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Early (preclinical) diagnosis of Parkinson's disease (PD) is a major challenge in modern neuroscience. The objective of this study was to experimentally evaluate a diagnostic challenge test with monoiodotyrosine (MIT), an endogenous inhibitor of tyrosine hydroxylase. Striatal dopamine was shown to decrease by 34% 2 h after subcutaneous injection of 100 mg/kg MIT to intact mice, with the effect not being amplified by a further increase in the MIT dose. The selected MIT dose caused motor impairment in a neurotoxic mouse model of preclinical PD, but not in the controls. This was because MIT reduced striatal dopamine to the threshold of motor symptoms manifestation only in PD mice. Therefore, using the experimental mouse model of preclinical PD, we have shown that a MIT challenge test may be used to detect latent nigrostriatal dysfunction.

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This review provides information on the non-motor peripheral manifestations of Parkinson's disease (PD) associated with a pathology of the visual analyzer and the auxiliary apparatus of the eye. The relationship between neurodegenerative processes that take place in the brain and in the eye opens new prospects to use preventive ophthalmologic examination to diagnose PD long before the characteristic motor symptoms appear. This will encourage the use of neuroprotective therapy, which stops, or at least slows down, neuronal death, instead of the current replacement therapy with dopamine agonists. An important result of an eye examination of patients with PD may be a non-invasive identification of new peripheral biomarkers manifesting themselves as changes in the composition of the lacrimal fluid.

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An important approach to an early diagnosis of Parkinson's disease (PD) is screening for peripheral biomarkers in patients at the early clinical stage. In this study, we evaluated catecholamine concentration changes in the tear fluid of untreated PD patients as biomarkers. Norepinephrine and dopamine concentrations in the tear fluid of patients were found to increase compared to those in age controls, which was especially pronounced on the side where motor symptoms appeared. On the contrary, the epinephrine concentration in the tear fluid of patients was reduced bilaterally. Since there was no reason to consider the markers found in the clinical stage of PD as markers of the preclinical stage, we additionally studied the tear fluid composition in mouse neurotoxic models of PD preclinical and clinical stages. The norepinephrine concentration in the tear fluid of mice from the clinical stage model was found to be higher than that in controls; in the preclinical stage model, the norepinephrine concentration had a tendency to increase. Therefore, both PD patients and mice from PD preclinical and clinical stage models manifest unidirectional changes in their tear fluid compositions, which may be considered as promising biomarkers for the development of early diagnosis.

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Parkinson's disease (PD) is a systemic neurodegenerative condition caused by the death of dopaminergic neurons of the nigrostriatal system of the brain. This disease is diagnosed after most neurons have already been lost, which explains the low efficiency of treatment. Hope for increasing treatment efficiency rests in the development of new strategies for early diagnosis of PD based on a search for peripheral markers that appear as early changes in non-motor functions. Since impairment of the visual function is one of the manifestations of PD, the purpose of our work was to identify biochemical and physiological changes in a mouse's eye and eyelid in models of preclinical (presymptomatic) and clinical (symptomatic) stages of PD. We found that the norepinephrine, dopamine, and serotonin levels in the mouse eye reduced not only in the model of the early clinical stage, but also in the model of preclinical stage, an indication that pathological changes in the monoaminergic systems of the brain had affected the eye even before the motor disorders emerged. Moreover, in both models of PD, mice had increased intraocular pressure, indicating the development of both metabolic and functional impairments, which can be used as diagnostic markers. Unlike in the eye, the serotonin level in the eyelid was increased in mice at both parkinsonism stages and in presymptomatic mice to a much higher extent than in symptomatic ones. Given that serotonin is involved in the regulation of lacrimal glands of the eyelid, an increase in its level in parkinsonian mice should alter the composition of tear fluid, which could serve as a diagnostic marker of early stage of PD. Thus, the changes in the metabolism of monoamines in the eye and eyelid observed in mice at the early stage of parkinsonism are accompanied by changes in the function of these structures and, therefore, can be used as diagnostic markers of the early stage of PD.

