Antihistamine use and the risk of injurious falls or fracture in elderly patients: a systematic review and meta-analysis.

Despite their anticholinergic side effects, first-generation antihistamines are widely prescribed to elderly patients. A systematic review was conducted to synthesize real-world evidence. First-generation antihistamine use is considerably associated with an increased risk of injurious falls or fracture among the elderly. INTRODUCTION: First-generation antihistamines are considered potentially inappropriate for elderly patients owing to anticholinergic side effects. We aimed to determine whether elderly patients taking antihistamines are at increased risk of injurious falls or fracture. METHODS: We identified studies in MEDLINE, EMBASE, and several local databases through November 2016. Observational studies on the association between antihistamine use and the risk of injurious falls or fracture were selected. Quality of the studies and the level of evidence were assessed. The random-effects model was employed for meta-analysis, and heterogeneity was examined based on I-square and Cochrane's Q test. Subgroup analyses were performed when the heterogeneity among studies could not be explained. RESULTS: From 473 identified studies, five (three case-control studies, one cohort study, and one case-crossover study) were included in our analysis based on eligibility criteria. First-generation antihistamine use showed significantly increased risk of injurious falls or fracture (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.49-2.76, heterogeneity: p = 0.41, I2 = 0%). Studies including antihistamines of all generations or containing no generation information were dealing with falls during hospitalization. Among these studies, the association was statistically significant without heterogeneity (OR 2.89, 95% CI 1.71-4.89, heterogeneity: p = 0.42, I2 = 0%). Due to the small number of studies included and unadjusted results, meaningful interpretation based on subgroup analysis was limited. CONCLUSIONS: First-generation antihistamine use is considerably associated with increased risk of injurious falls or fracture among the elderly. Clinicians need to exercise caution when prescribing first-generation antihistamines to elderly patients.

Rosenbluth Separation of the π

We report the first longitudinal-transverse separation of the deeply virtual exclusive π^{0} electroproduction cross section off the neutron and coherent deuteron. The corresponding four structure functions dσ_{L}/dt, dσ_{T}/dt, dσ_{LT}/dt, and dσ_{TT}/dt are extracted as a function of the momentum transfer to the recoil system at Q^{2}=1.75 GeV^{2} and x_{B}=0.36. The ed→edπ^{0} cross sections are found compatible with the small values expected from theoretical models. The en→enπ^{0} cross sections show a dominance from the response to transversely polarized photons, and are in good agreement with calculations based on the transversity generalized parton distributions of the nucleon. By combining these results with previous measurements of π^{0} electroproduction off the proton, we present a flavor decomposition of the u and d quark contributions to the cross section.

Rosenbluth Separation of the π

We present deeply virtual π^{0} electroproduction cross-section measurements at x_{B}=0.36 and three different Q^{2} values ranging from 1.5 to 2 GeV^{2}, obtained from Jefferson Lab Hall A experiment E07-007. The Rosenbluth technique is used to separate the longitudinal and transverse responses. Results demonstrate that the cross section is dominated by its transverse component and, thus, is far from the asymptotic limit predicted by perturbative quantum chromodynamics. Nonetheless, an indication of a nonzero longitudinal contribution is provided by the measured interference term σ_{LT}. Results are compared with several models based on the leading-twist approach of generalized parton distributions (GPDs). In particular, a fair agreement is obtained with models in which the scattering amplitude includes convolution terms of chiral-odd (transversity) GPDs of the nucleon with the twist-3 pion distribution amplitude. This experiment, together with previous extensive unseparated measurements, provides strong support to the exciting idea that transversity GPDs can be accessed via neutral pion electroproduction in the high-Q^{2} regime.

Novel dentin phosphoprotein frameshift mutations in dentinogenesis imperfecta type II.

The dentin sialophosphoprotein (DSPP) gene encodes the most abundant non-collagenous protein in tooth dentin and DSPP protein is cleaved into several segments including the highly phosphorylated dentin phosphoprotein (DPP). Mutations in the DSPP gene have been solely related to non-syndromic form of hereditary dentin defects. We recruited three Korean families with dentinogenesis imperfecta (DGI) type II and sequenced the exons and exon-intron boundaries of the DSPP gene based on the candidate gene approach. Direct sequencing of PCR products and allele-specific cloning of the highly repetitive exon 5 revealed novel single base pair (bp) deletional mutations (c.2688delT and c.3560delG) introducing hydrophobic amino acids in the hydrophilic repeat domain of the DPP coding region. All affected members of the three families showed exceptionally rapid pulp chambers obliteration, even before tooth eruption. Individuals with the c.3560delG mutation showed only mild, yellowish tooth discoloration, in contrast to the affected individuals from two families with c.2688delT mutation. We believe that these results will help us to understand the molecular pathogenesis of DGI type II as well as the normal process of dentin biomineralization.

