The effects of gonadectomy on bone size, mass, and volumetric density in growing rats are gender-, site-, and growth hormone-specific.

Peak volumetric bone mineral density (BMD) is determined by the growth in bone size relative to the mineral accrued within its periosteal envelope. Thus, reduced peak volumetric BMD may be the result of reduced mineral accrual relative to growth in bone size. Because sex steroids and growth hormone (GH) influence bone size and mass we asked: What are the effects of gonadectomy (Gx) on bone size, bone mineral content (BMC), areal and volumetric BMD in growing male and female rats? Does GH deficiency (GH-) reduce the amount of bone in the (smaller) bone, i.e., reduce volumetric BMD? Does GH- alter the effect of Gx on bone size and mineral accrual? Gx or sham surgery was performed at 6 weeks in GH- and GH replete (GH+) Fisher 344 male and female rats. Changes in bone size, volume, BMC, areal and volumetric BMD, measured using dual X-ray absorptiometry (DPX-L), were expressed as percentage of controls at 8 months (mean +/- SEM). All results shown were significant (p < 0.05 level) unless otherwise stated. In GH+ and GH- males, respectively, Gx was associated with: lower femur volume (24%, 25%), BMC (43%, 45%), areal BMD (21%, 14%), and volumetric BMD (30%, 28%); lower spine (L1-L3) volume (26%, 28%), BMC (26%, 30%), and areal BMD (28%, 12%), but not volumetric BMD. Following Gx, GH+ females had increased femur volume (11%), no effect on BMC, decreased areal BMD (6%) and decreased volumetric BMD (17%); GH- females had no change in femur volume, but decreased femur BMC (24%), areal BMD (10%), and volumetric BMD (25%). In GH+ and GH- females, respectively, Gx was associated with a decrease in spine (L1-L3) BMC (12%, 15%), areal BMD (16%, 15%), and volumetric BMD (10%, 16%) with no change in volume. Deficits in non-Gx GH- relative to non-Gx GH+ (males, females, respectively) were: femur BMC (49%, 37%), areal BMD (23%, 8%), volume (19%, 19%) and volumetric BMD (37%, 22%); spine (L1-L3) BMC (46%, 42%), areal BMD (37%, 43%), volume (10%, 15%), and volumetric BMD (40%, 33%). Testosterone and GH are growth promoting in growing male rats, producing independent effects on bone size and mass; deficiency produced smaller appendicular bones with reduced volumetric BMD because deficits in mass were greater than deficits in size. At the spine, the reduction in size and accrual were proportional, resulting in a smaller bone with normal volumetric BMD. In growing female rats, estrogen was growth limiting at appendicular sites; deficiency resulted in a GH-dependent increase in appendicular size, relatively reduced accrual, and so, reduced volumetric BMD in a bigger bone. At the spine, accrual was reduced while growth in size was normal, thus volumetric BMD was reduced in the normal sized bone. Understanding the pathogenesis of low volumetric BMD requires the study of the differing relative growth in size and mass of the axial and appendicular skeleton in the male and female and the regulators of the growth of these traits.     

Assessment of pacemaker chronotropic response: implementation of the Wilkoff mathematical model

There are few practical guidelines for proper adjustment of rate responsive pacemaker sensor parameters. This study describes the application of the chronotropic assessment exercise protocol (CAEP) and the Wilkoff model of chronotropic response to assess the adjustment of pacemaker sensor parameters. In 31 patients implanted 1 month previously with a dual sensor pacemaker, pacemaker sensor parameters were adjusted to yield a peak sensor rate of 100 beats/min on a simple 6-minute walk (low intensity treadmill exercise [LITE] protocol); the maximum sensor rate was set to the age predicted maximum heart rate (220-age). The rate response behavior of the pacemaker was then assessed using the slope of metabolic-chronotropic relation (MCR) during CAEP exercise. After adjustments based on the LITE protocol, CAEP exercise yielded MCR slopes of 0.92 +/- 0.25 for the entire study group, which compares well with the predicted normal slope of 1. However, 7 of the 31 patients had sensor MCR slopes during CAEP exercise that were 2 SD or more below expected. To test the sensitivity of this approach to suboptimal pacemaker programming or suboptimal exercise, simulations were performed with the maximum sensor rate programmed below age-predicted maximum heart rate or with exercise truncated before maximum exertion; with these conditions, MCR slopes were sharply lower for the entire group. The authors conclude that a simple treadmill walk (LITE) allowed for optimum programming of sensor parameters in most patients, but in a minority the chronotropic behavior was underresponsive. Failure to appropriately adjust pacemaker maximum sensor rate or failure to achieve peak exercise sharply limits the accuracy of this methodology.     

