A gene (Adhr(r)) which controls the activity of alcohol dehydrogenase in the scutellum of maize has been found. This gene is not allelic to the Adh(1) locus, which specifies the charge of the enzyme molecule and hence its migration rate. The two genes are linked and located about 17 crossover units apart. The Adh(r)(N) allele specifies equal activities of both the Adh(1)(S) and Adh(1)(F) products. The Adh(r)(L) allele gives lower activities of the Adh(1)(S) products only and operates in both the cis and the trans configurations.

Tumor-induced osteomalacia (TIO) is an acquired disorder of isolated renal phosphate wasting associated with tumors, typically of mesenchymal origin. Patients with TIO share similar biochemical and skeletal phenotypes with patients who have autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia. The study of TIO introduced the idea of the existence of circulating factors, referred to as 'phosphatonins', produced by the tumor, which act upon the kidney to reduce phosphate reabsorption. Although several factors have been identified, the phosphatonin FGF-23, also identified as the causative factor in ADHR, is currently the best characterized of these factors relative to phosphate handling. This review describes the importance of TIO in understanding phosphate homeostasis in the context of new endocrine interactions between the skeleton and the kidney.

It has recently been discovered that the Alcohol dehydrogenase and Alcohol dehydrogenase-related genes of Drosophila melanogaster and closely related species constitute a single transcription unit and that the Alcohol dehydrogenase-related gene is exclusively expressed from a dicistronic mRNA. Here, we show that in Drosophila lebanonensis, subgenus Scaptodrosophila, Adhr: is also transcribed as a dicistronic transcript with Adh Using degenerate primers designed on the sequence of the known Adhr proteins, we have been able to amplify and sequence a partial sequence of Adhr: in species representative of the whole subgenus Drosophila. This has allowed the study of the organization and expression of Adhr: in Drosophila buzzatii. We find that in D. buzzatii Adhr is transcribed as a monocistronic transcript. Adh and Adhr are believed to originate by duplication, and our data suggest that the cotranscription of these two genes was the primitive state, and that their independent transcription in the subgenus Drosophila is derived. We can rationalize the D. buzzatii condition as being correlated with the two genes evolving independent transcriptional control. However, why these two genes with clear divergence in the functions of their proteins should remain cotranscribed in groups as divergent as the subgenus Sophophora and the subgenus Scaptodrosophila remains a mystery.

The eukaryotic ribosome normally cannot be recruited upstream of internal ORFs and therefore polycistronic mRNAs are not efficiently translated in eukaryotic cells. However, examples of dicistronic mRNAs have been reported in Drosophila and other eukaryotes, and it was proposed that the intergenic spacers might contain internal ribosome entry site (IRES) elements. Here we have investigated the translation mechanism of the dicistronic Adh-Adhr mRNA of Drosophila melanogaster. The data indicate that the full-length intergenic spacer strongly enhances translation of the internal ORF of dicistronic reporters, both in S2 cells and adult flies. Interestingly, transcripts derived from intron-containing constructs gave rise to higher translation yields, suggesting a link between pre-mRNA splicing and efficient internal translation initiation.

BACKGROUND

Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemia in autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH). Iron status influences C-terminal FGF23 (incorporating fragments plus intact FGF23) in ADHR and healthy subjects, and intact FGF23 in ADHR. We hypothesized that in XLH serum iron would inversely correlate to C-terminal FGF23, but not to intact FGF23, mirroring the relationships in normal controls.

METHODS

Subjects included 25 untreated outpatients with XLH at a tertiary medical center and 158 healthy adult controls. Serum iron and plasma intact FGF23 and C-terminal FGF23 were measured in stored samples.

RESULTS

Intact FGF23 was greater than the control mean in 100% of XLH patients, and >2SD above the control mean in 88%, compared to 71% and 21% respectively for C-terminal FGF23. In XLH, iron correlated negatively to log-C-terminal FGF23 (r=-0.523, p<0.01), with a steeper slope than in controls (p<0.001). Iron was not related to log-intact FGF23 in either group. The log-ratio of intact FGF23 to C-terminal FGF23 was higher in XLH (0.00±0.44) than controls (-0.28±0.21, p<0.01), and correlated positively to serum iron (controls r=0.276, p<0.001; XLH r=0.428, p<0.05), with a steeper slope in XLH (p<0.01).