RUNX2 mutations in cleidocranial dysplasia patients.

OBJECTIVE: Mutations in the RUNX2 gene, a master regulator of bone formation, have been identified in cleidocranial dysplasia (CCD) patients. CCD is a rare autosomal-dominant disease characterized by the delayed closure of cranial sutures, defects in clavicle formation, and supernumerary teeth. The purposes of this study were to identify genetic causes of two CCD nuclear families and to report their clinical phenotypes. MATERIALS AND METHODS: We identified two CCD nuclear families and performed mutational analyses to clarify the underlying molecular genetic etiology. RESULTS: Mutational analysis revealed a novel nonsense mutation (c.273T>A, p.L93X) in family 1 and a de novo missense one (c.673C>T, p.R225W) in family 2. Individuals with a nonsense mutation showed maxillary hypoplasia, delayed eruption, multiple supernumerary teeth, and normal stature. In contrast, an individual with a de novo missense mutation in the Runt domain showed only one supernumerary tooth and short stature. CONCLUSIONS: Mutational and phenotypic analyses showed that the severity of mutations on the skeletal system may not necessarily correlate with that of the disruption of tooth development.

Identification of a novel FAM83H mutation and microhardness of an affected molar in autosomal dominant hypocalcified amelogenesis imperfecta.

AIM: To determine the underlying molecular genetic aetiology of a family with the hypocalcified form of amelogenesis imperfecta and to investigate the hardness of the enamel and dentine of a known FAM83H mutation. METHODOLOGY: Mutational screening of the FAM83H on the basis of candidate gene approach was performed. All exons and exon-intron boundaries was amplified and sequenced. A microhardness test was performed to measure the Vickers microhardness value. RESULTS: A novel nonsense mutation (c.1354C>T, p.Q452X) was identified in the last exon of FAM83H, which resulted in soft, uncalcified enamel. The affected enamel was extremely soft (about 17% of the normal control), but the underlying dentine was as hard as the normal control. CONCLUSIONS: Mutational analysis revealed a novel mutation in FAM83H gene. Hardness of dentine was not affected by the mutation, whilst the enamel was extremely soft.

Comparison of the Effect of Vessel Size Imaging and Cerebral Blood Volume Derived from Perfusion MR Imaging on Glioma Grading.

BACKGROUND AND PURPOSE: Vascular proliferation is a major criterion for grading gliomas on the basis of histology. Relative cerebral blood volume can provide pathophysiologic information about glioma grading. Vessel size imaging, in some animals, can be used to estimate the microvascular caliber of a glioma, but its clinical use remains unclear. Herein, we aimed to compare the predictive power of relative cerebral blood volume and vessel size imaging in glioma grading, with grading based on histology. MATERIALS AND METHODS: Seventy patients with glioma participated in the study; 30 patients underwent MR perfusion imaging with a spin-echo sequence and vessel size imaging with a gradient-echo and spin-echo sequence successively at 24-hour intervals before surgery. We analyzed the vessel size imaging values and relative cerebral blood volume of differently graded gliomas. The microvessel parameters were histologically evaluated and compared with those on MR imaging. The cutoff values of vessel size imaging and relative cerebral blood volume obtained from receiver operating characteristic curve analyses were used to predict glioma grading in another 40 patients. RESULTS: Vessel size imaging values and relative cerebral blood volume were both increased in high-grade gliomas compared with low-grade gliomas (P < .01). Moreover, vessel size imaging values had higher specificity and sensitivity in differentiating high-grade from low-grade gliomas compared with relative cerebral blood volume. In addition, a significant correlation was observed between vessel size imaging values and microvessel diameters (r > 0.8, P < .05) and between relative cerebral blood volume and microvessel area (r = 0.6579, P < .05). Most important, the use of vessel size imaging cutoff values to predict glioma grading was more accurate (100%) than use of relative cerebral blood volume (85%) values. CONCLUSIONS: Vessel size imaging can provide more accurate information on glioma grading and may serve as an effective biomarker for the prognosis of patients with gliomas.

The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers.

