Retrospective and Prospective Human Intravenous and Oral Pharmacokinetic Projection of Dipeptidyl peptidase-IV Inhibitors Using Simple Allometric Principles - Case Studies of ABT-279, ABT-341, Alogliptin, Carmegliptin, Sitagliptin and Vildagliptin.

PURPOSE: The purpose of this exercise was to explore the utility of allometric scaling approach for the prediction of intravenous and oral pharmacokinetics of six dipeptidy peptidase-IV (DPP-IV) inhibitors viz. ABT-279, ABT-341, alogliptin, carmegliptin, sitagliptin and vildagliptin. METHODS: The availability of intravenous and oral pharmacokinetic data in animals enabled the allometry scaling of 6 DPP-IV inhibitors. The relationship between the main pharmacokinetic parameters [viz. volume of distribution (Vd) and clearance (CL)] and body weight was studied across three or four mammalian species, using double logarithmic plots to predict the human pharmacokinetic parameters of CL and Vd using simple allometry. RESULTS: A simply allometry relationship: Y = aWb was found to be adequate for the prediction of intravenous and oral human clearance/volume of distribution for DPP-IV inhibitors. The allometric equations for alogliptin, carmegliptin, sitagliptin, vildagliptin, ABT-279 and ABT-341 were 1.867W0.780, 1.170W0.756, 2.020W0.529, 1.959 W0.847, 0.672 W1.016, 1.077W 0.649, respectively, to predict intravenous clearance (CL) and the corresponding equations to predict intravenous volume of distribution (Vd) were: 3.313W0.987, 6.096W0.992, 7.140W0.805, 2.742W0.941, 1.299W0.695 and 5.370W0.803. With the exception of a few discordant values the exponent rule appeared to hold for CL (0.75) and Vd (1.0) for the predictions of various DPP-IV inhibitors. Regardless of the routes, the predicted values were within 2-3 fold of observed values and intravenous allometry was better than oral allometry. CONCLUSION: Simple allometry retrospectively predicted with reasonable accuracy the human reported values of gliptins and could be used as a prospective tool for this class of drugs.

Understanding Darjeeling tea flavour on a molecular basis.

Darjeeling teas are the highest grown teas in the world and preferred for its flavour, aroma and quality. Apart from the genetic makeup of the plant, earlier reports suggest that insect infestation, particularly jassids and thrips triggers the aroma and flavour formation in Darjeeling tea. The present work encompasses the identification of the genes/transcriptomes responsible for the typical flavour of Darjeeling tea, besides understanding the role of jassids and thrips in particular, in producing the best cup character and quality. The quantitative real time PCR analysis was based on a suppression subtractive hybridisation forward library of B157 (tea clone infested with thrips), providing us transcripts related to aroma and flavour formation. We observed the expression of genes like leucine zipper, ntd, nced, geraniol synthase, raffinose synthase, trehalose synthase, amylase, farnesyl transferase, catalase, methyl transferase, linalool synthase, peroxidases, elicitor responsive proteins, linamarase, nerolidol linalool synthase 2, 12-oxophytodienoate reductase, glucosidase, MYB transcription factor, and alcohol dehydrogenase, highly regulated due to insect infestation, manufacturing stresses and mechanical injury. The first report on gene expression dynamics in thrips infested Darjeeling tea leaves can be extrapolated with increase in volatiles which is responsible for enhancing the quality of Darjeeling tea, specially the flavour and aroma of the infusion. We hope to model these responses in order to understand the molecular changes that occur during Darjeeling tea flavour formation.

TGF-beta 1 and 25-hydroxycholesterol stimulate osteoblast-like vascular cells to calcify.