CONCLUSIONS

Like controls, serum iron in XLH is inversely related to C-terminal FGF23 but not intact FGF23. XLH patients are more likely to have elevated intact FGF23 than C-terminal FGF23. The relationships of iron to FGF23 in XLH suggest that altered regulation of FGF23 cleaving may contribute to maintaining hypophosphatemia around an abnormal set-point.

BACKGROUND

Autosomal dominant hypophosphatemic rickets (ADHR) is the only hereditary disorder of renal phosphate wasting in which patients may regain the ability to conserve phosphate. Low iron status plays a role in the pathophysiology of ADHR.

OBJECTIVE

This study reports of a girl with ADHR, iron deficiency, and a paternal history of hypophosphatemic rickets that resolved without treatment. The girl's biochemical phenotype resolved with iron supplementation.

METHODS

A 26-month-old girl presented with typical features of hypophosphatemic rickets, short stature (79 cm; -2.82 SDS), and iron deficiency. Treatment with elemental phosphorus and calcitriol improved her biochemical profile and resolved the rickets. The girl's father had presented with rickets at age 11 months but never received medication. His final height was reduced (154.3 cm; -3.51 SDS), he had undergone corrective leg surgery and had an adult normal phosphate, fibroblast growth factor 23, and iron status. Father and daughter were found to have a heterozygous mutation in exon 3 of the FGF23 gene (c.536G>A, p.Arg179Gln), confirming ADHR.

METHODS

Withdrawal of rickets medication was attempted off and on iron supplementation.

RESULTS

Withdrawal of rickets medication in the girl was unsuccessful in the presence of low-normal serum iron levels at age 5.6 years but was later successful in the presence of high-normal serum iron levels following high-dose iron supplementation.

CONCLUSIONS

We report an association between iron supplementation and a complete loss of biochemical ADHR phenotype, allowing withdrawal of rickets medication. Experience from this case suggests that reduction and withdrawal of rickets medication should be attempted only after iron status has been optimized.

A 3.5-kb segment of the alcohol dehydrogenase (Adh) region that includes the Adh and Adh-related genes was sequenced in 139 Drosophila pseudoobscura strains collected from 13 populations. The Adh gene encodes four protein alleles and rejects a neutral model of protein evolution with the McDonald-Kreitman test, although the number of segregating synonymous sites is too high to conclude that adaptive selection has operated. The Adh-related gene encodes 18 protein haplotypes and fails to reject an equilibrium neutral model. The populations fail to show significant geographic differentiation of the Adh-related haplotypes. Eight of 404 single nucleotide polymorphisms (SNPs) in the Adh region were in significant linkage disequilibrium with three ADHR protein alleles. Coalescent simulations with and without recombination were used to derive the expected levels of significant linkage disequilibrium between SNPs and 18 protein haplotypes. Maximum levels of linkage disequilibrium are expected for protein alleles at moderate frequencies. In coalescent models without recombination, linkage disequilibrium decays between SNPs and high frequency haplotypes because common alleles mutate to haplotypes that are rare or that reach moderate frequency. The implication of this study is that linkage disequilibrium mapping has the highest probability of success with disease-causing alleles at frequencies of 10%.

Fibroblast growth factor-23 (FGF23) regulates phosphate reabsorption in the kidney and therefore plays an essential role in phosphate balance in humans. There is a host of defects that ultimately lead to excess FGF23 levels and thereby cause renal phosphate wasting and hypophosphatemic rickets. We describe the genetic, pathophysiologic, and clinical aspects of this group of disorders with a focus on X-linked hypophosphatemia (XLH), the best characterized of these abnormalities. We also discuss autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR) and tumor-induced osteomalacia (TIO) in addition to other rarer FGF23-mediated conditions. We contrast the FGF23-mediated disorders with FGF23-independent hypophosphatemia, specifically hypophosphatemic rickets with hypercalciuria (HHRH). Errant diagnosis of hypophosphatemic disorders is common. This review aims to enhance the recognition and appropriate diagnosis of hypophosphatemia and to guide appropriate treatment.