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PURPOSE: To estimate the possibility of detection of neurovascular ocular disorders in glaucoma by assessing the content of catecholamines and endothelins in lacrimal fluid. MATERIAL AND METHODS: The study included 47 patients with primary open-angle glaucoma (POAG). Tear eluate was analyzed by high performance liquid chromatography (HPLC) for catecholamines concentrations, and enzyme-linked immunoassay (ELISA) was used for evaluation of endothelins content. RESULTS: Endothelin-1 (ET-1) and big endothelin (bET) content in tears of patients with POAG was higher than in healthy controls. Concentration of dopamine (DA) in tears was lower and concentrations of L-dioxyphenylalanine and dihydroxyphenylacetic acid had a tendency for decrease. Noradrenaline content was equal in patients with POAG and controls. Adrenaline was not detected in any tear samples. CONCLUSION: Multidirectional changes of endothelins and DA levels in tears of patients with POAG was found. The increased concentration of ET-1 and its precursor bET promote vasoconstriction and decrease of aqueous humor outflow. The decrease of DA concentration is typical for neurodegenerative processes. Estimation of DA and endothelins concentrations in tears can enable early detection of neurovascular disorders in glaucoma patients and help evaluate their severity.

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BACKGROUND: Dryness-related heel skin problems are common; however, there are very few studies about heel skin dryness. The objective of this study was to develop new assessment methods for evaluating heel skin dryness, to clarify the characteristics associated with heal skin dryness, and assess the effectiveness of moisturizer use according to dryness severity. MATERIALS AND METHODS: We investigated the heel skin of 150 Korean women (aged 20-78 years). Heel skin images were taken using a DSLR camera and the distribution or severity of flakes, scaling, cracking, and fissures were visually assessed. Skin properties such as hydration, transepidermal water loss (TEWL), amount of dead skin cells, and efficacy of moisturizer were evaluated according to heel xerosis grade. Furthermore, as conventional evaluation methods for desquamation are not appropriate for heel skin, we developed new techniques using binarization of magnified images. RESULTS: Skin hydration tended to decrease and TEWL tended to increase as heel dryness grade increased. The amount of dead skin cells increased with increasing dryness grade using the new technique. Subjects in the severe dryness group achieved similar hydration levels as normal subjects at baseline after 3 hours of moisturizer application. CONCLUSION: Our new methods of visually classifying heel dryness and quantifying dead skin cells using magnified images effectively evaluated heel skin properties. As heel skin is prone to dryness, daily repetitive application of moisturizer might be helpful for hydrating dry heel skin, and ultimately preventing complications.

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Vibrational modes in the terahertz (THz) frequency range are good indicators of lead halide perovskite's crystallization phase. We performed real-time THz spectroscopy to monitor the crystallization kinetics in the perovskite films. First, THz absorptance was measured while the perovskite film was annealed at different temperatures. By analyzing the Avrami exponent, we observed an abrupt dimensionality switch (from 1D to 2D) with increasing temperature starting at approximately 90 °C. We also monitored the laser-induced crystallinity enhancement of the preannealed perovskite film. The THz absorptance increased initially, then subsequently decayed over a couple of hours, although the enhancement factor varies depending on the film crystallinity. In particular, the Avrami analysis implied that the light-induced crystallization was assisted by the 1D diffusion processes. The activation photon energy was measured at 2.3 eV, which indicated that enhanced crystallization originated from the photoinduced structural change of residual lead iodide at the grain boundary.

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The goal of this study was to investigate the changes in the concentrations of blood plasma catecholamines as possible biomarkers of Parkinson's disease (PD) in the mouse experimental model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A significant decrease was detected in the levels of dopamine and L-DOPA in the PD preclinical stage model as a result of the catecholamines systemic metabolism disfunction. In the PD early clinical stage models, the level of L-DOPA and dihydroxyphenylacetic acid decreased, which is consistent with the results of blood tests in untreated patients.

