Genetic association and cellular function of MC1R variant alleles in human pigmentation.

We have examined MC1R variant allele frequencies in the general population of South East Queensland and in a collection of adolescent dizygotic and monozygotic twins and family members to define statistical associations with hair and skin color, freckling, and mole count. Results of these studies are consistent with a linear recessive allelic model with multiplicative penetrance in the inheritance of red hair. Four alleles, D84E, R151C, R160W, and D294H, are strongly associated with red hair and fair skin with multinomial regression analysis showing odds ratios of 63, 118, 50, and 94, respectively. An additional three low-penetrance alleles V60L, V92M, and R163Q have odds ratios 6, 5, and 2 relative to the wild-type allele. To address the cellular effects of MC1R variant alleles in signal transduction, we expressed these receptors in permanently transfected HEK293 cells. Measurement of receptor activity via induction of a cAMP-responsive luciferase reporter gene found that the R151C and R160W receptors were active in the presence of NDP-MSH ligand, but at much reduced levels compared with that seen with the wild-type receptor. The ability to stimulate phosphorylation of the cAMP response element binding protein (CREB) transcription factor was also apparent in all stimulated MC1R variant allele-expressing HEK293 cell extracts as assessed by immunoblotting. In contrast, human melanoma cell lines showed wide variation in the their ability to undergo cAMP-mediated CREB phosphorylation. Culture of human melanocytes of known MC1R genotype may provide the best experimental approach to examine the functional consequences for each MC1R variant allele. With this objective, we have established more than 300 melanocyte cell strains of defined MC1R genotype.

A complement component C3-like protein from the tunicate, Styela plicata.

This study identifies a complement component C3-like protein in the solitary tunicate, Styela plicata. Three different polyclonal antibodies raised against C3 molecules from two species (humans and the tunicate, Halocynthia roretzi) were used to identify the C3-like protein in S. plicata hemolymph. The C3 cross-reactive protein is a 170kDa heterodimer composed of polypeptides (116 and 80kDa) that have molecular weights comparable to those of C3alpha and C3beta from other species. Amino acid sequencing and amino acid composition analysis confirmed that the C3-like protein from S. plicata is closely related to C3 from H. roretzi.

Dorsal root ganglion neurons show increased expression of the calcium channel alpha2delta-1 subunit following partial sciatic nerve injury.

Neuropathic pain is associated with changes in the electrophysiological and neurochemical properties of injured primary afferent neurons. A mRNA differential display study in rat L(4/5) dorsal root ganglia (DRGs) revealed upregulation of the calcium channel alpha2delta-1 subunit 2 weeks after partial sciatic nerve ligation (Seltzer model of neuropathic pain). The upregulated transcript appeared to represent previously unidentified sequence from the 3'-untranslated region of rat alpha2delta-1 mRNA. In situ hybridization using L(5) DRGs from sham operated rats showed that 73, 40 and 19% of small (<700 microm(2)), medium (700-1100 microm(2)) and large (>1100 microm(2)) neuronal profiles, respectively, expressed alpha2delta-1 mRNA. Two weeks following nerve injury there was a significant ipsilateral increase, both in the percentage of DRG neurons expressing alpha2delta-1 mRNA and in the intensity of the hybridization signal. Comparison of this ipsilateral expression with that in sham animals, revealed that for small, medium and large neurons, respectively, the proportion of neurons labelled increased by 1.2-, 1.8- and 2.7-fold, while the hybridization signal in alpha2delta-1-labelled neurons increased by 2.8-, 2.5- and 3.7-fold. The most intensely labelled neuronal profiles in ipsilateral, sham and contralateral DRGs, were generally those with small cross-sectional areas. The alpha2delta-1 auxiliary subunit is known to modulate calcium channel function in heterologous expression systems via its association with the pore-forming alpha1 calcium channel subunit. Therefore the increased levels of this subunit in the populations of primary afferents described may, via modulation of calcium-dependent processes such as neurotransmitter release and neuronal excitability, influence the processing of sensory information.