Autosomal dominant hypophosphatemic rickets (ADHR; MIM 193100) is a hereditary disorder characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D(3) levels. Recent studies have shown that the fibroblast growth factor 23 (FGF23) gene is responsible for this disease. FGF23 protein is a phosphaturic factor that is elevated in several diseases associated with hypophosphatemia and rickets but varies with disease status in ADHR. In the present study we observed a Chinese family of Han ethnic origin diagnosed with ADHR. The proband is a 30-year-old woman with no history of rickets but with multiple tooth abscesses as a young adult. She presented with progressive painful swelling of the left ankle after a blunt trauma at 26 years of age. She developed back pain, generalized weakness, and fatigue, and she could barely walk at age 27. She was found to have severe hypophosphatemia, low ratio of phosphorus tubule maximum (TmP) to glomerular filtration rate (GFR) (TmP/GFR), and elevated alkaline phosphatase at age 28. Her brother, 26 years old, presented with fatigue at 24 years of age and is normophosphatemic. The parents of this family had no history of rickets or hypophosphatemia. Direct sequence analysis of genomic DNA demonstrated a single heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene in three family members, including the proband, her brother, and their mother. Intact FGF23 assay of seven time points during the oral phosphate loading test showed no significant relationship between intact FGF23 and serum phosphorus levels of the subject with ADHR and a control. It is probably the first report of a Chinese family with ADHR.

BACKGROUND

The study of a distinct group of renal phosphate wasting disorders with bone disease which comprise X-linked hypophosphatemic rickets (XLH), autosomal dominant hypophosphatemic rickets (ADHR) and tumour-induced osteomalacia (TIO) gave rise to the identification of different hormone-like peptides, also known as phosphatonins. These factors are responsible for the major disease features that characterize XLH, ADHR and TIO. Recent reports on one of these phosphatonins, fibroblast growth factor-23 (FGF-23), point to a general role of this factor in mineral ion metabolism.

OBJECTIVE

The main focus regards recent evidence implicating FGF-23 in normal and disordered mineral homeostasis with special emphasis on chronic kidney disease. The interactions of FGF-23 with phosphate, parathyroid hormone and vitamin D are discussed in detail.

CONCLUSIONS

The FGF-23 has been shown to increase urinary phosphate excretion, inhibit bone mineralization and suppress 1,25-dihydroxy vitamin D(3)[1,25(OH)(2)D(3)], the main characteristics that XLH, ADHR and TIO have in common. Apart from its role in these phosphate wasting disorders serum FGF-23 is elevated in hypoparathyroidism and humoral hypercalcaemia of malignancy and responds to altered dietary phosphate and calcium supply in healthy subjects. The FGF-23 is also variably elevated in chronic kidney disease and associated secondary hyperparathyroidism where it correlates positively with serum phosphate and parathyroid hormone and negatively with 1,25(OH)(2)D(3). Such relationships, along with data from experimental studies, raise the question of whether FGF-23 contributes to the pathophysiology of chronic kidney disease.

Fibroblast growth factor 23 (FGF23) is a hormone that inhibits renal phosphate reabsorption and 1,25-dihydroxyvitamin D biosynthesis. The FGF23 subtilisin-like proprotein convertase recognition sequence ((176)RHTR(179)↓) is protected by O-glycosylation through ppGalNAc-T3 (GALNT3) activity. Thus, inactivating GALNT3 mutations render FGF23 susceptible to proteolysis, thereby reducing circulating intact hormone levels and leading to hyperphosphatemic familial tumoral calcinosis. To further delineate the role of glycosylation in the Fgf23 function, we generated an inducible FGF23 transgenic mouse expressing human mutant FGF23 (R176Q and R179Q) found in patients with autosomal dominant hypophosphatemic rickets (ADHR) and bred this animal to Galnt3 knockout mice, a model of familial tumoral calcinosis. Due to the low intact Fgf23 level, Galnt3 knockout mice with wild-type Fgf23 alleles were hyperphosphatemic. In contrast, carriers of the mutant FGF23 transgene, regardless of Galnt3 mutation status, had significantly higher serum intact FGF23, resulting in severe hypophosphatemia. Importantly, serum phosphorus and FGF23 were comparable between transgenic mice with or without normal Galnt3 alleles. To determine whether the presence of the ADHR mutation could improve biochemical and skeletal abnormalities in Galnt3-null mice, these mice were also mated to Fgf23 knock-in mice, carrying heterozygous or homozygous R176Q ADHR Fgf23 mutations. The knock-in mice with functional Galnt3 had normal Fgf23 but were slightly hypophosphatemic. The stabilized Fgf23 ADHR allele reversed the Galnt3-null phenotype and normalized total Fgf23, serum phosphorus, and bone Fgf23 mRNA. However, the skeletal phenotype was unaffected. In summary, these data demonstrate that O-glycosylation by ppGaINAc-T3 is only necessary for proper secretion of intact Fgf23 and, once secreted, does not affect Fgf23 function. Furthermore, the more stable Fgf23 ADHR mutant protein could normalize serum phosphorus in Galnt3 knockout mice.

