The incorporation of iodine in thyroid hormone may stem from its role as a prehistoric signal of ecologic opportunity: an evolutionary perspective and implications for modern diseases

To optimize fitness under conditions of varying Darwinian opportunity, organisms demonstrate tremendous plasticity in their life-history strategies based on their perception of available resources. Higher-energy environments generally promote more aggressive life-history strategies, such as faster growth, larger adult size, greater genetic variation, shorter lifespan, larger brood sizes, and offspring ratio skewed towards the larger-sized gender. While numerous mechanisms regulate life-history plasticity including genetic imprinting, methylation, and growth factors, evidence suggests that thyroid hormone plays a central role. Given the pivotal adaptive role of thyroid hormone, the teleology of its dependence on dietary iodine for production remains unexplained. We hypothesize that iodine may have emerged as a substrate for production of thyroid hormone in prehistoric ecosystems because the former represented a reliable proxy for ecologic potential that enabled the latter to modulate growth, reproduction, metabolic rate, and lifespan. Such a scenario may have existed in early marine ecosystems where ocean-surface vegetation, which concentrates iodine for its antimicrobial and antioxidant properties, formed the basis of the food chain. Teleologic parallels can be drawn to the food-chain accumulation of antimicrobials that also exhibit antioxidant properties and promote adult size, brood size, and offspring quality by modulating central hormonal axes. As each higher species in the food chain tunes its life-history strategy based on iodine intake, the coupling of this functional role of iodine with its value as a resource signal to the next member of the food-chain may promote runaway evolution. Whereas predators in prehistoric ecosystems successfully tuned their life-history strategy using iodine as a major input, the strategy may prove maladaptive in modern humans for whom the pattern of iodine intake is decoupled from resource availability. Iodine acquired through sodium iodide supplementation may independently contribute to some biologic dysfunctions currently attributed to sodium.     

Free-feeding and free-drinking patterns of male rats following treatment with opiate kappa agonists.

Three experiments investigated the effects of PD117302 and U50,488H on the patterns of food and water intake by male rats. Experiment 1 demonstrated early dose-related suppression of food and water intake after PD117302 (0, 1.25, 2.5, 5 mg/kg). The initial suppression of drinking was followed by a sustained increase 4-12 h after drug administration. Experiment 2 demonstrated that 2.5 mg/kg PD117302 failed to increase food intake whether given at the beginning of the night (high baseline food intake) or the beginning of the day (low baseline food intake). Experiment 3 showed that 0.5 mg/kg U50,488H significantly enhanced meal size but, at doses of 0.5, 1.0, and 2.0 mg/kg, had no effect on overall food intake. U50,488H also produced delayed, dose-related increases in water intake. The results suggest kappa receptors may have limited importance in modulating ad lib food intake and demonstrate the behavioural characteristics of increased drinking after excessive urine output.     

Microheterogeneity of Neisseria lipooligosaccharide: analysis of a UDP-glucose 4-epimerase mutant of Neisseria meningitidis NMB.

Neisseria meningitidis is the etiologic agent of epidemic bacterial meningitis. Lipooligosaccharide (LOS) is a principal virulence factor associated with the organism, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of LOS has demonstrated that there is considerable microheterogeneity in the molecule. To begin our understanding of the nature of this heterogeneity, we identified a Tn916-generated LOS mutant of N. meningitidis NMB (serotype L3, monoclonal antibodies 3F11+, 6B4+, and 4C4-) that was designated NMB-SS3 (monoclonal antibodies 3F11-, 6B4-, and 4C4+). The transposon insertion was localized to the amino terminus of the functional copy of the UDP-Glc 4-epimerase gene (galE). UDP-Glc 4-epimerase (EC 5.1.3.2) activity was present in N. meningitidis NMB but not in NMB-SS3, indicating that the Tn916 insertion had abolished this activity. Mass spectrometric analysis of the LOS from strain NMB revealed multiple species of LOS, which is consistent with extensive microheterogeneity. While the most predominant structure was consistent with a terminal lacto-N-neotetrose structure found in other strains of N. meningitidis, Gal beta 1-->4GlcNAc beta 1-->3Gal beta 1-->4Glc-->(GlcNAc)-->Hep2PEA-->KDO2 (where Hep is heptose, PEA is phosphoethanolamine, and KDO is 2-keto-3-deoxymannooctulosonic acid), structures containing repetitive hexoses which are not precursors of this structure were also identified. Compositional analysis of LOS from strain NMB-SS3 revealed that there were no galactoses present in the structure. Mass spectrometric analysis of O-deacylated LOS revealed the presence of multiple species, with the predominant LOS species in this mutant strain formed by the Hex-->(HexNAc)-->Hep2PEA-->KDO2 (where Hex is hexose and HexNAc is N-acetylhexosamine) structure. However, LOS structures with repetitive hexoses, e.g., Hexn-->(HexNAc)-->Hep2PEA-->KDO2 (n = 2, 3, or 4), emanating from one or both heptoses were also identified. Since this mutant cannot synthesize UDP-Gal, these structures must repetitive glucoses. These data suggest that NMB has a glycosyltransferase capable of polymerizing glucose moieties as an alternative biosynthetic pathway to the wild-type lacto-N-neotetrose structure.     