Efficacy and safety of sildenafil citrate for treatment of erectile dysfunction in a population with associated organic risk factors.

The objective of this study was to determine the efficacy and safety of sildenafil in patients with erectile dysfunction (ED) and associated organic risk factors in a multispecialty clinic. Patients (n = 521) were diagnosed with ED based on self-assessment. Associated risk factors were managed by medication or life-style modifications, or both, before treatment with sildenafil for ED. Patients received a 50-mg dose of sildenafil that could be adjusted to 100 mg or 25 mg based on tolerability and efficacy. Patients recorded the number of successful intercourse encounters for 6 to 8 weeks, and the number of adverse events. Overall, there was an 82% successful intercourse rate with sildenafil treatment. The predominant associated risk factors for ED were hypertension (39%), hypogonadism (37%), and multiple medications (34%). Common adverse events due to sildenafil treatment were mild to moderate in nature and resulted in <2% patient discontinuation. Clinicians should be particularly careful to evaluate patients presenting with ED because the condition can be accompanied by a wide spectrum of risk factors requiring monitoring and treatment. However, with adequate treatment and control of these risk factors, the use of sildenafil in a representative population of men with ED in a multispecialty clinic can achieve a higher efficacy rate than previous studies have indicated.

Humoral opsonins of the tunicate, Pyura stolonifera.

This study characterizes humoral opsonins from the tunicate, Pyura stolonifera. The predominant opsonic components in P. stolonifera hemolymph were found to be calcium-dependent lectins with broad carbohydrate specificities. The opsonic lectins were purified by carbohydrate affinity chromatography which eluted a complex pattern of proteins ranging in molecular mass from 80 to >200kDa. Reducing and two dimensional SDS-PAGE indicated that the diversity of mature lectins evident under non-reducing conditions resulted from the differential oligomerization of two polypeptide sub-units (35 and 22kDa). In addition to lectin-mediated opsonic activity, hemolymph was also found to contain proteolytically activated opsonins. These data suggest that multiple, possibly interactive opsonic systems co-exist in P. stolonifera.

Validity of the multi-directional reach test: a practical measure for limits of stability in older adults.

BACKGROUND: Falls occur not only in the forward direction, but also to the side and backward. The purpose of this study was to develop a portable and valid tool to measure limits of stability in the anterior-posterior and medial-lateral directions. METHODS: Two hundred fifty-four community-dwelling older persons were administered the Berg Balance Test (BBT), the Timed Up & Go Test (TUG), and the Multi-Directional Reach Test (MDRT). For the MDRT, subjects performed maximal reaches with the outstretched arm forward (FR), to the right (RR), to the left (LR), and leaning backward (BR), with feet flat on the floor. Reach was measured by the subject's total hand excursion along a yardstick affixed to a telescoping tripod. RESULTS: Mean scores on the MDRT were FR = 8.89 +/- 3.4 in., BR = 4.64 +/- 3.07 in., RR = 6.15 +/- 2.99 in., and LR = 6.61 +/- 2.88 in. Interclass Correlation (ICC2,1) for the reaches were greater than.92. Reliability analysis (Cronbach's Alpha,.842) demonstrated that directional reaches measure similar but unique aspects of the MDRT. The MDRT demonstrated significant correlation with the BBT sum and significant inverse relationship with the scores on the TUG. Regression analysis revealed that activity level contributed to scores in the forward, right, and left direction and that fear of falling contributed to scores in the backward direction. CONCLUSION: The Multi-Directional Reach Test is an inexpensive, reliable, and valid tool for measuring the limits of stability as derived by reach in four directions. Values obtained on relatively healthy community-dwelling older adults serve as norms for screening patient populations.

Horizontal plane head stabilization during locomotor tasks.

