Time-to-onset of diabetes with everolimus use: analysis of a spontaneous reporting system database.

The incidence of hyperglycemia and diabetes induced by everolimus has been shown in previous studies. Our study analyzed diabetes time-to-onset profiles after everolimus use in patients who underwent transplantation and patients with cancer. Using data from April 2007 to December 2018 in the Japanese Adverse Drug Event Report database, the reports with everolimus were classified according to its use as an immunosuppressant or anticancer drug. The median (25%-75%) days of diabetes time-to-onset in patients who underwent transplantation and patients with cancer were 172 (56-315) and 32 (18.5-57), respectively. There were no significant variations among patients with breast cancer, neuroendocrine tumor, and renal cell carcinoma. By conducting a Weibull shape parameter test, the lower limits of the 95% confidence intervals of the shape parameter ß values for the indications of the cancer types were >1, indicating the wear out failure type profile, whereas those for transplantation data indicated a random failure type profile. The diabetes time-to-onset profiles after everolimus use differed between usage as an anticancer drug and immunosuppressant and there were no significant variations among the type of cancer. It was suggested that the incidence of diabetes should be monitored for 1-2 months in patients with cancer, whereas continuous monitoring is needed in patients who undergo transplantation.

Investigation of immune complexes formed by mitochondrial antigens containing a new lipoylated site in sera of primary biliary cholangitis patients.

Primary biliary cholangitis (PBC) is characterized by the presence of serum anti-mitochondrial autoantibodies (AMAs). To date, four antigens among the 2-oxo-acid dehydrogenase complex family, which commonly have lipoyl domains as an epitope, have been identified as AMA-corresponding antigens (AMA-antigens). It has recently been reported that AMAs react more strongly with certain chemically modified mimics than with the native lipoyl domains in AMA-antigens. Moreover, high concentrations of circulating immune complexes (ICs) in PBC patients have been reported. However, the existence of ICs formed by AMAs and their antigens has not been reported to date. We hypothesized that AMAs and their antigens formed ICs in PBC sera, and analyzed sera of PBC and four autoimmune diseases (Sjögren's syndrome, systemic lupus erythematosus, systemic scleroderma, and rheumatoid arthritis) using immune complexome analysis, in which ICs are separated from serum and are identified by nano-liquid chromatography-tandem mass spectrometry. To correctly assign MS/MS spectra to peptide sequences, we used a protein-search algorithm that including lipoylation and certain xenobiotic modifications. We found three AMA-antigens, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the E2 subunit of the 2-oxo-glutarate dehydrogenase complex (OGDC-E2) and dihydrolipoamide dehydrogenase binding protein (E3BP), by detecting peptides containing lipoylation and xenobiotic modifications from PBC sera. Although the lipoylated sites of these peptides were different from the well-known sites, abnormal lipoylation and xenobiotic modification may lead to production of AMAs and the formation ICs. Further investigation of the lipoylated sites, xenobiotic modifications, and IC formation will lead to deepen our understanding of PBC pathogenesis.

Immune complexome analysis reveals the presence of immune complexes and identifies disease-specific immune complex antigens in saliva samples from patients with Sjögren's syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune disease that mainly damages the salivary and lacrimal glands. Immune complex (IC) formation triggers local inflammation through IC deposition and decreased antigen function. Some ICs can leak from the lesion and into the saliva, but no salivary ICs have been reported to date. We used immune complexome analysis to comprehensively identify antigens incorporated into IC (IC-antigens) in saliva samples from patients with SS (n = 9) or with xerostomia (n = 7). Neutrophil defensin 1 (67%), small proline-rich protein 2D (67%), myeloperoxidase (44%), neutrophil elastase (44%), cathepsin G (33%), nuclear mitotic apparatus 1 (33%) and phosphatidylinositol 4-phosphate 3-kinase C2 domain-containing subunit gamma (33%) were identified as new IC-antigens specifically and frequently detected in the saliva of SS patients. Of these, neutrophil defensin 1, myeloperoxidase, neutrophil elastase and cathepsin G are neutrophil intracellular proteins, which suggests that repeated destruction of neutrophils due to abnormal autoimmunity may be involved in the pathogenesis of SS. We also analyzed serum samples from three SS patients. There was little overlap of IC-antigens between two of the samples (fewer than 30% of the IC-antigens in the saliva samples), suggesting that many ICs are formed locally and independently of the circulation. In addition, we found that four SS-specific salivary antigens show sequence homology with several proteins of oral microbiomes but no antigen has homology with Epstein-Barr virus proteins. The homology between some IC-antigens and oral microbiome proteins may indicate the impact of oral infection on local autoimmunity through molecular mimicry theory.