Genetic Analysis Workshop II: pedigree analysis of a binary trait without assuming an underlying liability

A model for concordance in a binary measure that does not rely on the assumption of an underlying latent liability dichotomized about a threshold has been demonstrated for twin pairs [Hannah et al, 1983]. It is extended here to pedigrees of arbitrary structure by making an assumption that is, for small incidence rates, almost equivalent to postulating that relative risks are multiplicative. The model is applied to the workshop data to determine the extent to which the known structure of the simulated models can be recovered.     

Nitrite and Nitrate Concentrations and Metabolism in Breast Milk,Infant Formula,and Parenteral Nutrition

Dietary nitrate and nitrite are sources of gastric NO, which modulates blood flow, mucus production, and microbial flora. However, the intake and importance of these anions in infants is largely unknown. Nitrate and nitrite levels were measured in breast milk of mothers of preterm and term infants, infant formulas, and parenteral nutrition. Nitrite metabolism in breast milk was measured after freeze‐thawing, at different temperatures, varying oxygen tensions, and after inhibition of potential nitrite‐metabolizing enzymes. Nitrite concentrations averaged 0.07 ± 0.01 μM in milk of mothers of preterm infants, less than that of term infants (0.13 ± 0.02 μM) (P < .01). Nitrate concentrations averaged 13.6 ± 3.7 μM and 12.7 ± 4.9 μM, respectively. Nitrite and nitrate concentrations in infant formulas varied from undetectable to many‐fold more than breast milk. Concentrations in parenteral nutrition were equivalent to or lower than those of breast milk. Freeze‐thawing decreased nitrite concentration ~64%, falling with a half‐life of 32 minutes at 37°C. The disappearance of nitrite was oxygen‐dependent and prevented by ferricyanide and 3 inhibitors of lactoperoxidase. Nitrite concentrations in breast milk decrease with storage and freeze‐thawing, a decline likely mediated by lactoperoxidase. Compared to adults, infants ingest relatively little nitrite and nitrate, which may be of importance in the modulation of blood flow and the bacterial flora of the infant GI tract, especially given the protective effects of swallowed nitrite.     

Does acute bronchitis really exist? A reconceptualization of acute viral respiratory infections

BACKGROUND: Considerable overlap exists in patient presentations and physical findings in viral upper respiratory tract infections (URIs) and acute bronchitis. Our goal was to determine whether there are any clinical cues that could help physicians differentiate between these 2 conditions. METHODS: We performed a retrospective chart audit on 135 patients who had been given a diagnosis of acute bronchitis and a random sample of 409 patients with URIs over a 2.5-year period. Patient and provider characteristics, patient symptoms, and physical findings were compared with bivariate analyses and then entered into a logistic regression model. RESULTS: In bivariate analyses, a number of demographic variables, symptoms, and signs were associated with acute bronchitis. Multivariate analysis showed that the strongest independent predictors of acute bronchitis were cough (adjusted odds ratio [AOR]=21.12; 95% confidence interval [CI], 6.01-74.26), and wheezing on examination (AOR=12.16; 95% CI, 5.39-27.42). Nausea was the strongest independent predictor that the diagnosis would not be acute bronchitis (AOR=0.01; 95% CI, 0.01-0.85). However, there was considerable overlap between the 2 conditions, and the logistic model explained only 37% of the variation between the diagnoses. CONCLUSIONS: We hypothesize that sinusitis, URI, and acute bronchitis are all variations of the same clinical condition (acute respiratory infection) and should be conceptualized as a single clinical entity, with primary symptoms related to different anatomic areas rather than as different conditions.     

