a need for pneumococcal vaccine and the initiation of annual influenza immunization.

Airborne nosocomial infection: a contemporary perspective.

The history of airborne nosocomial infections is reviewed, and current beliefs about such infections are placed into their historical context. Possible sources, both animate and inanimate, of airborne nosocomial infections in the hospital environment are identified. Viruses, bacteria, and fungi that have been important causes of airborne nosocomial infections in the past are discussed, and examples of key studies that have confirmed an airborne route of transmission are presented. Where relevant, measures that have been used to control airborne transmission of nosocomial pathogens are discussed. Although outbreaks of airborne nosocomial infection have been uncommon, airborne transmission appears to account for about 10% of all endemic nosocomial infections.

Current immunization practices in adults.

Can the successes of pediatric immunization programs be matched in adults? The question relates both to infections due to waning immunity and to those primarily acquired in adulthood. It is given urgency by rising prevalence of vaccine-preventable diseases in adults. Strategies with available vaccines are reviewed, and vaccines in development are discussed.