Psoriasis associated with ACE inhibitors: an analysis of the FAERS database.

Many case reports have been published concerning the development or exacerbation of psoriasis after administration of angiotensin-converting enzyme (ACE) inhibitors. The aim of the present study was to investigate the association between psoriasis and ACE inhibitors using the US Food and Drug Administration Adverse Event Reporting System (FAERS) data. After excluding patients with psoriasis-related primary diseases, the association of psoriasis with 14 ACE inhibitors was examined using disproportional analyses reporting odds ratio (ROR) and information component (IC). Signals were detected for all 14 ACE inhibitors combined (ROR: 1.25, 95% confidence interval [CI]: 1.14-1.37; IC: 0.31, 95% CI: 0.17-0.44) and individually for lisinopril (ROR: 1.20, 95% CI: 1.05-1.37; IC: 0.25, 95% CI: 0.06-0.45), perindopril (ROR: 1.86, 95% CI: 1.38-2.52; IC: 0.86, 95% CI: 0.43-1.30), and ramipril (ROR: 1.63, 95% CI: 1.36-1.96; IC: 0.69, 95% CI: 0.42-0.96). ACE inhibitors are widely used in patients with hypertension, heart failure, and diabetes mellitus, which are considered comorbidities of psoriasis. Our results suggest that the involvement of ACE inhibitors should be considered in patients on ACE inhibitor therapy who have developed (or show exacerbated) psoriasis.

Evaluation of syncope association with α1-adrenoceptor blockers in males using the FAERS database: impact of concomitant hypertension.

Previous studies have revealed an association between the administration of α1-adrenoceptor blockers (α1Bs) and episodes of syncope in patients with benign prostatic hyperplasia (BPH). The objective of the present study was to evaluate the association between α1Bs and syncope in BPH patients with hypertension using two different pharmacoepidemiological indices. Using the US Food and Drug Administration Adverse Event Reporting System, we analyzed the whole dataset and subsets for specific indications, including hypertension, diabetes, and dyslipidemia, for males older than 40 years. The drugs of interest were alfuzosin, doxazosin, and terazosin as non-selective α1Bs and silodosin and tamsulosin as selective α1Bs. The reporting odds ratio (ROR) and information component (IC) were used for signal detection. The association between the non-selective α1Bs and syncope was observed for all the items examined. The results obtained using the whole dataset, as well as the diabetes and dyslipidemia subsets, were same for the selective and non-selective α1Bs in terms of the association with syncope, while no association with syncope was observed for both silodosin [ROR: 1.09, 95% confidence interval (CI): 0.61-1.93; IC: 0.10, 95% CI: -0.72-0.92] and tamsulosin (ROR: 1.08, 95% CI: 0.90-1.30; IC: 0.10, 95% CI: -0.17-0.37) in patients with hypertension. The data suggested that α1Bs, even those with receptor subtype selectivity, were associated with syncope. Thus, careful attention should be paid when prescribing α1Bs, especially to patients who do not take medications for hypertension.

Proteomic profile of circulating immune complexes in chronic Chagas disease.

Immune complexes (ICs) are the direct and real-time products of humoral immune responses. The identification of constituent foreign or autoantigens within ICs might bring new insights into the pathology of infectious diseases. We applied immune complexome analysis of plasma to the study of Chagas disease caused by Trypanosoma cruzi. Twenty seropositive plasma samples including cardiac and/or megacolon determinate patients (n = 11) and indeterminate (n = 9) were analysed along with 10 seronegative individuals to characterize the antigens bound to circulating ICs. We identified 39 T. cruzi antigens and 114 human autoantigens specific to patients with Chagas. Among those antigens, two T. cruzi antigens (surface protease GP63, glucose-6-isomerase) and six human autoantigens (CD180 antigen, ceruloplasmin, fibrinogen beta chain, fibrinogen beta chain isoform 2 preprotein, isoform gamma-A of fibrinogen γ-chain, serum paraoxonase) were detected in more than 50% of the patients tested. Human isoform short of complement factor H-related protein 2 and trans-sialidase of T. cruzi were more frequently found in the indeterminate (5/9 for both) compared with in the determinate Chagas (0/11, P = 0·046 for human, 1/11, P = 0·0498 for T. cruzi). The immune complexome could illustrate the difference of immune status between clinical forms of chronic Chagas disease.