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AIM: To provide the observation that hibicuslide C-induced cell death in yeast Candida albicans involves apoptosis mechanism. METHODS AND RESULTS: Hibicuslide C was isolated from Abutilon theophrasti by column chromatography. In reactive oxygen species (ROS) assay, C. albicans treated with hibicuslide C showed increase in ROS, and its accumulation induced fungal cell death. In particular, hydroxyl radicals were a large part of the ROS. Mitochondrial dysfunction including mitochondrial depolarization and release of cytochrome c, which is a pro-apoptotic factor, was detected by JC-1 assay and Western blot. CaspACE FITC-VAD-FMK staining using caspase inhibitor showed metacaspase activation. Also, the increase in intracellular Ca(2+), which is a signal molecule of apoptosis, was detected by Fura-2AM and Rhod-2AM assays. Finally, annexin V-FITC and PI double staining and TUNEL assay confirmed that hibicuslide C induces early apoptosis followed by secondary necrosis in C. albicans. CONCLUSIONS: Hibicuslide C exerts antifungal activity against C. albicans through new mechanism inducing apoptosis. SIGNIFICANCE AND IMPACT OF THE STUDY: Candida albicans is the common cause of nosocomial infections with high mortality. Our findings provide that hibicuslide C can be a model molecule that induces apoptosis in C. albicans.

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UNLABELLED: Aldehyde dehydrogenase 1 (ALDH1) has been regarded as a breast cancer stem cell marker. Several studies have reported that ALDH1 expression is associated with poor prognosis in breast cancer. We aimed, therefore, to determine the prognostic value of ALDH1 expression and its association with several biomarkers in breast cancer tissue using immunohistochemistry. Furthermore, we investigated the characteristics of and differences between cellular and stromal expression of ALDH1. We performed tissue microarray (TMA) analysis of 425 breast cancer tissue samples collected during surgery. Immunohistochemical staining was then performed to measure the expression of ALDH1 and other breast cancer biomarkers. Statistical analysis of the relationship between ALDH1 expression and clinicopathologic characteristics was performed for 390 TMA samples. We found that ALDH1 was expressed in 71 cases (18.2%) in the tumor cells and/or stroma. Of these cases, 38 (9.7%) showed ALDH1 expression in tumor cells and 38 (9.7%) showed ALDH1 expression in the stroma. ALDH1 expression was significantly associated with markers of a poor prognosis, such as young age, estrogen receptor negativity, progesterone receptor negativity, a high histological grade, and a high Ki-67 index. However, ALDH1 expression was not associated with p53, transforming growth factor-beta, Gli-1, YKL-40, or sonic hedgehog expression status. With regard to the expression site, the clinical characteristics did not differ between cases of cellular expression and those of stromal expression. However, ALDH1 expression in tumor cells was correlated with hormone receptor status, histological grade, molecular subtype, epidermal growth factor receptor expression status, and cytokeratin 5/6 expression status while stromal expression of ALDH1 was only correlated with hormone receptor status. Overall, these findings suggest that ALDH1 expression in tumor tissue is associated with a biologically aggressive phenotype. KEYWORDS: ALDH1, biologically aggressive, breast cancer.