Frequency characteristics of head stabilization were examined during locomotor tasks in healthy young adults(N = 8) who performed normal walking and 3 walking tasks designed to produce perturbations primarily in the horizontal plane. In the 3 walking tasks, the arms moved in phase with leg movement, with abnormally large amplitude, and at twice the frequency of leg movement. Head-in-space angular velocity was examined at the predominant frequencies of trunk motion. Head movements in space occurred at low frequencies (< 4.0 Hz) in all conditions and at higher frequencies (> 4.0 Hz) when the arms moved at twice the frequency of the legs. Head stabilization strategies were determined from head-on-trunk with respect to trunk frequency profiles derived from angular velocity data. During natural walking at low frequencies (< 3.0 Hz), head-on-trunk movement was less than trunk movement. At frequencies 3.0 Hz or greater, equal and opposite compensatory movement ensured head stability. When arm swing was altered, compensatory movement guaranteed head stability at all frequencies. Head stabilization was successful for frequencies up to 10.0 Hz during locomotor tasks. Maintaining head stability at high frequencies during voluntary tasks suggests that participants used feedforward mechanisms to coordinate head and trunk movements. Maintenance of head stability during dynamic tasks allows optimal conditions for vestibulo-ocular reflex function.

Storybook-based communication intervention for girls with Rett syndrome and their mothers.

PURPOSE: Storybook reading provides a natural language learning context in which to support early symbolic communication. In this study, we explored the impact of (1) resting hand splints, (2) light tech augmentative communication systems such as voice-output devices and symbols, and (3) very basic parent training on the symbolic communication and labelling behaviours of six girls with Rett syndrome. METHOD: Mothers and daughters were videotaped as they read familiar and unfamiliar storybooks in their homes. RESULTS: Group and individual data collected from the six girls indicated that they became more active and successful participants in the interactions during storybook reading. The girls employed a wider range of communication modes and increased the frequency of their labelling. Familiar storybook reading encouraged greater symbolic communication than unfamiliar storybooks in half the girls. CONCLUSION: This study suggests that motivated parents may not require expensive technologies or lengthy training in order to enhance their children's early communication and participation in storybook reading.

Head stability in older adults during walking with and without visual input.

The purposes of this study were to 1) characterize head stabilization in older adults across the frequency spectrum of walking, and 2) assess the ability of older adults to adapt head-trunk coordination to maintain head stability in the absence of vision. Sagittal plane head and trunk angular velocities in space were measured for 17 healthy older adults while walking with eyes open (EO) and eyes closed (EC). Average walking velocity and cadence were also determined. Frequency analyses were used to examine head velocities in space and head-on-trunk with respect to trunk gain and phase values across the frequency spectrum of walking. Average walking velocity decreased with EC. Head stability was maintained during EO, but decreased during EC as indicated by increased head velocities across the frequency spectrum. Gain values increased while phase values remained similar during EC walking demonstrating diminished coordination of head-trunk movements. When relying on vestibular and proprioceptive information, older adults were unable to adapt head-trunk movements suggesting impaired plasticity of these systems with age.

Nerve injury-associated kinase: a sterile 20-like protein kinase up-regulated in dorsal root ganglia in a rat model of neuropathic pain.

Partial injury of the rat sciatic nerve elicits a variety of characteristic chemical, electrophysical and anatomical changes in primary sensory neurons and constitutes a physiologically relevant model of neuropathic pain. To elucidate molecular mechanisms that underlie the physiology of neuropathic pain, we have used messenger RNA differential display to identify genes that exhibit increased ipsilateral expression in L4/5 dorsal root ganglia, following unilateral partial ligation of the rat sciatic nerve. One set of partial complementary DNA clones identified in this screen was found to encode a protein kinase, nerve injury-associated kinase. Cloning of the full-length human nerve injury-associated kinase complementary DNA, together with recombinant expression analysis, reveal nerve injury-associated kinase to be a functional member of a subgroup of sterile 20-like protein kinases characterised by the presence of a putative carboxy terminal autoregulatory domain. Induction of nerve injury-associated kinase expression in dorsal root ganglia in the rat neuropathic pain model was confirmed by quantitative reverse transcription-polymerase chain reaction, and RNA in situ hybridization analysis revealed enhanced levels of nerve injury-associated kinase within neurons.Together, our data implicate nerve injury-associated kinase as a novel upstream component of an intracellular signalling cascade that is up-regulated in dorsal root ganglia neurons in response to sciatic nerve injury.