Regressive logistic and proportional hazards disease models for within-family analyses of measured genotypes,with application to a CYP17 polymorphism and breast cancer

Various statistical methods have been proposed to evaluate associations between measured genetic variants and disease, including some using family designs. For breast cancer and rare variants, we applied a modified segregation analysis method that uses the population cancer incidence and population-based case families in which a mutation is known to be segregating. Here we extend the method to a common polymorphism, and use a regressive logistic approach to model familial aggregation by conditioning each individual on their mother's breast cancer history. We considered three models: 1) class A regressive logistic model; 2) age-of-onset regressive logistic model; and 3) proportional hazards familial model. Maximum likelihood estimates were calculated using the software MENDEL. We applied these methods to data from the Australian Breast Cancer Family Study on the CYP17 5'UTR T-->C MspA1 polymorphism measured for 1,447 case probands, 787 controls, and 213 relatives of case probands found to have the CC genotype. Breast cancer data for first- and second-degree relatives of case probands were used. The three methods gave consistent estimates. The best-fitting model involved a recessive inheritance, with homozygotes being at an increased risk of 47% (95% CI, 28-68%). The cumulative risk of the disease up to age 70 years was estimated to be 10% or 22% for a CYP17 homozygote whose mother was unaffected or affected, respectively. This analytical approach is well-suited to the data that arise from population-based case-control-family studies, in which cases, controls and relatives are studied, and genotype is measured for some but not all subjects.     

Disease-specific prospective family study cohorts enriched for familial risk

Most common diseases demonstrate familial aggregation; the ratio of the risk for relatives of affected people to the risk for relatives of unaffected people (the familial risk ratio)) > 1. This implies there are underlying genetic and/or environmental risk factors shared by relatives. The risk gradient across this underlying 'familial risk profile', which can be predicted from family history and measured familial risk factors, is typically strong. Under a multiplicative model, the ratio of the risk for people in the upper 25% of familial risk to the risk for those in the lower 25% (the inter-quartile risk gradient) is an order of magnitude greater than the familial risk ratio. If familial risk ratio = 2 for first-degree relatives, in terms of familial risk profile: (a) people in the upper quartile will be at more than 20 times the risk of those in the lower quartile; and (b) about 90% of disease will occur in people above the median. Historically, therefore, epidemiology has compared cases with controls dissimilar for underlying familial risk profile. Were gene-environment and gene-gene interactions to exist, environmental and genetic effects could be stronger for people with increased familial risk profile. Studies in which controls are better matched to cases for familial risk profile might be more informative, especially if both cases and controls are over-sampled for increased familial risk. Prospective family study cohort (ProF-SC) designs involving people across a range of familial risk profile provide such a resource for epidemiological, genetic, behavioural, psycho-social and health utilisation research. The prospective aspect gives credibility to risk estimates. The familial aspect allows family-based designs, matching for unmeasured factors, adjusting for underlying familial risk profile, and enhanced cohort maintenance.     

Apolipoprotein E gene associations in age-related macular degeneration: the Melbourne Collaborative Cohort Study

The apolipoprotein E gene (APOE) has been found to be associated with age-related macular degeneration (AMD). Reported associations have been questioned, as they are opposite those for Alzheimer's disease and cardiovascular disease. The authors examined associations between APOE genotype and AMD using a case-control study (2,287 cases and 2,287 controls individually matched on age, sex, and country of origin) nested within Melbourne Collaborative Cohort Study participants aged 48-86 years at AMD detection. The odds ratio for early AMD among participants with ε2-containing genotypes (ε2ε2/ε2ε3/ε2ε4) was 1.32 (95% confidence interval (CI): 1.11, 1.58; P = 0.002) versus persons with genotype ε3ε3. Associations with early AMD varied by smoking status; ε2-containing genotypes were positively associated with early AMD for never and previous smokers (never smokers: odds ratio (OR) = 1.40, 95% CI: 1.12, 1.76 (P = 0.003); previous smokers: OR = 1.39, 95% CI: 1.00, 1.93 (P = 0.05)) but not for current smokers (OR = 0.66, 95% CI: 0.34, 1.30 (P = 0.2; interaction P = 0.05). The ε4-containing genotype group (ε3ε4/ε4ε4) had an inverse association with early AMD among current smokers only (OR = 0.41, 95% CI: 0.22, 0.77 (P = 0.005)). These results highlight the importance of stratifying by smoking status in elderly populations. Smokers who survive to old age may be more likely to possess unknown genotypes which modify exposure-disease associations.