Saliva as a potential tool for diagnosis of dry mouth including Sjögren's syndrome.

OBJECTIVES: Recently, the use of saliva as a diagnostic tool has gained considerable attention because it is non-invasive and easy to perform repeatedly. In this study, we focused on soluble molecules in saliva to establish a new diagnostic method for xerostomia. MATERIALS AND METHODS: Saliva was obtained from 90 patients with Sjögren's syndrome (SS), 22 patients with xerostomia associated with neurogenic/neuropsychiatric disorders and drugs (XND), 30 patients with radiation-induced xerostomia (RX), and 36 healthy controls. Concentrations of helper T (Th) cytokines in saliva were measured by flow cytometric analysis. Concentrations of secretory IgA (SIgA) and chromogranin A (CgA) were measured by ELISA. RESULTS: Unstimulated and stimulated whole saliva from patients with SS, XND, and RX was significantly reduced compared with controls. Th1 and Th2 cytokines from SS patients were significantly higher than controls. Furthermore, Th2 cytokines were closely associated with strong lymphocytic accumulation in salivary glands from SS patients, while Th1 and Th17 cytokines were negatively associated. SIgA levels were not significantly different between all patient groups and controls. CgA levels from XND patients were significantly higher than controls. CONCLUSIONS: The measurement of cytokines, CgA, and SIgA in saliva is suggested to be useful for the diagnosis of xerostomia and also to reveal disease status.

Muscle atrophy in chronic inflammatory demyelinating polyneuropathy: a computed tomography assessment.

BACKGROUND AND PURPOSE: Muscle atrophy is generally mild in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) compared with the severity and duration of the muscle weakness. Muscle atrophy was evaluated using computed tomography (CT) in patients with CIDP. METHODS: Thirty-one patients with typical CIDP who satisfied the diagnostic criteria for the definite CIDP classification proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society were assessed. The clinicopathological findings in patients with muscle atrophy were also compared with those in patients without atrophy. RESULTS: Computed tomography evidence was found of marked muscle atrophy with findings suggestive of fatty degeneration in 11 of the 31 patients with CIDP. CT-assessed muscle atrophy was in the lower extremities, particularly in the ankle plantarflexor muscles. Muscle weakness, which reflects the presence of muscle atrophy, tended to be more pronounced in the lower extremities than in the upper extremities in patients with muscle atrophy, whereas the upper and lower limbs tended to be equally affected in patients without muscle atrophy. Nerve conduction examinations revealed significantly greater reductions in compound muscle action potential amplitudes in the tibial nerves of patients with muscle atrophy. Sural nerve biopsy findings were similar in both groups. The functional prognoses after immunomodulatory therapies were significantly poorer amongst patients with muscle atrophy. CONCLUSIONS: Muscle atrophy was present in a subgroup of patients with CIDP, including patients with a typical form of the disease. These patients tended to demonstrate predominant motor impairments of the lower extremities and poorer functional prognoses.

Assessment of hepatocellular carcinoma by contrast-enhanced ultrasound with perfluorobutane microbubbles: comparison with dynamic CT.

OBJECTIVE: The aim of this study was to evaluate tumour vascularity and Kupffer cell imaging in hepatocellular carcinoma (HCC) using contrast-enhanced ultrasonography (CEUS) with Sonazoid (perfluorobutane) and to compare performance with dynamic CT. METHODS: We studied 118 nodules in 88 patients with HCC. HCC was diagnosed as a hyperenhancement lesion in the arterial phase with washout in the portal phase on dynamic CT or by percutaneous biopsy. We observed tumour vascularity at the early vascular phase (10-30 s after contrast injection) and Kupffer imaging at the post-vascular phase (after 10 min). RESULTS: Detection of vascularity at the early vascular phase was 88% in nodules that were found to be hypervascular on dynamic CT and 28% in hypo-/isovascular nodules; the detection of local recurrence nodules was 92%. The detection of vascularity was significantly lower in nodules >9 cm deep than in those ≤9 cm deep, but was not affected by tumour size. The detection of tumours at the post-vascular phase on CEUS was 83% in nodules with low density in the portal phase on dynamic CT and 82% in nodules with isodensity. The rate did not depend on the severity of underlying liver disease; rates decreased in nodules deeper than 9 cm, those smaller than 2 cm in diameter and in iso-enhancing nodules at the early vascular phase of CEUS. CONCLUSION: CEUS with Sonazoid is a useful tool for assessing the vascularity of HCC and is equal to that of dynamic CT; however, the detectability of HCC vascularity is affected by location.