Clinical experience with intraurethral alprostadil (MUSE) in the treatment of men with erectile dysfunction. A retrospective study. Medicated urethral system for erection.

OBJECTIVE: The Food and Drug Administration (USA) approved the transurethral administration of prostaglandin (alprostadil in January 1997), which had an efficacy of approximately 50% in clinical trials. We studied its effectiveness in clinical practice. METHODS: Patient and partner education was followed by an initial office trial of a medicated urethral system for erection (MUSE) after other medical risk factors were corrected during a 2- to 4-month period. The initial titration dose of alprostadil was usually 125 or 250 microg. Further titration, if needed, was instituted by the patient at home. Success was determined as the satisfactory completion of sexual intercourse in more than 66% of attempts, with a minimum of two being required. RESULTS: Two hundred and seventy patients entered the trials, and follow-up information was available in 229 (85%). The overall success rate was 56%. The dose required was 500 microg in 49.2% and 1,000 microg in 42.2%. Of the 44% in whom treatment failed, 61.4% did so because of lack of efficacy and 38.6% because of side effects (genital pain or urethral bleeding). Minor urogenital symptoms, which did not interfere with treatment, occurred in an additional 40% of patients. CONCLUSIONS: The efficacy of transurethral administration of alprostadil (56%) is higher than the initial published clinical trial data and higher than recent reported clinical experiences, although higher doses were required in our study. Men over 50 years of age, having an organic cause for erectile dysfunction, had better responses. Patient and partner education is important for successful treatment, and the in-office initial titration is an integral part of this success. Prior correction of medical risk factors may enhance the success rate.

A collectin-like protein from tunicates.

Collectins are a sub-family of C-type lectins from mammals and birds that are characterized by their collagen-like domains. The mammalian collectin, mannose binding lectin, has attracted considerable interest because it can activate complement components via a lectin-mediated complement pathway that is independent of immunoglobulins. In this study, we have identified a calcium-dependent lectin from the invertebrate (tunicate), Styela plicata, that bears substantial similarities to mammalian collectins. The tunicate lectin, which was isolated by carbohydrate affinity chromatography, has a reduced apparent molecular mass of 43 kDa. The 43 kDa reduced polypeptide appeared as dimers, trimers and hexamers when analyzed by non-reducing and two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis, while gel filtration suggested that the native form of the protein was a nonamer. Amino acid sequence and amino acid composition analysis revealed obvious similarities between the tunicate lectin and mammalian collectins, notably the inclusion of a collagenous domain and a short, cysteine bearing N-terminal domain. The identification of a collectin-like protein in an invertebrate such as S. plicata, which does not express immunoglobulin, indicates that lectin-mediated complement pathways may predate the origin of antibodies.

Identification of differentially expressed genes in dorsal root ganglia following partial sciatic nerve injury.

Partial sciatic nerve injury, a model of neuropathic pain, elicits a variety of neurochemical, electrophysiological and neuroanatomical changes in primary sensory neurons. We have used the technique of messenger RNA differential display to identify genes with altered expression in these neurons which may contribute to the development of aberrant sensation following such peripheral nerve damage. This approach identified 14 distinct complementary DNA clones, representing transcripts with increased ipsilateral expression in L4/5 dorsal root ganglia, two weeks after unilateral partial ligation of the rat sciatic nerve. Both Zucker diabetic fatty rats and their lean counterparts were used in this study but none of the transcripts identified showed an induction that was confined to one of the two groups. The majority of the clones did not show significant sequence similarity to previously reported genes and therefore may represent novel messenger RNA sequences or, alternatively, unknown regions of partially characterised messenger RNAs. Two of the clones represented transcripts for the known proteins muscle LIM protein and acidic epididymal glycoprotein, neither of which had previously been associated with expression in the nervous system. Reverse transcriptase-polymerase chain reaction analysis and in situ hybridization confirmed that the messenger RNA expression of both muscle LIM protein and acidic epididymal glycoprotein was induced in an ipsilateral-specific manner. Their localisations, examined with in situ hybridization in L5 dorsal root ganglia, were limited in each case to a sub-population of neuronal profiles. Those neuronal profiles that demonstrated muscle LIM protein hybridization were distributed across the profile size range, whereas the distribution of acidic epididymal glycoprotein-positive profiles appeared to be skewed towards smaller profiles. The induction of muscle LIM protein and acidic epididymal glycoprotein in dorsal root ganglia may play an important functional role in the adaptive response of primary sensory neurons following partial sciatic nerve injury.