Breast and prostate cancer are the most well-characterized cancers of the type that have their development and growth controlled by the endocrine system. These cancers are the leading causes of cancer death in women and men, respectively, in the United States. Being hormone-dependent tumors, antihormone therapies usually are effective in prevention and treatment. However, the emergence of resistance is common, especially for locally advanced tumors and metastatic tumors, in which case resistance is predictable. The phenotypes of these resistant tumors include receptor-positive, ligand-dependent; receptor-positive, ligand-independent; and receptor-negative, ligand-independent. The underlying mechanisms of these phenotypes are complicated, involving not only sex hormones and sex hormone receptors, but also several growth factors and growth factor receptors, with different signaling pathways existing alone or together, and with each pathway possibly linking to one another. In this review, we will discuss the potential mechanisms of antihormone-therapy resistance in breast and prostate cancers, especially focusing on the similarities and differences of these two cancers. We will also discuss novel agents that have been applied in clinical practice or with clinical potential in the future.

VP2 capsid domain of the H-1 parvovirus determines susceptibility of human cancer cells to H-1 viral infection.

Although H-1 parvovirus is used as an antitumor agent, not much is known about the relationship between its specific tropism and oncolytic activity. We hypothesize that VP2, a major capsid protein of H-1 virus, determines H-1-specific tropism. To assess this, we constructed chimeric H-1 viruses expressing Kilham rat virus (KRV) capsid proteins, in their complete or partial forms. Chimeric H-1 viruses (CH1, CH2 and CH3) containing the whole KRV VP2 domain could not induce cytolysis in HeLa, A549 and Panc-1 cells. However, the other chimeric H-1 viruses (CH4 and CH5) expressing a partial KRV VP2 domain induced cytolysis. Additionally, the significant cytopathic effect caused by CH4 and CH5 infection in HeLa cells resulted from preferential viral amplification via DNA replication, RNA transcription and protein synthesis. Modeling of VP2 capsid protein showed that two variable regions (VRs) (VR0 and VR2) of H-1 VP2 protein protrude outward, because of the insertion of extra amino-acid residues, as compared with those of KRV VP2 protein. This might explain the precedence of H-1 VP2 protein over KRV in determining oncolytic activity in human cancer cells. Taking these results together, we propose that the VP2 protein of oncolytic H-1 parvovirus determines its specific tropism in human cancer cells.

Increased aryl hydrocarbon receptor expression in patients with allergic rhinitis.

BACKGROUND: A predominant Th17 population is a marker of allergic rhinitis (AR). As a ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR) plays a vital role in promoting or inhibiting the development of specific Th cells. However, its role in AR remains undefined. OBJECTIVE: To analyze the potential role of AhR in the pathogenesis of AR. METHODS: In total, 30 AR patients and 13 healthy controls were recruited for this study and AR patients had clinical features, as demonstrated by rhinoconjunctivitis quality of life questionnaires, total symptom scores and visual analog scale scores. The expression of AhR, IL-17 and IL-22 and the presence of Th17 cells in peripheral blood mononuclear cells were measured before and after treatment with the nontoxic AhR ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). RESULTS: Pretreatment ITE studies revealed that all AR patients had a significant increase in AhR expression compared with controls and AhR expression positively correlated with clinical parameters. After ITE intervention, a severe reduction in the differentiation of Th17 cells and the production of IL-17 and IL-22 was noted in both AR patients and normal subjects. Simultaneously, a dramatic enhancement of AhR expression was also observed in all healthy controls, but not in AR patients. CONCLUSION: The results suggested that the AhR may be one of the mechanisms underlying the Th17 response during the pathogenesis of AR and AhR levels were closely related to clinical severity in all AR patients. Additionally, ITE may represent a new drug candidate in the treatment of AR.

Clinical analysis of the characterization of magnetic resonance imaging in 102 cases of refractory haematospermia.