Previous studies in our laboratory demonstrated messenger RNA for bone morphogenetic protein-2a in human calcified plaque, suggesting that arterial calcification is a regulated process, similar to osteogenesis. To further test this hypothesis, we have isolated and cloned a subpopulation of cells from bovine aortic media that show osteoblastic potential. These novel cells are primarily distinguished from smooth muscle cells by expression of a surface marker preliminarily identified as a modified form of the ganglioside sialyl-lactosylceramide (GM3). Osteoblastic potential was indicated by high levels of alkaline phosphatase and collagen I, expression of osteopontin and osteonectin (SPARC), and production of bone-specific osteocalcin and hydroxyapatite. Cultures of these cells were stimulated to form increased numbers of calcium-mineral-producing nodules by the oxysterol 25-hydroxycholesterol as well as by transforming growth factor-beta 1, both known to be present in atherosclerotic lesions. The stimulation of calcifying vascular cells in the artery wall by these two factors suggests a possible mechanism for the colocalization of calcification with atherosclerosis in vivo.

The efficacy of fluticasone furoate administered in the morning or evening is comparable in patients with persistent asthma.

BACKGROUND: The inhaled corticosteroid fluticasone furoate (FF) is efficacious as a once-daily treatment for the management of asthma. Asthma is associated with circadian changes, with worsening lung function at night. We compared the efficacy of once-daily FF in the morning or evening for the treatment of asthma. METHODS: Adults with persistent bronchial asthma were enrolled into this randomised, repeat-dose, double-blind, double-dummy, placebo-controlled, three-way crossover study. After a 14-day run-in period, patients received either: FF 100 µg in the morning (AM); FF 100 µg in the evening (PM); or placebo, via the ELLIPTA(®) dry powder inhaler. Patients received all three treatments (14 ± 2 day duration) separated by a 14- to 21-day washout period. The primary endpoint was 24-h weighted mean forced expiratory volume in 1 s (FEV1) measured at the end of each 14-day treatment. RESULTS: A total of 28 patients aged between 19 and 67 years were randomised and 21 (75%) completed all three study arms. Once-daily administration of FF 100 µg resulted in an increased 24-hour weighted mean FEV1; differences between the adjusted means for AM and PM FF dosing versus placebo were 0.077 L (90% confidence interval [CI]: 0.001, 0.152) and 0.105 L (90% CI: 0.029, 0.180), respectively (adjusted mean difference: -0.028 L [90% CI: -0.102, 0.045]). AM or PM doses had comparable incidences of adverse events (AEs; 18/23 versus 18/24, respectively), no serious AEs occurred. CONCLUSION: AM and PM doses of once-daily FF 100 µg produced comparable improvements in lung function relative to placebo.

Factors affecting the fine specificity and sensitivity of serum antiganglioside antibodies in ELISA.

The major problem associated with ELISA of serum antiganglioside antibodies is the high background values (absorbancy of sera added to wells without ganglioside), which interfere with the accurate assessment of the fine specificity and sensitivity of these antibodies. This investigation identifies factors elevating the background values and/or decreasing the fine specificity, and describes strategies to minimize their influence. Using sera of neuropathy and melanoma patients, we found that highest background values were observed with the polystyrene 'tissue culture' microtiter plates; of the various 'non-tissue culture' microtiter plates tested, the lowest background values (> 0.060) were observed with Costar-3590 (H), Immunolon-3, Immunolon-1, Falcon-3915 (in increasing order). Background artifact of polystyrene microtest plates was significantly reduced by gamma irradiation (at 40 kRad) and/or use of detergent Tween-20 (0.1%) in the washing step. Even after controlling the background values, the fine specificity, namely, the ability of the antibody to distinguish between the target epitope of an antigen and epitopes of related antigens (when moles of antigen/well is constant) varied with different microtiter plates. Using sera with high affinity and specificity for GM2, GD3 or GM3, we observed that Immunolon-1, Immunolon-3 and particularly Falcon-3915 were superior for assessing the abilities of the antibodies to distinguish closely related epitopes found on other gangliosides. The reactivity of antiganglioside antibodies was more consistent after detergent treatment. The reactivity of antibodies to GD3 is significantly enhanced after treatment with Tween-20, but that of antibodies reacting to GM1 and GM2 is reduced. Fine specificity of the antiglycolipid antibodies was resolved better by coating glycolipids in mol/well rather than by weight/well. Based on these results, a protocol for a sensitive and reproducible ELISA for serum antiganglioside antibodies is recommended. The protocol takes into consideration the suitability of polystyrene plates, coating based on the number of molecules, pertinency of the solvent for coating, use of human serum albumin for blocking, dilution and washing steps and use of 0.1% Tween-20 to further minimize the background absorbancy.

