Body mass estimation from footprint size in hominins.

Although many studies relating stature to foot length have been carried out, the relationship between foot size and body mass remains poorly understood. Here we investigate this relationship in 193 adult and 50 juvenile habitually unshod/minimally shod individuals from five different populations-Machiguenga, Daasanach, Pumé, Hadzabe, and Samoans-varying greatly in body size and shape. Body mass is highly correlated with foot size, and can be predicted from foot area (maximum length × breadth) in the combined sample with an average error of about 10%. However, comparisons among populations indicate that body shape, as represented by the body mass index (BMI), has a significant effect on foot size proportions, with higher BMI samples exhibiting relatively smaller feet. Thus, we also derive equations for estimating body mass from both foot size and BMI, with BMI in footprint samples taken as an average value for a taxon or population, estimated independently from skeletal remains. Techniques are also developed for estimating body mass in juveniles, who have relatively larger feet than adults, and for converting between foot and footprint size. Sample applications are given for five Pliocene through Holocene hominin footprint samples from Laetoli (Australopithecus afarensis), Ileret (probable Homo erectus), Happisburgh (possible Homo antecessor), Le Rozel (archaic Homo sapiens), and Barcin Höyük (H. sapiens). Body mass estimates for Homo footprint samples appear reasonable when compared to skeletal estimates for related samples. However, estimates for the Laetoli footprint sample using the new formulae appear to be too high when compared to skeletal estimates for A. afarensis. Based on the proportions of A.L. 288-1, this is apparently a result of relatively large feet in this taxon. A different method using a ratio between body mass and foot area in A.L. 288-1 provides estimates more concordant with skeletal estimates and should be used for A. afarensis.

Granulomatous conduit for intrathecal infusion of morphine and bupivacaine.

OBJECTIVE: Intrathecal drug delivery systems (IT-DDSs) have gained more widespread use in patients with non-cancer-related pain, notably failed back surgery syndrome and spinal arachnoiditis. Secondary to the longer life spans of these patients, more complications have been discovered with IT-DDSs. With an estimated incidence of 1% to 3%, an uncommon but serious complication is that of granuloma formation. CASE REPORT: We describe a case of a 38-year-old woman with a malfunctioning IT-DDS containing morphine and bupivacaine. The device had stopped providing relief for several months because of presumed leakage from the connection site between the pump and the proximal catheter. The IT-DDS spontaneously resumed functioning. The IT-DDS was explanted for low battery life, upon which we discovered that the leakage site had been encapsulated by drug concretion and granuloma formation, thus providing a sealed conduit that reestablished drug flow between the pump and the catheter. CONCLUSIONS: This case report reinforces the view that the infusate is the causal agent of this lesion.

Efficacy and safety of AIR inhaled insulin compared to insulin lispro in patients with type 1 diabetes mellitus in a 6-month, randomized, noninferiority trial.

BACKGROUND: Patients with type 1 diabetes may prefer features of AIR inhaled insulin (developed by Alkermes, Inc. [Cambridge, MA] and Eli Lilly and Company [Indianapolis, IN]; AIR is a registered trademark of Alkermes, Inc.) over insulin injection, but the two methods need to be compared for efficacy and safety. METHODS: This multicenter, 6-month, parallel-group, noninferiority trial had 500 patients with type 1 diabetes randomized to morning doses of basal insulin glargine plus either preprandial injectable insulin lispro or preprandial AIR insulin. We hypothesized that AIR insulin is noninferior (upper bound of the 95% confidence interval < or = 0.4%) to insulin lispro for change-from-baseline hemoglobin A1C (A1C). RESULTS: Baseline A1C was 7.95 +/- 0.08% for both groups. At end point, A1C was lower with insulin lispro than with AIR insulin by 0.27% (95% confidence interval 0.11, 0.43; P< 0.001). Noninferiority of AIR insulin to insulin lispro was not demonstrated, but similar percentages of patients in each group achieved A1C <7.0% (P = 0.448). Overall daily blood glucose was similar between groups at baseline (P = 0.879) and end point (P = 0.161). Two-hour postprandial blood glucose change from baseline was significantly (P < 0.001) higher with AIR insulin (20.77 +/- 4.33 mg/dL at 3 months and 15.85 +/- 3.08 mg/dL at end point) than with insulin lispro (3.29 +/- 4.14 mg/dL at 3 months and 1.67 +/- 2.91 mg/dL at end point). Overall hypoglycemia was similar between treatment groups (P = 0.355). The AIR insulin group had greater decrease in diffusing capacity of the lung for carbon monoxide at end point (P = 0.020) and greater incidence of cough (P = 0.024) and dyspnea (P = 0.030). Body weight decreased in the AIR insulin group and increased in the insulin lispro group. CONCLUSIONS: Insulin lispro provided lower A1C than AIR insulin, but the difference may not be clinically relevant.