Carotid sinus reflex function in the alloxan diabetic rabbit.

Baroreflex function was studied in three groups of adult rabbits. Seven animals were given alloxan (100-200 mg/kg) and became diabetic (group D) with mean blood sugar values of 348 +/- 30 mg/dl. Eight animals were given alloxan, but did not develop significant hyperglycemia (135 mg/dl) (group A). Nine controls (group C) were also studied (glucose, 101 mg/dl). All animals were anesthetized with pentobarbital (30 mg/kg). Blood pressure (BP) and heart rate (HR) responses to bilateral carotid occlusion (BCO) were measured before and after depressor nerve sectioning (DNx) and sinus nerve sectioning (SNx). Before sectioning, BCO caused a rise in BP of 30 +/- 4 mmHg in group C. 35 +/- 3 in group A, and 36 +/- 4 in group D. HR increased about 13 beats/min in each group. After DNx, resting BP increased in group C from 97 to 104 mmHg (P less than 0.005), but no change occurred in the other groups. Responses to BCO were significantly but similarly enhanced in all groups after DNx. HR did not increase in group D. Resting BP increased after SNx only in the controls (group C). Differences in BP elevation with BCO before and after SNx ("pure" reflex response) were identical, averaging about 35 mmHg. Thus, no alteration of BP or HR responses to BCO was identified in early alloxan diabetes. However, resting tone in the buffer nerves may have been less.     

Factors associated with BMI, weight perceptions and trying to lose weight in African-American smokers

This study examined sociodemographic, behavioral and psychosocial factors associated with BMI, weight perceptions and trying to lose weight among African-American smokers (N=600, M=44.2 years, 70% female). Sixty-eight percent of the sample were overweight or obese (sample BMI M=28.0, SD=6.7). Three separate, simultaneous multivariable regression models were used to determine which factors were associated with BMI, weight perceptions and trying to lose weight. Poorer health, female gender and high-school education or higher were significantly associated with higher BMIs (p<0.05). Being female (OR=5.8, 95% CI=3.6-9.3) and having a higher BMI (OR=0.6, 95% CI=0.5-0.6) was associated with perception of overweight and smoking more cigarettes per day (OR=1.0, 95% CI=1.0-1.1), and perceiving oneself as overweight (OR=14.1, 95% CI=8.2-24.2) was associated with trying to lose weight. Participants somewhat underestimated their BMI in their weight perceptions. Those who perceived themselves as overweight were more likely to be trying to lose weight; therefore, increasing participant awareness of actual BMI status may lead to improved weight-control efforts in African-American smokers. Several expected associations with outcomes were not found, suggesting that BMI and weight constructs are not well-understood in this population.     

Plaque assay for virulent Legionella pneumophila.