Relationship between balance abilities and mobility aids in elderly patients at discharge from an acute care setting.

BACKGROUND AND PURPOSE: At the time of discharge from the acute care setting, patients may not be evaluated for a mobility aid and it is possible this may represent an unmet need. The first purpose of this study was to examine the agreement between the Berg Balance Test (BBT) (Newton, 1997) and the Global Balance Rating scale (GBR) (Leahy, 1991) in terms of acute care patients' need for mobility aids. The second was to determine if there was an increase in mobility aid usage at the time of discharge. METHOD: Thirty inpatients (mean age 76.7 years) were assessed by use of the BBT and the GBR. The therapist rating patients with the GBR also determined the type of mobility aid provided at discharge. RESULTS: At admission, 23/30 individuals did not use a mobility aid and server, used a cane. At discharge, nine subjects were independent ambulators, 10 needed a cane and 11 needed a walker. There was no significant agreement between the GBR in relation to the BBT to determine the need for a mobility aid. There was a significant increase (p = 0.05) in the number of subjects using a mobility aid at the time of discharge as compared to admission to the acute care setting. CONCLUSIONS: Therapists should not rely on the GBR as an indicator of balance, hence the need for an assistive device until reliability and validity measures have been conducted. Therapists should use a functional assessment tool, such as the BBT, since it is reliable and a valid measure of balance ability and has been demonstrated to predict cane use. Since patients are relatively inactive in the acute care setting, referral to physical therapy for functional assessment and mobility aid recommendations should be an integral part of discharge planning.

Acute administration of cocaine, but not amphetamine, increases the level of synaptotagmin IV mRNA in the dorsal striatum of rat.

Synaptotagmin IV (Syt IV) is an inducible member of a multi-gene family of synaptic vesicle proteins that participate in Ca2+-dependent and Ca2+-independent interactions during membrane trafficking. We have examined the pattern of expression of Syt IV mRNA following the administration of cocaine and amphetamine. A single acute dose of cocaine, but not amphetamine, resulted in a transient increase, as determined by in situ hybridization, in the steady-state level of Syt IV mRNA in the dorsal striatum of rats 1 h after the administration of the drug. No change in the hybridization pattern of the Syt IV-specific probe to other regions of the rat brain were observed following cocaine or amphetamine administration at the time points examined (1, 3, 6, 12 and 24 h). The pattern of synaptotagmin I-(Syt I) specific hybridization remained constant, relative to controls, for both the cocaine- and amphetamine-treated animals. Northern hybridization analysis of mRNA isolated from striatal tissue using oligonucleotide probes specific to Syt I and Syt IV demonstrated that the probes hybridized exclusively to transcripts of the sizes previously reported for these two synaptotagmins and confirmed that the relative level of Syt IV to Syt I mRNA increased following the administration of cocaine but not amphetamine. These results indicate that these drugs have different effects on altering the levels of Syt IV mRNA. This work, in conjunction with earlier work that demonstrated that cocaine and amphetamine have different effects on the expression of immediate early genes such as c-Fos, supports the hypothesis that these psychotropic agents evoke different patterns of gene expression which may lead to alteration in synaptic efficacy.

The human S100 protein MRP-14 is a novel activator of the beta 2 integrin Mac-1 on neutrophils.