Safety and efficacy of AIR inhaled insulin compared with subcutaneous insulin in patients having diabetes and asthma: A 12-month, randomized, noninferiority trial.

BACKGROUND: Long-term safety and efficacy of AIR((R)) inhaled insulin (Eli Lilly and Co., Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) in patients with diabetes and concomitant lung disease remain to be established. METHODS: This 1-year, randomized, open-label, active comparator, two-arm, parallel study compared the safety and efficacy of AIR insulin to subcutaneous (SC) insulin in patients having type 1 or type 2 diabetes and asthma. Patients with type 2 diabetes continued taking their prestudy oral antihyperglycemic medication. RESULTS: Change in hemoglobin A1C from baseline to end point was similar for the AIR insulin and SC insulin groups (-0.063 +/- 0.128% and -0.315 +/- 0.128% respectively, P = 0.105), but noninferiority failed to be achieved (the upper limit of the 95% confidence interval [-0.053, 0.555] was >0.4%). The total daily prandial dose increased more in the AIR insulin group than in the SC insulin group (0.150 U/kg and 0.044 U/kg, respectively, P = 0.002). Safety profiles were generally comparable between treatments. At end point, forced expiratory volume in 1 s (FEV(1))/forced vital capacity (FVC) postbronchodilator (-0.016 +/- 0.005 vs. 0.002 +/- 0.005, P = 0.006) and diffusing capacity of the lung for carbon monoxide (-1.214 +/- 0.325 mL/min/torr vs. -0.383 +/- 0.311 mL/min/torr, P = 0.028) both decreased more in the AIR insulin group than in the SC insulin group, but the differences were not present at follow-up. FEV(1) and FVC were similar between treatment groups at end point. Incidences of hypoglycemia were comparable between groups. Insulin antibody binding increased more in the AIR insulin group. Cough was the most common adverse event; however, there was no difference in incidence between the AIR insulin (15.3%) and SC insulin (12.4%) treatment groups (P = 0.572). CONCLUSIONS: In patients who have diabetes and asthma, AIR insulin demonstrated glycemic efficacy similar to SC insulin. Additionally, the safety profile of AIR insulin in patients with and without asthma is consistent.

Two-year efficacy and safety of AIR inhaled insulin in patients with type 1 diabetes: An open-label randomized controlled trial.

BACKGROUND: Patients with type 1 diabetes require intensive insulin therapy for optimal glycemic control. AIR((R)) inhaled insulin (system from Eli Lilly and Company, Indianapolis, IN) (AIR is a registered trademark of Alkermes, Inc., Cambridge, MA) may be an efficacious and safe alternative to subcutaneously injected (SC) mealtime insulin. METHODS: This was a Phase 3, 2-year, randomized, open-label, active-comparator, parallel-group study in 385 patients with type 1 diabetes who were randomly assigned to receive AIR insulin or SC insulin (regular human insulin or insulin lispro) at mealtimes. Both groups received insulin glargine once daily. Efficacy measures included mean change in hemoglobin A1C (A1C) from baseline to end point, eight-point self-monitored blood glucose profiles, and insulin dosage. Safety assessments included hypoglycemic events, pulmonary function tests, adverse events, and insulin antibody levels. RESULTS: In both treatment groups, only 20% of subjects reached the target of A1C <7.0%. A significant A1C difference of 0.44% was seen favoring SC insulin, with no difference between the groups in insulin doses or hypoglycemic events at end point. Patients in both treatment groups experienced progressive decreases in lung function, but larger (reversible) decrements in diffusing capacity of the lung for carbon monoxide (DL(CO)) were associated with AIR insulin treatment. Greater weight gain was seen with SC insulin treatment. CONCLUSIONS: The AIR inhaled insulin program was terminated by the sponsor prior to availability of any Phase 3 data for reasons unrelated to safety or efficacy. Despite early termination, this trial provides evidence that AIR insulin was less efficacious in lowering A1C and was associated with a greater decrease in DL(CO) and increased incidence of cough than SC insulin in patients with type 1 diabetes.

The impact of diabetes and age on pulmonary function: data from the National Health and Nutrition Examination Survey.

Using data from NHANES III, we evaluated the effect of diabetes on the age-related decline in lung function. The Diabetes group (n=471) had significantly lower mean FEV(1) and FVC values than the No Diabetes group (n=4317), but pulmonary function declined with increasing age at a similar rate for both groups.