The sequence of the genomic region that contains the Adh and Adhr genes of Drosophila funebris was used to demonstrate that both genes are present in species of the funebris group. The sequence of this genomic region reveals a 2.9-kb tandem duplication which encompasses 1.6 kb of the 5' flanking region, the entire Adh gene, and two thirds of the first exon of the Adhr gene in D. funebris. This duplication is not fixed in this species since some strains do not carry the duplication. The Adh duplication has also been found in another species of the funebris group, Drosophila macrospina macrospina. The sequence analysis of the 5'-flanking region of the Adh gene indicates a single promoter and shows stretches of high similarity with cis-acting elements responsible for the expression of Adh in Drosophila melanogaster. In confirmation of this indication, the larval and adult transcripts have the same length, which corresponds to the transcription from the promoter proximal to the coding region. The codon bias of the Adh gene of D. funebris is among the lowest reported for any Adh gene in the Drosophilidae species and is very similar to that of the Adhr gene. The Adhr gene evolves slightly faster than Adh at synonymous positions. At nonsynonymous positions, the Adh gene evolves 2.5 times faster than Adhr in the species pair D. funebris-Drosophila immigrans, while in other interspecific comparisons the average is about 1.25. However, in comparisons between some species within the melanogaster and obscura groups, Adh evolves at half the rate of Adhr. The phylogenetic trees constructed with the coding region of the Adh gene cluster D. funebris and D. immigrans and clearly separate them from the clade in which virilis, repleta, and Hawaiian species are grouped. Using the evolutionary synonymous rate estimated for Hawaiian species, the divergence time of D. funebris from the virilis-repleta-Hawaiian clade was estimated as 34.3 Myr, and the divergence time of D. funebris and D. immigrans was estimated as 23.5 Myr.

Time-resolved NMR spectroscopy was applied to study ribozyme-mediated RNA catalysis in a mutant of the hairpin ribozyme, the adenine-dependent hairpin ribozyme (ADHR; M. Meli, et al. J. Biol. Chem. 2003, 278, 9835-9842) with atomic resolution. The mutant ADHR was designed to investigate the role of cofactors in RNA catalytic mechanisms in order to understand cellular processes that could have been present in the archaic "RNA world" and of their evolution towards functional RNAs in modern cellular processes, as for example, found in the glmS ribozyme. Conformational changes due to RNA cleavage were analyzed following spectral changes of the NMR imino proton resonances that could be assigned both for the pre- and postcleaved conformation for this 80-nucleotide long RNA. (31)P NMR spectroscopic studies allowed us to confirm the formation of a cyclic phosphodiester as a result of the cleavage process. For ADHR, both metal ions and the cofactor adenine are essential for self-cleaving activity. The interaction of the ribozyme with the cofactor adenine is found to be transient and too weak to significantly change the RNA structure or to modulate the spectroscopic characteristics of the cofactor. ADHR therefore represents a ribozyme in which high activation barriers have to be overcome to populate cleavage-competent states that exhibit short life times. We show that conformational dynamics, but not the chemistry, constitute the rate-limiting step in catalysis of the adenine-dependent hairpin ribozyme.

Three metabolic bone diseases display similar characteristics such as hypophosphatemia due to chronically elevated renal phosphate clearance, inappropriately low 1,25 (OH)2 vitamin D serum levels, and variable bone disease (rickets and osteomalacia). X-linked dominant hypophosphatemic rickets (XLH), also called vitamin D-resistant rickets and autosomal dominant hypophosphatemic rickets (ADHR) represent two inherited diseases, whereas oncogenic hypophosphatemia (OHO), also known as tumor induced osteomalacia (TIO), is an acquired paraneoplastic syndrome that, in certain aspects, has much in common with XLH and ADHR. Although the primary causes for these disorders are distinct and well established, their similar features suggest a unifying pathophysiological basis. This review summarizes what is known about the mechanisms that underlie these diseases and includes most up-to-date information about recently introduced factors that might be involved in the regulation of phosphate homeostasis and skeletal mineralization.