Immunopathologic features of Staphylococcus aureus endophthalmitis in the rat.

PURPOSE: To study the clinical, histopathologic, and immunologic responses to Staphylococcus aureus endophthalmitis in rats. METHODS: Experimental Lewis rats received an intravitreal injection of viable S. aureus (65 organisms), and control rats received sterile saline. The clinical scores, cellular infiltrate, delayed hypersensitivity reaction in skin tests, and serum and vitreous enzyme-linked immunosorbent assay titers of immunoglobulin (Ig) M, IgG, and IgA to ribitol teichoic acid (RTA), the major antigenic determinant of S. aureus cell wall, were measured and compared on days 3, 7, 10, 14, 21, and 30. The differences were statistically assessed using Mann-Whitney nonparametric t-tests and analysis of variance. RESULTS: The red reflex was abolished in the majority of rats between days 3 and 21. Ocular inflammation resolved by day 30. The vitreous of eyes injected with S. aureus showed bacterial growth on days 3 and 7, followed by a decrease in numbers on days 10 and 14 and disappearance on days 21 and 30. In the vitreous, a peak neutrophil count was observed at day 3 that rapidly declined by day 7. The number of lymphocytes and plasma cells peaked on day 3 but declined more slowly. Plasma cells and Mott cells were seen on days 10 and 14, suggesting intraocular antibody production. IgM titers to RTA increased progressively in serum and vitreous, reached a peak on day 21, and declined on day 30. A weak IgG but absent IgA response to RTA was observed in serum and vitreous. S. aureus endophthalmitis was not associated with delayed hypersensitivity to the bacteria in skin tests. CONCLUSIONS: S. aureus endophthalmitis is associated with the infiltration of neutrophils, lymphocytes, monocytes, and plasma cells in vitreous. Neutrophils, the predominant infiltrating cells, may be involved in bactericidal activity and opsonophagocytosis. In rat staphylococcal endophthalmitis, IgM rather than IgG may be the protective antibody.

The effect of Staphylococcus aureus phage lysate vaccine on a rabbit model of staphylococcal blepharitis, phlyctenulosis, and catarrhal infiltrates.

PURPOSE: To evaluate the effect of Staphylococcus aureus phage lysate (SPL) vaccination on the development of blepharitis, corneal phlyctenules, and catarrhal infiltrates and on the development of antibodies and the delayed-type hypersensitivity response to S. aureus. METHODS: Eighty rabbits received an intradermal immunization of cell wall-complete Freund's adjuvant followed by a booster immunization. Rabbits were given topical applications of viable S. aureus in both eyes and 40 rabbits received subcutaneous SPL vaccinations. Clinical observations were made weekly. An enzyme-linked immunosorbent assay was used to measure IgG, IgA, and IgM antibody levels to ribitol teichoic acid in sera, corneas, and tears. The delayed-type hypersensitivity response was evaluated by skin testing after subcutaneous injection of staphylococcal antigens. RESULTS: In the SPL-vaccinated group, phlyctenules developed in eight of 40 rabbits while blepharitis developed in 13 of 40. In the nonvaccinated group, phlyctenules developed in three of 40 rabbits and blepharitis developed in five of 40. The number of rabbits with blepharitis was significantly higher in the SPL-vaccinated group than in the nonvaccinated group. In general, the antibody response to ribitol teichoic acid was enhanced, while the delayed-type hypersensitivity response to S. aureus was depressed. CONCLUSIONS: Vaccination with SPL was not found to have a beneficial effect on the development of blepharitis, phlyctenules, and catarrhal infiltrates in our rabbit model.