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TAZ, a transcriptional modulator, has a key role in cell proliferation, differentiation and stem cell self-renewal. TAZ activity is regulated by several signalling pathways, including Hippo, GPCR and Wnt signalling, but the regulatory mechanisms of TAZ activation are not yet clearly understood. In this report, we show that TAZ is regulated by canonical Wnt signalling during osteogenic differentiation. Wnt3a increases TAZ expression and an inhibitor of GSK3ß, a downstream effector of Wnt signalling, induces TAZ. Wnt3a facilitates the dephosphorylation of TAZ, which stabilises TAZ and prevents it from binding 14-3-3 proteins, thus inducing the nuclear localisation of TAZ. Dephosphorylation of TAZ occurs via PP1A, and depletion of PP1A blocks Wnt3a-induced TAZ stabilisation. Wnt3a-induced TAZ activates osteoblastic differentiation and siRNA-induced TAZ depletion decreases Wnt3a-induced osteoblast differentiation. Taken together, these results show that TAZ mediates Wnt3a-stimulated osteogenic differentiation through PP1A, suggesting that the Wnt signal regulates the Hippo pathway.

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The authors describe a novel operative technique in a child with PUJ obstruction in a horseshoe kidney, where a pyeloplasty was clinically indicated but unsafe because of insufficient length of ureter and predicted technical difficulty in transposing large renal vessels coursing to the renal hilum. During the operation, there was a favourably positioned extra renal lower pole calyceal infundibulum identified, of similar dimensions to the spatulated ureter and this was chosen for an end to side tension free anastomosis. As far as the authors are aware this technique of extra renal ureterocalycostomy has not been described before.

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Osteoclasts (OCs) are the only bone-resorbing cells and are critically involved in various bone-associated diseases, including osteoporosis and rheumatoid arthritis. Differentiation of OCs from bone marrow macrophage cells (BMMs) is regulated by RANK and the adaptor protein (DAP12/FcRγ)-mediated costimulatory signals. However, it is unknown how RANKL/RANK signal stimulates phosphorylation of DAP12/FcRγ to initiate the costimulatory signals. As reported here, we found that OC differentiation and acquisition of bone resorption capacity were suppressed in RANKL-stimulated Fyn(-/-) or Fyn-siRNA-transfected BMMs, but could be restored by overexpression of Fyn kinase in Fyn(-/-) BMMs. However, the RANKL-stimulated proliferation of BMMs was unaffected by the absence of Fyn. In addition, RANKL-stimulated Fyn(-/-) BMMs no longer exhibited the optimal induction of typical OC markers such as NFATc1, c-Fos, c-Src, TRAF6, and cathepsin K or costimulatory signals such as the activating phosphorylations of Syk, PLCγ2, and Gab2. These were restored by overexpression of Fyn in Fyn(-/-) BMMs. Immunoprecipitation studies also indicated that the adaptor proteins DAP12/FcRγ and Syk interacted with RANK during RANKL stimulation in BMMs in a Fyn-dependent manner. Phosphorylation of the DAP12/FcRγ and the recruitment of Syk by DAP12/FcRγ were suppressed in Fyn(-/-) BMMs. This is the first demonstration that Fyn relays the initial RANK/RANKL signal to the ITAM-containing adaptors DAP12/FcRγ for OC differentiation.

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AIMS: We evaluated the antibody response to a single-dose adjuvanted, inactivated, pandemic H1N1 influenza vaccination in patients with diabetes and assessed factors associated with the failure to induce antibody responses. METHODS: Eighty-two patients with Type 2 diabetes were vaccinated and antibody responses were determined with haemagglutination inhibition assay and anti-haemagglutinin antibody ELISA. RESULTS: Among 70 antibody-negative patients at baseline, 34 (48.6%) achieved seroconversion; 28 (60.9%) in the young adults group and six (25%) in the elderly group acquired H1N1-specific antibodies. Patients in the older age range or with longer duration of diabetes had a lower seroconversion rate. CONCLUSIONS: Our data show low cross-reactive antibody carrying rate and low seroconversion rate in patients with diabetes. Until larger-scale, case-controlled trials become available, older patients and patients with a longer duration of diabetes should be considered for the two-dose vaccination or have antibody titres measured after the first vaccination.