Accelerated evolution and loss of a domain of the sperm-egg-binding protein SED1 in ancestral primates.

Proteins involved in sperm-egg binding have been shown to evolve rapidly in several groups of invertebrates and vertebrates. Mammalian SED1 (secreted protein containing N-terminal Notch-like type II epidermal growth factor (EGF) repeats and C-terminal discoidin/F5/8 C domains) is a recently identified sperm surface protein that binds the egg zona pellucida and facilitates sperm-egg adhesion. SED1-null male mice are subfertile. Here we examine the SED1 gene from 11 mammalian species and provide evidence that it underwent accelerated evolution in ancestral primates, most likely driven by positive selection. Specifically, the intensity of the positive selection across various protein domains of SED1 was heterogeneous. Although one of the 2 Notch-like EGF domains, which mediate protein-protein binding, was lost in primate SED1, the second EGF domain evolved under strong positive selection favoring polar to nonpolar amino acid replacements. By contrast, the 2 discoidin/F5/8 type C domains, which are involved in protein-cell membrane binding, do not show definite signs of positive selection. The structural modification and occurrence of directional selection in ancestral primates but not any other lineage suggest that the function of SED1 may have changed during primate evolution. These results reveal a different evolutionary pattern of SED1 from that of many other sperm-egg-binding proteins, which often show diversifying selection occurring in multiple lineages.

Positive selection for indel substitutions in the rodent sperm protein catsper1.

Catsper1 is a voltage-gated calcium channel located in the plasma membrane of the sperm tail and is necessary for sperm motility and fertility in mice. We here examine the evolutionary pattern of Catsper1 from nine species of the rodent subfamily Murinae of family Muridae. We show that the rate of insertion/deletion (indel) substitutions in exon 1 of the gene is 4-15 times that in introns or neutral genomic regions, suggesting the presence of strong positive selection that promotes fixations of indel mutations in exon 1. The number of indel polymorphisms within species appears higher than expected from interspecific comparisons, although there are too little data to provide a statistically significant conclusion. These results, together with an earlier report in primates, indicate that positive selection promoting length variation in Catsper1 may be widespread in mammals. A structural model of Catsper1 suggested the importance of the exon 1-encoded region in regulating channel inactivation, which may affect sperm mobility and sperm competition. Our findings provide a necessary foundation for future experimental investigations of Catsper1's function in sperm physiology and role in sperm competition using rodent models.

Rapid evolution of primate antiviral enzyme APOBEC3G.

Human cytidine deaminase APOBEC3G and the virion infectivity factor (vif) of the human immunodeficiency virus (HIV) are a pair of antagonistic molecules. In the absence of vif, APOBEC3G induces a high rate of dC to dU mutations in the nascent reverse transcripts of HIV that leads to the degradation of the HIV genome. HIV vif, on the other hand, can suppress the translation and trigger the degradation of human APOBEC3G. Here, we studied the rate of APOBEC3G gene evolution from five hominoids and two Old World monkeys. Averaged across the entire coding region, the rate of non-synonymous nucleotide substitutions is approximately 1.4 times the rate of synonymous substitutions, strongly suggesting that APOBEC3G has been under positive Darwinian selection. A comparison between the nucleotide polymorphisms within humans and the substitutions among the seven primates reveals a significant excess of non-synonymous substitutions. Furthermore, the rate of charge-altering non-synonymous substitution is approximately 1.8 times that of charge-conserving substitution, indicating that the selection is promoting the diversity of the protein charge profile. However, no difference in selective pressure on APOBEC3G is detected between hosts and non-hosts of HIV or simian immunodeficiency virus (SIV). These results, together with recent findings that the antiviral activity of APOBEC3G is not limited to HIV/SIV, suggest that the selective pressure on APOBEC3G is not solely from HIV/SIV and that APOBEC3G is a broad antiviral enzyme. The identification of pervasive positive selection for charge-altering amino acid substitutions supports the hypothesis of electrostatic interactions between APOBEC3G and vif or its functional equivalents.

Genetic evidence for the coexistence of pheromone perception and full trichromatic vision in howler monkeys.