In vitro neurotoxicity of the antitumor agent 9-methoxy-N2-methylellipticinium acetate (MMEA): role of brain cytochrome P-450.

9-methoxy-N2-methylellipticinium acetate (MMEA) is representative of a series of quaternized ellipticine derivatives that are selectively cytotoxic to human brain tumor cell lines derived from non-neuronal (glial) cells (Acton et al, 1994). In an attempt to determine whether MMEA may exhibit toxicity to normal brain cells, we have examined the effect of the drug, in vitro, using sagittal slices of rat brain. Incubation of rat brain slices in an artificial cerebrospinal fluid medium containing MMEA resulted in dose-dependent leakage of lactate dehydrogenase (LDH) into the surrounding medium. However, other subcellular marker enzymes such as Na(+)-K+ATPase (plasma membrane), cytochrome c oxidase, isocitrate dehydrogenase, NADH-dehydrogenase (mitochondrial), N-acetylglucosaminidase, acid phosphate (lysosomal), glyceraldehyde-3-phosphate dehydrogenase and enolase (glycolytic enzymes) were unaffected even at the highest tested concentrations of MMEA (10 and 100 microM). Preincubation of slices with reserpine (1 nM) or, dopamine or serotonin-specific reuptake inhibitors abolished MMEA-induced toxicity in brain slices. Pretreatment of slices with piperonyl butoxide and metyrapone, inhibitor of cytochrome P-450, also prevented the toxicity of MMEA. Further, brain slices prepared from phenobarbital-treated rats showed enhanced sensitivity to MMEA; significant leakage of LDH was observed at MMEA concentrations as low as 1 nM. The present studies demonstrate the toxicity of MMEA in rat brain slices, in vitro, and suggest a role for brain cytochrome P-450 in the neurotoxicity of MMEA [corrected].

Immunopathologic features of Staphylococcus epidermidis-induced endophthalmitis in the rat.

PURPOSE: To investigate the clinical, histopathologic and immunologic responses to Staphylococcus epidermidis endophthalmitis in a rat model. METHODS: Experimental rats received an intravitreal injection of viable S. epidermidis (7000 organisms), while control rats received sterile saline. The clinical scores, cellular infiltrate in vitreous, and levels of serum and vitreous IgM, IgG and IgA to glycerol teichoic acid (GTA), the major antigenic determinant of S. epidermidis cell wall, were all measured from day 1 to day 30 after injection. RESULTS: The ocular inflammation was largely resolved by day 14. The red reflex was abolished in 50% of rats between days 3 and 10. The bacteria were cleared from the vitreous by day 7. In vitreous, the neutrophils peaked at day 1 and decreased by day 7, and plasma cells were seen between days 1 and 3. Presence of B cells (CD45+/CD3-) was confirmed by flow cytometric analysis of pooled vitreous humor. IgM and IgG but not IgA antibodies to GTA were found in vitreous of injected eyes. The peak of anti-GTA IgM was observed in vitreous of S. epidermidis-infected rats on day 1 and declined by day 7. In contrast to vitreous antibodies, serum anti-GTA IgM antibodies were significantly elevated throughout the course of S. epidermidis endophthalmitis. A weak IgG but no IgA response were observed in serum. Anti-GTA antibodies were also found in low level in normal sera but not in normal vitreous. CONCLUSIONS: The vitreous antibodies may be involved in neutrophil-mediated opsonophagocytosis leading to 'spontaneous sterility' of the bacteria, and may play a role in the immunopathogenesis of staphylococcal endophthalmitis in the rat.

Finger ridge count and finger print pattern in maturity onset diabetes mellitus.