To analyze the pathogenesis of persistent and refractory haematospermia and to evaluate the aetiological diagnostic value of magnetic resonance imaging (MRI) for this type of haematospermia. Clinical data from 102 patients with persistent and refractory haematospermia was retrospectively analysed. Data collected included history, symptoms, as well as ultrasound and MRI of the morphological features of the bilateral seminal vesicles (SV) and ejaculatory duct (ED) areas. Criteria for inclusion were haematospermia symptoms that occurred more than six times, that lasted more than 6 months, and that did not improve after >1 month of conservative treatment. Patients underwent seminal vesiculoscopy with a post-surgery follow-up of 3-48 months [average (18.1 ± 10.3) months]. Of the 102 patients that underwent MRI examination, data from 88 patients (86.3%) showed typical and characteristic changes in the ED area, including the signal intensity changes in 60 (58.8%), SV volume changes in 32(31.4%), the formation of cysts such as prostatic utricular cysts in 27 (26.5%), Müllerian cysts in 4 (3.9%), ED cysts in 5 (4.9%) and a SV cyst in 1(1.0%). The MRI findings were confirmed by seminal vesiculoscopy and all patients received appropriate treatment. In 14 patients (13.7%), no obvious abnormal changes were observed with MRIs, however, these patients were diagnosed and successfully managed using seminal vesiculoscopy. Some degrees of ED obstruction was usually found during surgery. The symptoms of haematospermia disappeared 1-2 months after surgery in all patients. Two patients had a recurrence of haematospermia, underwent the same treatment, and recovered during the follow-up period. The aetiology of the most cases of the refractory haematospermia can be distinguished using the three-dimensional MRI. Typical abnormalities observed on MR images are signal intensity, SV volume changes and cyst formation. MRI has significant etiological diagnostic value and provides reliable information for the subsequent treatment of patients with persistent and refractory haematospermia.

Nucleolar protein GLTSCR2 stabilizes p53 in response to ribosomal stresses.

p53 is a key regulator of cell growth and death by controlling cell cycle progression and apoptosis under conditions of stress such as DNA damage or oncogenic stimulation. As these processes are critical for cell function and inhibition of tumor development, p53 regulatory pathways are strictly monitored in cells. Recently, it was recognized that nucleolar proteins, including nucleophosmin/B23, ribosomal protein L11, and alternate reading frame (ARF), form the nucleolus-ARF-murine double minute 2 (MDM2) axis in p53 regulatory pathways, which increases p53 stability by suppressing the activity of MDM2. In this work, we show that nucleolar protein glioma tumor-suppressor candidate region gene 2 (GLTSCR2) translocates to the nucleoplasm under ribosomal stress, where it interacts with and stabilizes p53 and inhibits cell cycle progression without the involvement of the major upstream p53 regulator, ARF. Furthermore, ectopic expression of GLTSCR2 significantly suppressed growth of cancer cells in a xenograft animal model via p53-dependent pathway. Our data identify GLTSCR2 as a new member of the nucleolus-nucleoplasmic axis for p53 regulation. ARF-independent direct regulation of p53 by GLTSCR2 may be a key mechanism and therapeutic target for cell death or growth inhibition when nucleolus-ARF-p53 pathways are inactivated by genetic or epigenetic modifications of ARF, which are the second most common types of genetic change observed in human cancers.

The dual toning technique for melasma treatment with the 1064 nm Nd: YAG laser: A preliminary study.

BACKGROUND AND AIMS: Melasma is a treatment-resistant and acquired pigmentary facial skin condition of uncertain etiology particularly prevalent in the older Asian female. Traditional bleaching agents have offered some success. Intense pulsed light (IPL), fractionated nonablative and more recently ablative laser technology have also been used, but were associated with postoperative hyperpigmentation in the Asian skin. The present study examined the consecutive application of 2 modes of the 1064 nm Nd:YAG laser in the 'dual toning' process. SUBJECTS AND METHODS: Thirty females, mean age 41.4 ± 11.96 yr, Fitzpatrick skin type IV, participated in the prospective uncontrolled study. All subjects were treated with the 1064 nm Nd:YAG laser, first with the 5 ns Q-switched mode, 1.2 J/cm(2), 8 mm collimated handpiece with multiple passes and then immediately after with the micropulsed mode, 300 µs, 7.0 J/cm(2), 5 mm handpiece, multiple passes. Mild and even erythema was the endpoint. Treatments were given every other week until maximum improvement was obtained. Improvement was rated at a final assessment 6 weeks after the final treatment on a 5 point scale where 1 was little or no improvement and 5 was maximum improvement. RESULTS: At the final treatment session and at the 6-week assessment, 20 of the 30 patients (67%) saw a fair to excellent degree of improvement, 7 (23%) had visible improvement and little or no improvement was seen in 3 (10%) patients. There were no unexpected side effects in any patients. CONCLUSIONS: The dual toning technique using the 1064 nm Nd:YAG laser was safe and effective, and well-tolerated by all patents without anesthesia. Larger controlled studies are merited with more objective measurement techniques to confirm the results of this preliminary study.