Nicotine stimulates transcriptional activity of the human dopamine transporter gene.

Nicotine modulates dopaminergic activity in the central nervous system by acting on the reuptake system, including the dopamine transporter (DAT), although precisely remains unclear. Here we investigated the effect of nicotine on the transcriptional regulation of the human DAT (hDAT) gene by conducting luciferase reporter assays. Nicotine enhanced the transcription of hDAT gene constructs in transiently transfected SK-N-SH cells. Hexamethonium, a neuronal (ganglionic) nicotinic acetylcholine receptor antagonist, blocked the action of nicotine. Functional analyses placed the nicotine-responsive region -3.5 to -1.0 kb (from the transcription start site) upstream of the core promotor region. Deletion of intron 1, known as a silencer element of the hDAT gene, abolished nicotine's stimulatory effect. Nicotine failed to stimulate DAT promotor activity in non-neuronal CHO or COS-7 cells or in SK-N-AS cells, another neuronal cell line recently reported as a model for investigating DAT gene expression. These results suggest a nicotinic cholinergic mechanism to be involved in the nicotine-induced up-regulation of DAT gene expression.

Nocturnal blood glucose and IGFBP-1 changes in type 1 diabetes: Differences in the dawn phenomenon between insulin regimens.

OBJECTIVE: Insulin-like growth factor binding protein-1 (IGFBP-1) is known to regulate the bioavailability of insulin-like growth factor (IGF) and the levels of IGFBP-1 are increased in the morning in patients with type 1 diabetes mellitus. We investigated the nocturnal fluctuations of glucose, IGFBP-1, and free IGF-1 levels with three insulin regimens. RESEARCH DESIGN AND METHODS: Forty-eight type 1 diabetes patients were divided into three groups according to their basal insulin therapy (continuous subcutaneous insulin infusion [CSII], insulin glargine, NPH insulin). Blood samples were obtained every 2 h between 2 300 h and 0700 h to measure plasma glucose, IGFBP-1 and free IGF-1 levels. RESULTS: The dawn phenomenon was more frequent with NPH (62.1%) than with glargine (16.6%, p<0.05) and CSII (14.3%, p<0.05). In the NPH group, the serum IGFBP-1 levels were markedly increased from 21.0+/-3.6 ng/ml at 2 300 h to 200.3+/-21.8 ng/ml at 0700 h and free IGF-1 levels were inversely decreased; these changes were partially suppressed in the CSII and glargine groups. CONCLUSIONS: The use of insulin regimens that provide sufficient insulin levels in the early morning can suppress the dawn phenomenon, leading to improved glycemic control. The increase in circulating IGFBP-1 in the morning, as a result of waning of insulin action, lowers free IGF-1 levels and may cause insulin resistance.

A case of idiopathic hypereosinophilic syndrome with leptomeningeal dissemination and intraventricular mass lesion: an autopsy report.

A 43-year-old female presented with idiopathic hypereosinophilic syndrome (HES) manifesting as an intraventricular mass lesion and leptomeningeal and cerebral parenchymal infiltration by eosinophils, lymphocytes and macrophages. She had no history of either malignancy or allergic disorder. She complained of hearing disturbance caused by eosinophilic otitis media. Eosinophilia was detected in the peripheral blood. Hearing disturbance and eosinophilia improved with corticosteroid treatment. Six months later, she was admitted with disturbances of consciousness. Magnetic resonance imaging revealed a mass lesion in the right lateral ventricle and leptomeningeal involvement around the brain stem. Her symptoms deteriorated rapidly, and she died of brain stem malfunction. Autopsy demonstrated significant infiltration by eosinophils and lymphocytes into the mass lesion in the ventricle, subarachnoid space, perivascular space and parenchyma of the medulla oblongata. Histological examination of the bone marrow and other organs did not detect any evidence of parasites, malignancies, or systemic disorders in any organ. The final diagnosis was idiopathic HES. The present case shows that leptomeningeal dissemination and infiltration by eosinophils into the cerebral ventricles and brain stem should be considered in the course of idiopathic HES.

Conceptual design of experimental equipment for large-diameter NTD-Si.