Total finger ridge count, absolute finger ridge count and finger print pattern were studied in 150 maturity onset diabetes mellitus patients and compared to 120 controls. Significant findings were: in males, with both hands combined and separately (i) an increase in radial and ulnar loops and arches (ii) A decrease in whorls. (iii) In females, an increase in ulnar loops and a decrease in whorls in the left hand was observed.

A modified thionin acridine-orange stain for mast cells.

For in vitro studies in mesentery, toluidine blue and thionin dyes are generally used. We have tried thionin and acridine orange stains and found it to be good as it showed good colour contrast between mast cells and the background tissue. The two dyes were selected to give good colour contrast.

Accessory origin of the piriformis muscle.

Incidental finding of an accessory slip of the piriformis muscle in the gluteal region is reported. Following routine dissection of the gluteal region in three formalin-fixed cadavers, an accessory slip of the piriformis was observed. The accessory slip was cleaned, attachments were identified, and dimensions were measured in two parts as fleshy and tendinous parts with a graduated scale to the nearest millimetre. The accessory slip was innervated by a small twig from the sciatic nerve. Having considered the available literature, the accessory slip of piriformis is rare, and if found, could be a cause for the undiagnosed chronic pain in the back and gluteal region, as this accessory slip may compress the sciatic nerve.

Attenuated murine cytomegalovirus binds to N-acetylglucosamine, and shift to virulence may involve recognition of sialic acids.

Treatment of cells with lectins specific for N-acetylglucosamine (GlcNAc) blocked infection by mouse cytomegalovirus (MCMV), and GlcNAc pretreatment of the lectin blocked this effect. MCMV failed to infect N-acetylglucosaminidase (GlcNAcase)-treated mouse embryo fibroblasts (MEF). GlcNAc and GlcNAc-containing synthetic oligosaccharides directly inhibited viral infectivity. Ulex lectin inhibition of infection was shown to be due to inhibition of surface adsorption of 35S-labeled virus. Also, GlcNAcase eluted 35S-labeled virus adsorbed to MEF at 4 degrees C and inhibited plaque formation if added after adsorption at this temperature. These findings indicate that GlcNAc binding is involved in attachment rather than in some later step in infection. High-performance thin-layer chromatography overlay of [35S]MCMV indicated that it binds to a GlcNAc-containing asialoglycolipid. Analogous experiments indicated that MCMV made virulent by in vivo salivary gland passage binds to sialic acids in addition to GlcNAc. Treatment of MEF with sialic acid-binding lectins blocked infectivity. Incubation of virus with sialic acids also prevented infection. N-acetylneuraminic acid was 10(3)-fold more potent than N-glycolylneuraminic acid. Sialidase-treated target cells were not efficiently infected by the virus. Thus, MCMV binds to GlcNAc on the cell surface, and the shift to virulence (by in vivo salivary gland passage) correlates with viral recognition of sialic acids.

Monoclonal IgM antibodies from cytomegalovirus-infected mice recognize the GlcNAc-containing receptor determinant of murine CMV as well as neutralizing anti-CMV IgG antibodies.

This study examines monoclonal antibodies derived from mice at different time points after infection with attenuated murine cytomegalovirus (MCMV). The antibodies obtained from mice at 3 weeks p.i. were of IgG type (designated V-antibodies) and several could neutralize the virus. Those obtained at 5 weeks p.i. were of the IgM class (designated R-antibodies), bound to uninfected (MEF, mouse embryo fibroblast) cells, and thereby blocked MCMV plaque formation. In ELISA, the IgM monoclonals (R-antibodies) bound to GalB1-3GlcNAc and GalB1-4GlcNAc, the receptor determinants for MCMV. Similarly, these GlcNAc-containing residues blocked the binding of purified IgM monoclonal antibodies (MAbs) to MEF. The R- and V-series of antibodies showed mutual binding activities; for example, IgM MAb R-2D8 bound specifically to four (V-8C4, V-1C7, V-8C7, V-9C5) of six neutralizing IgG MAbs in ELISA. The same neutralizing IgG MAbs bound to antireceptor IgM antibodies in an immunoblot assay. This suggests that the IgM monoclonals directed against the known cell surface receptor determinant are anti-idiotypic antibodies against neutralizing antiviral IgG antibodies. The neutralizing antiviral IgG MAbs bound to 60- and 66-kDa MCMV polypeptides on Western blots, suggesting that these viral polypeptides may be important in MCMV binding to this receptor. The R-series might represent anti-idiotype antibodies capable of down-regulating antiviral V-antibodies and may also represent a mechanism for the induction of IgM autoantibodies directed at cell surface glycolipids present in autoimmune CMV-associated neuropathies.