The 14-kDa myeloid-related protein (MRP-14) and its heterodimeric partner, MRP-8, are members of the S100 family of calcium-binding proteins (S100A9 and S100A8, respectively). Their importance in neutrophil function is implied by their unusual abundance in neutrophil cytosol (approximately 40% of cytosolic protein). Previous work from our laboratory has demonstrated the extracellular association of these proteins with vascular endothelium adjacent to transmigrating leukocytes. We report here a function for MRP-14 as a stimulator of neutrophil adhesion mediated by the beta 2 integrin, Mac-1. MRP-14 is an affinity regulator of Mac-1 because it promotes binding of soluble ligand and expression of an "activation reporter" epitope of high affinity beta 2 integrins recognized by mAb24. The activity of MRP-14 is confined to regulating integrin function because, unlike other inflammatory agonists, there was no release of L-selectin, up-regulation of cytosolic Mac-1, or induction of neutrophil respiratory burst or calcium flux. Furthermore, MRP-14 does not act as a chemoattractant or cause alterations in cell shape or cytoskeleton. MRP-8 has a regulatory role in MRP-14 activity, inhibiting the adhesion induced by MRP-14 through the formation of the heterodimer. In terms of mechanism of action, MRP-14 does not increase Mac-1 function by direct binding to this integrin but recognizes a distinct receptor on neutrophils. This receptor interaction is pertussis toxin sensitive, indicating that MRP-14-generated signals leading to a Mac-1 affinity increase are heterotrimeric G protein dependent. We postulate that MRP-14 and MRP-8 are important in vivo candidates for the regulated adhesion of neutrophils through control of Mac-1 activity.

Mianserin-induced down-regulation of human 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptors stably expressed in the human neuroblastoma cell line SH-SY5Y.

We have assessed the ability of the serotonergic antagonist mianserin to modulate the number and functional activity of human 5-hydroxytryptamine2A (5-HT2A) and 5-HT2C receptors stably expressed in the human neuroblastoma cell line SH-SY5Y. Incubation of cells expressing the 5-HT2A receptor with mianserin (100 nM) for 24 h caused a significant decrease (48%) in the binding capacity of [3H] ketanserin. This receptor down-regulation was associated with a corresponding decrease in the maximal production of inositol phosphates induced by 5-HT but not by carbachol. Exposure of cells expressing the 5-HT2C receptor to mianserin (100 nM) for 72 h but not for 24 h similarly resulted in a significant reduction (44%) in [3H]mesulergine binding. Corresponding analysis of inositol phosphate production by 5-HT at the 5-HT2C receptor after incubation with mianserin showed no change in maximal response after 24 h. No change in the binding capacity of either radioligand was seen after incubation with mianserin for 1 h. A decrease in the binding affinity of both radioligands was also observed after mianserin treatment, but this decrease was similar after 1 h of incubation to that seen after 24 or 72 h, and was probably due to the retention of mianserin within the tissue. We conclude that antagonist down-regulation is evident at human 5-HT2A and 5-HT2C receptors stably expressed in a human neuroblastoma cell line and is probably mediated by a direct action of mianserin at the receptor.

Balance screening of an inner city older adult population.

OBJECTIVE: Until recently, studies of balance abilities were conducted on nursing home residents or volunteers in a clinical laboratory setting. Little is known about balance abilities of older adults living independently in large urban cities or who represent different ethnic backgrounds. The purpose of this study was to describe balance abilities in these individuals. SUBJECTS: Older adults (n = 251) ranging in age from 60 to 95 years of age (X = 74.3, SD = 7.7) participated. The majority of individuals (85.7%) were African-American or Hispanic. PROCEDURE: The elders were screened for past and current medical conditions, activity level, and confidence in performing interactions with the environment (instrumental activities of daily living), and were administered the Berg Balance Scale, Timed Up and Go, and Reach in Four Directions Test. RESULTS: The mode on the Berg Balance Scale was 53 (maximum 56). Mean on the Timed Up and Go was 15 seconds, and Reach in Four Directions Test was: forward, 8.9 in; backward, 4.6 in; right, 6.8 in; and left 6.6 in. Multiple regression analysis revealed that the frequency of performing activities and the comfort in performing activities without fear of falling significantly contributed to the scores on the balance tests. The results of this study can serve as norms for balance testing in urban-dwelling older adult populations from diverse backgrounds and may be useful for clinicians who are developing health promotion and fall prevention programs.