An irradiation-experimental equipment for 12in neutron transmutation doping silicon (NTD-Si) was designed conceptually by using MCNP5 in order to improve the neutron flux distribution of the radial direction. As a result of the calculations, the neutron absorption reaction ratio of the circumference to the center could be limited within 1.09 using a thermal neutron filter that covers the surface of the silicon ingot. The uniformity of the (30)Si neutron absorption was less than 5.3%.

Short-term changes in temporomandibular joint function in subjects with cleft lip and palate treated with maxillary distraction osteogenesis.

OBJECTIVES: To investigate the short-term effects of maxillary distraction osteogenesis (DO) on temporomandibular joint (TMJ) function in 21 subjects with cleft lip and palate (CLP). Design - Morphological changes in the maxillofacial region were measured using lateral cephalometric radiographs taken immediately before (pre-DO) and after DO (post-DO) and 1 year after DO (1-year follow-up). A questionnaire was evaluated using a visual analog scale. A chi-square test was used to compare the prevalence of TMJ symptoms between pre-DO and 1-year follow-up. The Spearman correlation coefficient was used to determine the correlation between changes in cephalometric variables and TMJ symptoms in association with maxillary DO. Statistical significance was set at p < 0.05. Results - The ANB (anteroposterior relationship of the maxilla with the mandible) angle and the mandibular plane angle at pre-DO, post-DO, and 1-year follow-up were -4.3 degrees , +5.8 degrees , +4.3 degrees and 32.1 degrees , 33.5 degrees , 33.6 degrees , respectively. The average amounts of anterior and downward movement of the maxilla at post-DO and 1-year follow-up were 8.3, -1.3 and 0.9, 1.1 mm, respectively. The prevalence of TMJ symptoms showed no significant increase in association with maxillary DO. Moreover, there was no significant correlation between changes in cephalometric variables and TMJ symptoms. Conclusion - These results suggest that there was no short-term (i.e., up to 1 year after DO) effect of maxillary DO on TMJ function in subjects with CLP.

Insulin-like growth factor I regulates apoptosis in condylar cartilage.

Endogenous insulin-like growth factor-I (IGF-I) is known to affect the growth and development of condylar cartilage. However, the critical effect of IGF-I on cell survival is still unknown. We hypothesized that endogenous IGF-I could regulate the survival of cells of the mandibular condylar cartilage. Mandibular condyles dissected from 12-day-old rats were cultured for 1, 3, and 5 days in medium containing antisense oligodeoxynucleotide (AS-ODN) for IGF-I. Real-time RT-PCR analysis showed that the levels of IGF-I and IGF binding protein (IGFBP)3 mRNAs in the AS-ODN group were significantly decreased. After 3 days' culture, the number of necrotic cells was observed in the undifferentiated mesenchymal cell layer. These cells were TUNEL-positive and confirmed to be apoptotic by electron microscopic observation. Immunoblotting revealed that expression of cleaved caspase3 was increased with AS-ODN. These results may suggest that the cells in the undifferentiated mesenchymal cell layer of the mandibular condyle require IGF-I for survival.

A simple method for evaluation of tongue position.

Neck extension because of contraction of cervical extensor muscles often brings about a lower-positioned tongue secondary to jaw opening in patients with congenital myopathy (CM). We hypothesized that neck extension in control subjects would reproduce the lower position of the tongue similar to that found in a CM patient. A simple method was formulated to evaluate the tongue position in terms of tongue pressure on the maxillary molar. A pair of pressure sensors was attached to the buccal and lingual surfaces of the upper molar for both the CM patient and four control subjects. Changes in the buccal and tongue pressures were recorded at the neck extension position for the CM patient and during both the natural head position and neck extension for the control subjects. There was a remarkable difference between buccal and tongue pressures in the neck extension position in the CM patient: tongue pressure was not detected at all, indicating there was no contact between tongue and upper molar. The buccal and tongue pressures were approximately equal in the natural head position in the control subjects. However, both buccal and tongue pressures were reduced during neck extension in the control subjects, with a greater decrease in the tongue pressure than the buccal pressure. These findings suggest that neck extension in a control subject reproduces the lower position of the tongue observed in CM patients. We propose that the pressure sensor enables evaluation of the tongue position, but further investigation is required.

5-Methoxy-N,N-diisopropyltryptamine (Foxy), a selective and high affinity inhibitor of serotonin transporter.