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To evaluate a suitable electrode material for the efficient green energy generation of a bio-fuel cell, carbonaceous based carbon cloth, carbon paper, and carbon felt electrodes were investigated under different mediators. The larger surface area, low resistance, and open network of interwoven fibers of the carbon felt electrode facilitated higher electron transfer from the microbial organisms to the electrode surface than that of other carbonaceous electrodes. Carbon paper electrode exhibited lower fuel cell performances due to its lower roughness and high tortuous nature. The green power generation experiments were also carried out under different mediators such as 2-hydroxy-l,4-naphthoquinone and thionin. The electrons mitigation and power generation was augmented by 2-hydroxy-l,4-naphthoquinone than thionin due to its high solubility, stability, and minimal adsorption characteristic to the electrodes. By the combined efforts of extended electrons generation and transportation, bio-fuel cell performances were extended and endorsed its doable applications in bio-fuel cells.

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UNLABELLED: Both papers in this section relate to the always difficult subject of hypospadias repair. One of them describes the anatomy of the external urethral meatus, and the other a technique for repairing coronal or subcoronal hypospadias. OBJECTIVE: To investigate the normal external urethral meatal anatomy in boys, and to examine the proportional relationship between meatal length and degree of ventral glans closure. PATIENTS AND METHODS: In all, 92 boys with presumed normal penile anatomy were considered eligible for the study; 17 were not assessed because either the boy or parents declined to participate, leaving 75 boys (mean age 6.9 years, range 0.3-15) who completed the study. Photographic records of the meatal appearance were obtained and meatal height and ventral glans closure measured using ophthalmic callipers. RESULTS: All 75 boys in the study had a vertical slit-like meatus that commenced at the tip of the penis and ran ventrally. The mean (sd) vertical meatal length was 5.4 (1) mm and the mean length of ventral glans closure was 4.7 (1.2) mm. There was an age-dependent increase in meatal length and a similar association was identified for the length of ventral glans closure. There was also a statistically significant proportional relationship between meatal length and length of glans closure (r = 0.36, confidence interval 0.14-0.54, P < 0.002). CONCLUSION: The position and size of the external urethral meatus in normal boys is consistent, and ventral glans closure is equal to or slightly less than meatal length. These data might be of interest to hypospadiologists in their efforts to reconstruct normal glanular anatomy.

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The purpose of this study was to investigate the correlations between high-risk human papillomavirus (HPV) load and p16 (INK4a) or Ki-67, and to identify biomarkers that may predict residual disease after conization with positive margins. The following samples were analyzed: 49 paraffin-embedded specimens from patients with cervical intraepithelial neoplasia (CIN), including 12 CIN 2 conization specimens and 37 CIN 3 conization specimens. Immunohistochemical analysis was performed with antibodies to p16 (INK4a) and Ki-67. Hybrid Capture II testing was used to detect high-risk HPV DNA. The mean HPV loads within each of the p16 (INK4a)-staining cases were 9.5 (relative light units/positive control) RLU/PC for negative staining, 531.8 RLU/PC for 1+ staining, 140.2 RLU/PC for 2+ staining, and 545.1 RLU/PC for 3+ staining. HPV loads differed significantly according to p16 (INK4a) expression (P = 0.0021). The mean HPV loads within Ki-67 staining cases were 28.2 RLU/PC for 1+ staining, 189.6 RLU/PC for 2+ staining, and 563.3 RLU/PC for 3+ staining. HPV loads differed significantly according to Ki-67 expression (P = 0.0259). The expression of p16 (INK4a) (P = 0.0012) and Ki-67 (P = 0.0006) were significantly associated with the CIN grade. In univariate and multiple logistic regression analysis, age, parity, cytology, lesion grade in the cone, high-risk HPV load, and the expression of p16 (INK4a) and Ki-67 were not significantly associated with residual lesions after conization with positive margins (P > 0.05). In conclusion, high-risk HPV load showed significant differences according to the expression of p16 (INK4a) and Ki-67, while none of the prognostic factors were significantly associated with residual disease after conization with positive margins.

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