MicroRNA-193a represses c-kit expression and functions as a methylation-silenced tumor suppressor in acute myeloid leukemia.

Aberrant activation of c-kit proto-oncogene contributes to abnormal cell proliferation by altering the tyrosine kinase signaling and constitutes a crucial impetus for leukemogenesis. Epigenetic silencing of tumor-suppressive microRNAs (miRNAs) is a key oncogenic mechanism for the activation of oncogenes in tumors. In this study, several miRNAs potentially binding to the 3'-untranslated region of human c-kit mRNA were screened by luciferase reporter assays. Among these miRNAs, miR-193a was embedded in a CpG island and epigenetically repressed by promoter hypermethylation in acute myeloid leukemia (AML) cell lines and primary AML blasts, but not in normal bone marrow cells. Importantly, miR-193a levels were inversely correlated with c-kit levels measured in 9 leukemia cell lines and 27 primary AML samples. Restoring miR-193a expression in AML cells harboring c-kit mutation and/or overexpression, either by synthetic miR-193a transfection or by DNA hypomethylating agent 5-azacytidine (5-aza) treatment, resulted in a significant reduction in c-kit expression at both RNA and protein levels and inhibition of cell growth. The growth-inhibitory activity of miR-193a was associated with apoptosis and granulocytic differentiation. Moreover, 5-aza-induced c-kit reduction could be partially blocked by miR-193a inhibitor, leading to a reversal of antiproliferative and proapoptotic effects of 5-aza. These data reveal a critical role for methylation-repressed miR-193a in myeloid leukemogenesis and the therapeutic promise of upregulating miR-193a expression for c-kit-positive AML.

MMP20 hemopexin domain mutation in amelogenesis imperfecta.

Proteolytic enzymes serve important functions during dental enamel formation, and mutations in the kallikrein 4 (KLK4) and enamelysin (MMP20) genes cause autosomal-recessive amelogenesis imperfecta (ARAI). So far, only 1 KLK4 and 3 MMP20 mutations have been reported in ARAI kindreds. To determine whether ARAI in a family with a hypomaturation-type enamel defect is caused by mutations in the genes encoding enamel proteolytic enzymes, we performed mutational analysis on candidate genes. Mutational and haplotype analyses revealed an ARAI-causing point mutation (c.910G>A, p.A304T) in exon 6 of MMP20 that results in a single amino acid substitution in the hemopexin domain. Western blot analysis showed decreased expression of the mutant protein, but zymogram analysis demonstrated that this mutant was a functional protein. The proband and an affected brother were homozygous for the mutation, and both unaffected parents were carriers. The enamel of newly erupted teeth had normal thickness, but was chalky white and became darker with age.

Novel WDR72 mutation and cytoplasmic localization.

The proven candidate genes for amelogenesis imperfecta (AI) are AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72. We performed mutation analyses on seven families with hypomaturation AI. A novel WDR72 dinucleotide deletion mutation (g.57,426_57,427delAT; c.1467_ 1468delAT; p.V491fsX497) was identified in both alleles of probands from Mexico and Turkey. Haplotype analyses showed that the mutations arose independently in the two families. The disease perfectly segregated with the genotype. Only persons with both copies of the mutant allele were affected. Their hypomineralized enamel suffered attrition and orange-brown staining following eruption. Expression of WDR72 fused to green fluorescent protein showed a cytoplasmic localization exclusively and was absent from the nucleus. We conclude that WDR72 is a cytoplasmic protein that is critical for dental enamel formation.

Candidate gene strategy reveals ENAM mutations.

Amelogenesis imperfecta (AI) is a genetically and phenotypically heterogeneous genetic disorder affecting tooth enamel without other non-oral syndromic conditions. Based on a review of the literature, the authors constructed a candidate-gene-based mutational analysis strategy. To test the strategy, they identified two Turkish families with hypoplastic enamel without any other non-oral syndromic phenotype. The authors analyzed all exons and exon/intron boundaries of the enamelin (ENAM) gene for family 1 and the DLX3 and ENAM genes for family 2, to identify the underlying genetic etiology. The analysis revealed 2 ENAM mutations (autosomal-dominant g.14917delT and autosomal-recessive g.13185-13186insAG mutations). A single T deletion in exon 10 is a novel deletional mutation (g.14917delT, c.2991delT), which is predicted to result in a frameshift with a premature termination codon (p.L998fsX1062). This result supports the use of a candidate-gene-based strategy to study the genetic basis for AI.