Phosphate homeostasis in humans is a complex phenomenon involving the interplay of several different organs and circulating hormones. Among the latter, parathyroid hormone (PTh), and vitamin D3 (Vit D3) were thought to be the main regulators of serum phosphate concentration since they mediated the intestinal, renal and bone responses that follow fluctuations in serum phosphate levels. The study of three rare disorders - tumor-induced osteomalacia (TIo), autosomal dominant hypophosphatemic rickets (ADhr) and X-linked hypophosphatemic rickets (XLh) - has offered a completely new insight into phosphate metabolism by unraveling the role of a group of peptides that can directly affect serum phosphate concentration by increasing urinary phosphate excretion. fibroblast growth factor-23 (fGf-23) is the most extensively studied ''phosphatonin''. The production, mechanism of action, effects in various target tissues, and its role in common clinical disorders are the focus of this review.

The Drosophila fat body protein 2 gene (Fbp2) is an ancient duplication of the alcohol dehydrogenase gene (Adh) which encodes a protein that differs substantially from ADH in its methionine content. In D. melanogaster, there is one methionine in ADH, while there are 51 (20% of all amino acids) in FBP2. Methionine is involved in 46% of amino acid replacements when Fbp2 DNA sequences are compared between D. melanogaster and D. pseudoobscura. Methionine accumulation does not affect conserved residues of the ADH-ADHr-FBP2 multigene family. The multigene family has evolved by replacement of mildly hydrophobic amino acids by methionine with no apparent reversion. Its short-term evolution was compared between two Drosophila species, while its long-term evolution was compared between two genera belonging respectively to acalyptrate and calyptrate Diptera, Drosophila and Sarcophaga. The pattern of nucleotide substitution was consistent with an independent accumulation of methionines at the Fbp2 locus in each lineage. Under a steady-state model, the rate of methionine accumulation was constant in the lineage leading to Drosophila, and was twice as fast as that in the calyptrate lineage. Substitution rates were consistent with a slight positive selective advantage for each methionine change in about one-half of amino acid sites in Drosophila. This shows that selection can potentially account for a large proportion of amino acid replacements in the molecular evolution of proteins.

The 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a master regulator of glycolysis in cancer cells by synthesizing fructose-2,6-bisphosphate (F-2,6-BP), a potent allosteric activator of phosphofructokinase-1 (PFK-1), which is a rate-limiting enzyme of glycolysis. PFKFB3 is an attractive target for cancer treatment. It is valuable to discover promising inhibitors by using 3D-QSAR pharmacophore modeling, virtual screening, molecular docking and molecular dynamics simulation. Twenty molecules with known activity were used to build 3D-QSAR pharmacophore models. The best pharmacophore model was ADHR called Hypo1, which had the highest correlation value of 0.98 and the lowest RMSD of 0.82. Then, the Hypo1 was validated by cost value method, test set method and decoy set validation method. Next, the Hypo1 combined with Lipinski's rule of five and ADMET properties were employed to screen databases including Asinex and Specs, total of 1,048,159 molecules. The hits retrieved from screening were docked into protein by different procedures including HTVS, SP and XP. Finally, nine molecules were picked out as potential PFKFB3 inhibitors. The stability of PFKFB3-lead complexes was verified by 40 ns molecular dynamics simulation. The binding free energy and the energy contribution of per residue to the binding energy were calculated by MM-PBSA based on molecular dynamics simulation.

Extracellular phosphate concentrations are maintained by coordinated regulation of specific homeostatic mechanisms. A novel gene, the type IIb sodium-phosphate cotransporter (Npt2b), was recently cloned and is expressed within intestinal tissues, indicating that the transporter may be an important regulator of phosphate reabsorption. Another gene, human stanniocalcin-2 (STC2), was previously shown to decrease phosphate uptake into kidney cells in vitro. Because of the important role that STC2 may play in phosphate homeostasis, we considered the peptide hormone a candidate for the phosphate wasting disease autosomal dominant hypophosphatemic rickets (ADHR), previously localized to chromosome 12p13. The purpose of our study was to determine the chromosomal localization of human NPT2b and STC2. In the present work, NPT2b was localized to human chromosome 4p15-p16, and STC2 to 5q33-tel. Because STC2 did not map to 12p13, the hormone was excluded as the ADHR gene, however it should be considered a candidate for other diseases involving phosphate homeostasis.

Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations impairing cleavage of fibroblast growth factor 23 (FGF23). FGF23 gene expression increases during iron deficiency. In humans and mice with the ADHR mutation, iron deficiency results in increased intact FGF23 concentrations and hypophosphatemia. We conducted a prospective open label pilot clinical trial of oral iron replacement over 12 months in ADHR patients to test the hypothesis that oral iron administration would normalize FGF23 concentrations. Eligibility criteria included: FGF23 mutation; and either serum iron <50 μg/dL; or serum iron 50 to 100 μg/dL combined with hypophosphatemia and intact FGF23 >30 pg/mL at screening. Key exclusion criteria were kidney disease and pregnancy. Oral iron supplementation started at 65 mg daily and was titrated based on fasting serum iron concentration. The primary outcome was decrease in fasting intact FGF23 by ≥20% from baseline. Six adults (three male, three female) having the FGF23-R176Q mutation were enrolled; five completed the 12-month protocol. At baseline three of five subjects had severely symptomatic hypophosphatemia (phosphorus <2.5 mg/dL) and received calcitriol with or without phosphate concurrent with oral iron during the trial. The primary outcome was met by 4 of 5 (80%) subjects all by month 4, and 5 of 5 had normal intact FGF23 at month 12. Median (minimum, maximum) intact FGF23 concentration decreased from 172 (20, 192) pg/mL at baseline to 47 (17, 78) pg/mL at month 4 and 42 (19, 63) pg/mL at month 12. Median ferritin increased from 18.6 (7.7, 82.5) ng/mL at baseline to 78.0 (49.6, 261.0) ng/mL at month 12. During iron treatment, all three subjects with baseline hypophosphatemia normalized serum phosphorus, had markedly improved symptoms, and were able to discontinue calcitriol and phosphate. Oral iron repletion normalized FGF23 and phosphorus in symptomatic, iron-deficient ADHR subjects. Thus, the standard approach to ADHR should include recognition, treatment, and prevention of iron deficiency. © 2019 American Society for Bone and Mineral Research.

BACKGROUND

Attention deficit hyperactivity disorder (ADHD) is a syndrome that affects between 3 5% of the population of school aged children, and may be accompanied by learning, language, behavioural or motor disorders. Although various electroencephalographic alterations have been described in these patients, their pathological significance has not been determined. There have also been reports of children with neuropsychological and language disorders having epileptiform anomalies in the EEG recording.

METHODS

We conducted a study of 15 children, with no history of seizures, who had been referred to Child Neurology for treatment and who satisfied the criteria for ADHD according to the DSM IV and the ADHRS (attention deficit/hyperactivity rating scale).

RESULTS

The EEG recording in the waking state showed significant anomalies in two of our patients (acute spike and wave paroxysmal activity in the left temporoparietal region and spike wave discharges during hyperventilation). The polysomnographic study revealed specific alterations in four children. There was a continuous spike wave trace during slow sleep (CSWS) in one case, paroxysmal activity (slow acute waves, spikes) in the temporoparietal region with secondary generalization or transmission (two cases), and frequent generalized paroxysmal discharges of slow acute waves in all phases of sleep (one case).

CONCLUSIONS

The neurophysiological disorders observed in some of our patients could make it necessary to consider performing a night time polysomnographic study in certain cases of ADHD.

BACKGROUND

Assessments of spinal stiffness have become more popular in recent years as a noninvasive objective biomechanical means to evaluate the human spine. Studies investigating posteroanterior (PA) forces in spinal stiffness assessment have shown relationships to spinal level, body type, and lumbar extensor muscle activity. Such measures may be important determinants to discriminate between patients with low back pain (LBP) and asymptomatic subjects.

OBJECTIVE

To determine the relationships between dynamic PA spinal stiffness and radiographic measures of lower lumbar disk height and disk degeneration.