A method for the rapid establishment of normal adult mammalian colonic epithelial cell cultures.

Normal colonic epithelial cell cultures of mammalian origin are required to facilitate the study of both normal cellular functions as well as pathogenesis of certain (human) colonic diseases. To date, little information is available regarding the growth requirements of colonic epithelial cells in culture of either animal or human origin. Such data would enable the development of a long-term culture system for these cells. In this study, we present methodology that results in the establishment of homogeneous cultures of adult rabbit colonic epithelia reproducibly, quickly, and in quantity. The epithelial nature of the cultures is unambiguously established by intermediate filament typing using antikeratin antibodies. Such cultures can now be used for a variety of functional studies as well as to investigate the growth requirements of colonic epithelia in culture.

Augmentation of natural antiganglioside IgM antibodies in lower motor neuron disease (LMND) and role of CD5+ B cells.

IgM antibodies directed against neuronal gangliosides GM1, GM2, GD1a, GD1b and GT1b occur in normal individuals and their level significantly decreases with age. Patients with lower motor neuron disease (LMND) produce high levels of these autoantibodies. AntiGM1 IgM is selectively augmented. In these patients, the CD5+ (B1) and CD5- (B2) subsets of B cells are not distinct entities but range from those without detectable CD5 marker to those with high CD5+ expression. B1 B cells were sorted to homogeneity, but B2 B cell cannot be isolated to homogeneity because of the presence of B1 cells with low CD5 expression. In short term cultures both the subsets produced IgM antibodies, but the antibodies reacted better with desialylated GM1 than with GM1. Cycloheximide (Cx) (0.35 mM) largely blocked IgM synthesis of the B1 B cells but inhibition of the B2 B cells was incomplete, possibly due to shedding of cytophilic antibodies as well as to the presence of B1 phenotype with loss of CD5 expression. CD5+ B cells may be involved in the production of antiglycolipid IgM.

Tyrosyl motif in amelogenins binds N-acetyl-D-glucosamine.

Ameloblasts secrete amelogenins on the pre-existing enamel matrix glycoproteins at the dentine-enamel junction. The hypothesis that amelogenins may interact with enamel matrix glycoproteins is tested by hemagglutination of purified, native (porcine) and recombinant murine amelogenins (rM179 and rM166) and hemagglutination inhibition with sugars. Amelogenin agglutination of murine erythrocytes was specifically inhibited by N-acetylglucosamine (GlcNAc), chitobiose, and chitotetraose and by ovalbumin with terminal GlcNAc. The GlcNAc affinity was confirmed by dosimetric binding of rM179 with [14C]GlcNAc, specific binding in relation to varying concentrations of GlcNAc, Scatchard plot analysis and competitive inhibition with cold GlcNAc. The hemagglutination activity and [14C]GlcNAc affinity were retained by the NH2-terminal tyrosine-rich amelogenin peptide (TRAP) but not by the leucine-rich amelogenin peptide, LRAP (a polypeptide sharing 33 amino acid residues of TRAP), or by the C-terminal 13 residue polypeptide of amelogenin (rM179). Since TRAP but not the 33-residue sequence of the TRAP shared by LRAP bound to [14C]GlcNAc, we inferred that the GlcNAc binding motif was located in the 13-residue tyrosyl C-terminal domain of TRAP (PYPSYGYEPMGGW), which was absent from LRAP. [14C]GlcNAc did indeed bind to this "amelogenin tyrosyl motif peptide" but not when the tyrosyl residues were substituted with phenylalanine or when the third proline was replaced by threonine. Significantly, this latter modification mimics a point mutation identified in a case of human X-linked amelogenesis imperfecta. The amelogenin tyrosyl motif peptide sequence showed a similarity to the secondary GlcNAc-binding site of wheat germ agglutinin.