Methods of assessing virulence of Legionella pneumophila, the etiologic agent of Legionnaires disease, include the infection of guinea pigs, fertile chicken eggs, and mammalian and protozoan cell cultures. Guinea pig assays, in particular, are expensive, laborious, or unsuitable for routine screening of Legionella isolates. We have developed a virulence assay that requires the enumeration of viruslike plaques which are the result of virulent L. pneumophila infecting mouse L929 cells. Each plaque is the consequence of the initial infection of an L cell with a single bacterium. A nonvirulent mutant derived from the serial passage of virulent L. pneumophila on Mueller-Hinton agar fails to survive within L cells and consequently fails to produce plaques.     

A computer protocol to predict myocardial infarction in emergency department patients with chest pain

To achieve more appropriate triage to the coronary care unit of patients presenting with acute chest pain, we used clinical data on 1379 patients at two hospitals to construct a simple computer protocol to predict the presence of myocardial infarction. When we tested this protocol prospectively in 4770 patients at two university hospitals and four community hospitals, the computer-derived protocol had a significantly higher specificity (74 vs. 71 percent) in predicting the absence of infarction than physicians deciding whether to admit patients to the coronary care unit, and it had a similar sensitivity in detecting the presence of infarction (88.0 vs. 87.8 percent). Decisions based solely on the computer protocol would have reduced the admission of patients without infarction to the coronary care unit by 11.5 percent without adversely affecting the admission of patients in whom emergent complications developed that required intensive care. Although this protocol should not be used to override careful clinical judgment in individual cases, the computer protocol for the most part yields accurate estimates of the probability of myocardial infarction. Decisions about admission to the coronary care unit based on the protocol would have been as effective as those actually made by the unaided physicians who cared for the patients, and less costly. Whether physicians who are aided by the protocol perform better than unaided physicians cannot be determined without further study.     

Involvement of protein kinase c in responses of rat dorsal horn neurons to mechanical stimuli and periaqueductal gray descending inhibition

 The effects of a protein kinase C (PKC) activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), on the activity and periaqueductal gray (PAG)-induced inhibition of rat dorsal horn neurons of the lumbar spinal cord were tested. A microdialysis fiber was placed through the dorsal horn for the purpose of local application of pharmacological agents. Extracellular single-unit recordings from dorsal horn neurons were made near the microdialysis fiber. TPA was tested on nociceptive dorsal horn cells. There was a significant increase in the background activity and responses to ”brush”, with no changes in responses to pressure and pinch stimuli. TPA also significantly blocked the PAG-induced inhibition of responses to brush, press, and pinch. These effects were eliminated by coadministration of the PKC inhibitor NPC-15437. The solvent, which contained dimethyl sulfoxide, was also tested for its effect on the responses to peripheral mechanical stimuli and PAG-induced inhibition of the dorsal horn neurons. There were no significant changes. This experiment suggests that activation of the PKC second messenger system might increase the activity of dorsal horn neurons and their responses to peripheral stimuli; in addition, the phorbol ester attenuated the PAG-induced descending inhibition of the dorsal horn neuron activity. Received: 15 May 1996 / Accepted: 14 November 1996     

HLA-DR, DQ antigens in North American Caucasians

HLA-DR, DQ specificities are determined by serological methods in 2,586 North American Caucasians. Antigen frequency, gene frequency and haplotype frequency are computed for each phenotype observed. The DR and DQ loci antigen distributions are well-fitted to a Hardy-Weinberg equilibrium (p greater than 0.25 for DR locus, p greater than 0.10 for DQ locus). All World Health Organization (WHO) recognized HLA-DR,DQ specificities were found except HLA-DRw18, which has been identified only in the black population. DR and DQ linkage disequilibria among recently defined splits is observed. The following DR and DQ associations are found: DR1 and DQw5; DR4 and DQw7, DQw8; DR7 and DQw2, DQw9; DR8 and DQw4, DQw6, DQw7; DR9 and DQw2, DQw9; DRw10 and DQw5; DRw11 and DQw6, DQw7; DRw12 and DQw5, DQw7; DRw13 and DQw6, DQw7; DRw14 and DQw5, DQW7; DRw15 and DQw6, DQw7; DRw16 and DQw5; DRw17 and DQw2. In this large study population, the following unusual DR and DQ associations are found: DR4, DQw2; DR4, DQw1; DR1, DQw7; DR7, DQw5; DRw17, DQw6; and other unusual haplotype phenotypes containing DRX, DQX.