METHODS

L4 and L5 posterior disk height (PDH), vertebral body height (PVH), anterior disk height (ADH), and vertebral body height (AVH) were obtained from digitized plain film anteroposterior (AP) and lateral radiographs of 18 symptomatic LBP patients presenting to a chiropractic office (8 female patients and 10 male patients, aged 15-69 years, mean 44.3, SD 15.4 years). Disk degeneration (DD) and facet arthrosis (FA) were qualitatively assessed from the films by an independent examiner. Anterior disk height ratios (ADHR = ADH/AVH) and posterior disk height ratios (PDHR = PDH/PVH) were calculated from the disk height measurements and were compared to L4 and L5 posteroanterior spinal stiffness obtained using a previously validated mechanical impedance stiffness assessment procedure.

RESULTS

One third of the subjects were found to have radiographic evidence of mild or moderate DD and approximately two thirds of the subjects showed signs of mild or moderate FA. The L4 and L5 anterior disk height and posterior disk height were approximately one half and one fifth of the respective vertebral body heights, and the PA stiffness was greater at L4 than at L5. Male subjects had a greater ADHR than female subjects, but female subjects had a greater L4 and L5 PA stiffness in comparison to male subjects; however, these differences were not statistically significant. Posteroanterior L5 vertebral stiffness was found to be significantly correlated to the L5 PDHR.

CONCLUSIONS

Computations of spinal input impedance are relatively simple to perform, can provide a noninvasive measure of the dynamic mechanical behavior of the spine, appear to have potential to discriminate pathologic changes to the spine, and warrant further study on a larger sample of normal subjects and patients.

PTH and active vitamin D are well known as classical phosphate regulating hormones. However, presence of some phosphaturic factors is assumed from investigations about TIO, XLH, ADHR. Those diseases cause hypophsophatemia, hyperphosphaturia, low vitamin D and rickets/ostepmalacia. FGF-23, which has been detected from TIO tumors, can induce hypophosphatemia by direct inhibition on phosphate reabsorption and by suppressing 1,25 (OH)(2)D(3) production through the inhibition of 25-hydroxyvitaminD 1alpha-hydroxylase, in the kidney. We have still other phosphatonin candidates such as MEPE, FRP4, etc. The role of these substances are not clear yet. Future investigations are required to clarify their roles in phosphate metabolism.

This report describes the structure and expression of the outspread (osp) gene of Drosophila melanogaster. Previous work showed that chromosomal breakpoints associated with mutations of the osp locus map to both sides of the alcohol dehydrogenase gene (Adh), suggesting that Adh and the adjacent gene Adhr are nested in osp. We extended a chromosomal walk and mapped additional osp mutations to define the maximum molecular limit of osp as 119 kb. We identified a 6-kb transcript that hybridizes to osp region DNA and is altered or absent in osp mutants. Accumulation of this RNA peaks during embryonic and pupal periods. The osp cDNAs comprise two distinct classes based on alternative splicing patterns. The 5' end of the longest cDNA was extended by PCR amplification. When hybridized to the osp walk, the 5' extension verifies that Adh and Adhr are nested in osp and shows that osp has a transcription unit of>> or = 74 kb. In situ hybridization shows that osp is expressed both maternally and zygotically. In the ovary, osp is transcribed in nurse cells and localized in the oocyte. In embryos, expression is most abundant in the developing visceral and somatic musculature.

Hypophosphatemic rickets (HR) is a syndrome of hypophosphatemia and rickets that resembles vitamin D deficiency, which is caused by malfunction of renal tubules in phosphate reabsorption. Phosphate is an essential mineral, which is important for bone and tooth structure. It is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast-growth-factor 23 (FGF23). X-linked hypophosphatemia (XLH), autosomal dominant HR (ADHR), and autosomal recessive HR (ARHR) are examples of hereditary forms of HR, which are mainly caused by mutations in the phosphate regulating endopeptidase homolog, X-linked (PHEX), FGF23, and, dentin matrix protein-1 (DMP1) and ecto-nucleotide pyro phosphatase/phosphodiesterase 1 (ENPP1) genes, respectively. Mutations in these genes are believed to cause elevation of circulating FGF23 protein. Increase in FGF23 disrupts phosphate homeostasis, leading to HR. This review aims to summarize phosphate homeostasis and focuses on the genes and mutations related to XLH, ADHR, and ARHR. A compilation of XLH mutation hotspots based on the PHEX gene database and mutations found in the FGF23, DMP1, and ENPP1 genes are also made available in this review.