Amelogenin-cytokeratin 14 interaction in ameloblasts during enamel formation.

The enamel protein amelogenin binds to the GlcNAc-mimicking peptide (GMp) (Ravindranath, R. M. H., Tam, W., Nguyen, P., and Fincham, A. G. (2000) J. Biol. Chem. 275, 39654-39661). The GMp motif is found in the N-terminal region of CK14, a differentiation marker for ameloblasts. The binding affinity of CK14 and amelogenin was confirmed by dosimetric binding of CK14 to recombinant amelogenin (rM179), and to the tyrosine-rich amelogenin polypeptide. The specific binding site for CK14 was identified in the amelogenin trityrosyl motif peptide (ATMP) of tyrosine-rich amelogenin polypeptide and specific interaction between CK14 and [(3)H]ATMP was confirmed by Scatchard analysis. Blocking rM179 with GlcNAc, GMp, or CK14 with ATMP abrogates the CK14-amelogenin interaction. CK14 failed to bind to ATMP when the third proline was substituted with threonine, as in some cases of human X-linked amelogenesis imperfecta or when tyrosyl residues were substituted with phenylalanine. Morphometry of developing teeth distinguished three phases of enamel formation; growth initiation phase (days 0-1), prolific growth phase (days 1-7), and growth cessation phase (post-day 7). Confocal microscopy revealed co-assembly of CK14/amelogenin in the perinuclear region of ameloblasts on day 0, migration of the co-assembled CK14/amelogenin to the apical region of the ameloblasts from day 1, reaching a peak on days 3-5, and a collapse of the co-assembly. Autoradiography with [(3)H]ATMP and [(3)H]GMp corroborated the dissociation of the co-assembly at the ameloblast Tomes' process. It is proposed that CK14 play a chaperon role for nascent amelogenin polypeptide during amelogenesis.

Fingerprint ridge-count difference between adjacent fingertips (dR45) predicts upper-body tissue distribution: evidence for early gestational programming.

Fingerprint ridge counts, which remain constant from the 19th week of pregnancy, are related to fingertip growth during early gestation. Each finger corresponds neurologically to a spinal-cord segment ranging from C6 (thumb, relatively cephalad) to C8 (fifth finger, relatively caudad). The authors hypothesized that large ridge-count differences between fingertips (cephalad > caudad) might reflect fetal inhibition of caudal growth. Among 69 male Atlanta, Georgia, military recruits (1994-1997; aged 17-22 years), they tested associations of the anthropometric waist-to-thigh ratio with 20 ridge-count differences. Waist-to-thigh ratio was associated with the ridge-count difference between the right fourth and fifth fingertips only (dR45; r = 0.36, p = 0.003). The race-adjusted standardized regression coefficient was 0.22 (95% confidence interval: 0.03, 0.41). Since upper-body tissue distribution indicates disease risk, the authors then tested the association of age (an indicator of survivorship) with dR45 in a sample of 135 male patients from Bangalore, India (1989-1990; aged 38-82 years). Age was inversely associated with dR45 (r = -0.17, p = 0.04), notably among the 75 men with diabetes (r = -0.22, p = 0.06). An increased dR45 predicts an upper-body tissue distribution originating before the midpoint of pregnancy. The cause of this developmental pattern is unknown, but it may lead to reduced survivorship.