Vertebrate pheromones are water-soluble chemicals perceived mainly by the vomeronasal organ (VNO) for intraspecific communications. Humans, apes, and Old World (OW) monkeys lack functional genes responsible for the pheromone signal transduction and are generally insensitive to vomeronasal pheromones. It has been hypothesized that the evolutionary deterioration of pheromone sensitivity occurred because pheromone communication became redundant after the emergence of full trichromatic color vision via the duplication of the X-chromosome-linked red/green opsin gene in the common ancestor of hominoids and OW monkeys. Interestingly, full trichromacy also evolved in the New World (NW) howler monkeys via an independent duplication of the same gene. Here we sequenced from three species of howler monkeys an essential component of the VNO pheromone transduction pathway, the gene encoding the ion channel TRP2. In contrast to those of hominoids and OW monkeys, the howler TRP2 sequences have none of the characteristics of pseudogenes. This and other observations indicate that howler monkeys have maintained both their systems of pheromone communication and full trichromatic vision, suggesting that the presence of full trichromacy alone does not lead to the loss of pheromone communication. We suggest that the ecological differences between OW and NW primates, particularly in habitat selection, may have also affected the evolution of pheromone perception.

Evolutionary deterioration of the vomeronasal pheromone transduction pathway in catarrhine primates.

Pheromones are water-soluble chemicals released and sensed by individuals of the same species to elicit social and reproductive behaviors or physiological changes; they are perceived primarily by the vomeronasal organ (VNO) in terrestrial vertebrates. Humans and some related primates possess only vestigial VNOs and have no or significantly reduced ability to detect pheromones, a phenomenon not well understood at the molecular level. Here we show that genes encoding the TRP2 ion channel and V1R pheromone receptors, two components of the vomeronasal pheromone signal transduction pathway, have been impaired and removed from functional constraints since shortly before the separation of hominoids and Old World monkeys approximately 23 million years ago, and that the random inactivation of pheromone receptor genes is an ongoing process even in present-day humans. The phylogenetic distribution of vomeronasal pheromone insensitivity is concordant with those of conspicuous female sexual swelling and male trichromatic color vision, suggesting that a vision-based signaling-sensory mechanism may have in part replaced the VNO-mediated chemical-based system in the social/reproductive activities of hominoids and Old World monkeys (catarrhines).

Accelerated protein evolution and origins of human-specific features: Foxp2 as an example.

Genes responsible for human-specific phenotypes may have been under altered selective pressures in human evolution and thus exhibit changes in substitution rate and pattern at the protein sequence level. Using comparative analysis of human, chimpanzee, and mouse protein sequences, we identified two genes (PRM2 and FOXP2) with significantly enhanced evolutionary rates in the hominid lineage. PRM2 is a histone-like protein essential to spermatogenesis and was previously reported to be a likely target of sexual selection in humans and chimpanzees. FOXP2 is a transcription factor involved in speech and language development. Human FOXP2 experienced a >60-fold increase in substitution rate and incorporated two fixed amino acid changes in a broadly defined transcription suppression domain. A survey of a diverse group of placental mammals reveals the uniqueness of the human FOXP2 sequence and a population genetic analysis indicates possible adaptive selection behind the accelerated evolution. Taken together, our results suggest an important role that FOXP2 may have played in the origin of human speech and demonstrate a strategy for identifying candidate genes underlying the emergences of human-specific features.

Swift and sure-footed on the Savanna: A study of Hadzabe gaits and feet in Northern Tanzania.

Data on footprints and gait of 54 Hadzabe, 6-70 years of age expand understanding of pedal morphology of unshod people and assist the development of ideas about the evolution of hominid bipedality and upright posture. Contrary to published data on gaits and pedal morphology of unshod populations, Hadzabe (also known as Hadza) from northern Tanzania exhibit values of stride length, relative stride length, and walking speeds that exceed those of rural and small-town populations. In all observable plantar features, including foot indices, an interdigital space between the hallux and second toe, fanning of the foot anteriorly, and foot angles (in-toeing and out-toeing), Hadzabe feet are comparable with those of never-shod Machiguengas in Perú. On average, Hadzabe hallucal gaps and ball widths are narrower than those of Machiguengas and other unshod short people. Hadzabe feet are also characterized by valgus halluces versus the varus halluces of never-shod Machiguengas and certain West Africans. Although characterized by a valgus toe, Hadzabe hallucal angles, which do not exceed 20°, are lower than those of Northern Hemispheric urbanites and shod rural populations of the Southern and Northern Hemispheres. Hadzabe also exhibit less medial and lateral rotation of the hip joint than Machiguengas do. The heel and the longitudinal arch impressions of the Hadzabe footprints closely resemble those of the Laetoli bipeds in the manner of weight distribution during locomotion. The striking similarity of footprint impressions, especially the heel and the longitudinal arch, between Hadzabe and Laetoli hominid footprints clearly imply that the pedal features of the Laetoli printmakers are remarkably humanoid. Am. J. Hum. Biol. 9:303-321, 1997. © 1997 Wiley-Liss, Inc.