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine derivative, known also as Foxy or Foxy methoxy. However, few studies have examined its effects in vitro. In the present study, we investigated the actions of 5-MeO-DIPT against monoamine neurotransmitter transporters, including the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using COS-7 cells heterologously expressing these transporters and rat brain synaptosomes. 5-MeO-DIPT specifically inhibited the uptake of [3H]serotonin (5-HT) by the SERT-expressing COS-7 cells and rat striatal synaptosomes in a high affinity manner at concentrations similar to those for cocaine. The effect was reversible and competitive. 5-MeO-DIPT failed to stimulate reverse transport of [3H]5-HT through SERT, while it prevented the releasing action of methamphetamine. 5-MeO-DIPT induced cell toxicity at high concentrations in COS-7 cells, and it was not influenced by the expression of SERT. These results demonstrated that 5-MeO-DIPT acts as a competitive SERT inhibitor and has an inability to cause reverse transport, underlying its serotonergic actions.

Laser burn wound healing in naso-labial region of fetal and neonatal mice.

OBJECTIVE: To investigate the characteristics of wound healing in the mouse naso-labial region in both the fetal and neonatal stages, histological and immunohistochemical analyses were performed using a newly established laser burn wound healing system. MATERIALS AND METHODS: Fetal mice at embryonic day 14 (E 14) were wounded as a model of fetal wound healing. To compare it, neonatal mice at day 5 after birth (d 5) were adopted as a model of neonatal wound healing. The healing process was examined by van Gieson staining and immunohistochemistry for fibronectin and tenascin. RESULTS: Relatively large damage remained after wound healing even in fetal mice. In both types of wound healing, rapid regeneration of muscle tissues were observed. Fibronectin and tenascin immunostaining was detected not only in wound healing region, but also in the endomysium of regenerating muscle tissues. Especially, tenascin showed a restricted expression pattern. CONCLUSIONS: Rapid regeneration of muscle tissues in the naso-labial region in both the fetal and neonatal mice seemed to leave relatively large damage even in the fetal wound healing. Contracted force exerted by muscle tissues may be a reason for this phenomenon. Fibronectin and tenascin were closely related to the wound healing process including muscle regeneration in this region.

Application of magnetic resonance imaging movie to assess articulatory movement.

OBJECTIVE: To introduce the technique of magnetic resonance imaging (MRI) movie and to propose its feasibility for investigating articulatory movement. SUBJECTS: Five healthy adult females participated in the study. METHODS: Dynamic changes in oropharyngeal structures were assessed with MRI movie during the articulation of a bilabial consonant. RESULTS: Movements of the velum and tongue at a time resolution of 30 ms were complex at the tip of the tongue and the anterior part of the velum. These movements that were seen with a time resolution of 30 ms could not be interpolated or in any way derived from the results obtained with a time resolution of 120 ms. CONCLUSION: The results suggest that MRI movie may be useful in the evaluation of articulation. It is important to reduce the time resolution to 30 ms to obtain images of articulators.

A case of amelogenesis imperfecta, cleft lip and palate and polycystic kidney disease.

OBJECTIVE: Amelogenesis imperfecta (AI) is a heterogeneous group of genetic disorders characterized by developmental abnormalities of tooth enamel. The AI is also seen as part of multi-organ abnormalities, e.g. with cone-rod dystrophy, hypothalamo-hypophyseal insufficiency and renal failure. The present patient with AI and nephrocalcinosis exhibited a phenotype different from previous cases with renal failure. To highlight the characteristics of this rare case, extensive analysis that included histological, biochemical and genetic examinations was performed. PATIENT: The present Japanese male patient exhibited dentition with AI and bilateral cleft lip and palate. Ground sections of his extracted tooth showed that it was hypomaturation-type AI, unlike previous cases with nephrocalcinosis were hypoplastic-type. He showed nephrocalcinosis and hematuria at 15 years of age but these symptoms appeared to be secondary to polycystic kidney disease. He showed skeletal Class II pattern with a retrognathic profile and retroclined incisors of both arches. A dolicofacial appearance was seen with an enlarged gonial angle. Biochemical makers including serum alkaline phosphatase, parathyroid hormone, calcitonin, calcium, and phosphate, were all in the normal range. Sequence analysis of the genes encoding amelogenin and enamelin, which are known to be responsible for hypoplastic-type AI, did not reveal any mutations. Since mouse null mutant of homeobox transcription factor, Msx2, exhibits a phenotype resembling AI, the human homolog of this gene, MSX2, was sequenced. There was a missense mutation of T447C that resulted in the conversion of methionine to threonine at 129.