Peyronie's disease is associated with Paget's disease of bone.

Peyronie's disease is an idiopathic disorder in which an inflammatory fibrosis occurs in the tunica albuginea of the corpora cavernosa which causes the erect penis to become deformed. Peyronie's disease has a prevalence of 1% in men over age 50 years. Paget's disease of bone is a chronic skeletal disease with areas of increased bone turnover leading to pain, deformity, and in some cases arthritis. Because of a high rate of Peyronie's disease in subjects in a Paget's disease industry-sponsored drug trial, we asked whether there was an association between Peyronie's disease and Paget's disease of bone. We evaluated 61 men with Paget's disease attending our clinic for metabolic bone disease in a tertiary referral hospital, reviewed hospital records of all men discharged from our three hospitals with the diagnosis of Peyronie's disease, and mailed a validated questionnaire about shape of the erect penis to 1500 male members of the Paget Foundation. In the clinic population of men with Paget's disease of bone, 51 of 61 (83.6%) reported having normal erections; 10 patients (16.4%) were impotent. Sixteen of the 51 men (31.4%) had developed a bend or deformity in their erect penis which was confirmed by a urologist's examination to be Peyronie's disease. When the men with Paget's disease with and without Peyronie's disease were compared, there was no difference in their ages, years with Paget's disease, or serum alkaline phosphatase level. Upon medical record review, 1 patient of 262 (0.4%) with Peyronie's disease was found to have Paget's disease of bone. The men with Paget's disease returned their questionnaires for a response rate of 44.8% and reported Peyronie's disease with a prevalence of 14.5%. We suggest that Peyronie's disease is associated with Paget's disease of bone. Furthermore, we suggest that Peyronie's disease may be a previously unrecognized complication of Paget's disease of bone.

Antiresorptive effect of a single infusion of microgram quantities of zoledronate in Paget's disease of bone.

Zoledronate (CGP 42446) is a third generation imidazole ring containing bisphosphonate that has been found in animal studies to be up to 850 times more potent than pamidronate. In this first study reporting the effects of this drug in humans, 16 patients with active Paget's disease of bone [baseline serum alkaline phosphatase activity (SAP) at least twice the upper limit of normal] were treated in a fixed ascending dose-ranging protocol with a single 1-hour infusion of either 24, 72, 216, or 400 microg of zoledronate (four patients per dose). SAP and two markers of bone resorption, 24-hour urinary hydroxyproline/creatinine excretion (OHP) and 24-hour urinary calcium/creatinine excretion, were measured at baseline, 24 hours postinfusion (day 1) and on postinfusion days 3, 7, 10, and 14. Safety parameters including vital signs, hemogram, and chemistries were measured at the same time points. At the 24- and 72-microg doses there were no consistent or meaningful changes in the bone resorption markers. However, with the 216 microg dose, urinary OHP decreased from baseline by a mean of 16-19% on days 3, 7, 10, and 14; with the 400 microg dose, OHP decreased by a mean of 33-48% at days 1, 7, and 10 and by 16% at day 14. Urinary calcium/creatinine decreased from baseline with the 216 microg dose by a mean of 15-40% on days 1, 3, 7, 10, and 14 and with the 400 microg dose by a mean of 55-71% on days 3, 7, 10, and 14. As expected, there was no reduction in SAP during the 14-day postinfusion period. There was no evidence of an acute phase reaction (pyrexia, myalgia, or arthralgia), leukopenia, or renal or hepatic toxicity. We conclude that single infusions of microgram amounts of zoledronate were capable of inhibiting bone resorption in patients with active Paget's disease during a 2-week study interval. This anti-bone resorbing effect was not associated with any clinically or biochemically observed toxicity. This potent new bisphosphonate appears to be a promising compound for the management of skeletal disorders characterized by increased bone resorption.