Miliary fibromas in tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is a hamartoma syndrome characterized by multiple skin lesions, such as angiofibromas, shagreen patch and miliary fibromas (MiF). OBJECTIVE: To determine the clinical and histological features of MiF. METHODS: A retrospective analysis was conducted on 133 adults with TSC. Photography was used to characterize the appearance and location of MiF. Histological features in five skin samples from four individuals were evaluated by a board-certified dermatopathologist. RESULTS: MiF were observed in 19 of 133 (14%) individuals with TSC. MiF were 1- to 3-mm skin-coloured, sessile papules scattered on the back and rarely buttocks or thighs. Most were scattered in a bilaterally symmetric distribution, but others were asymmetric or associated with a shagreen patch. Histological features of MiF included expansion of the papillary and periadnexal dermis with variable hamartomatous abnormalities involving adjacent epithelial components. CONCLUSIONS: MiF are distinct from other cutaneous lesions in TSC such as shagreen patches and angiofibromas. Recognition of this entity is important in defining the spectrum of TSC disease and reassuring individuals with TSC that these lesions are benign.

Thyroid nodules in xeroderma pigmentosum patients: a feature of premature aging.

PURPOSE: Xeroderma pigmentosum (XP) is an autosomal recessive disease with defective DNA repair, a markedly increased risk of skin cancer, and premature aging. Reports from North Africa have described thyroid nodules in XP patients, but thyroid nodule prevalence has never been determined in XP patients enrolled in our natural history study at the National Institutes of Health (NIH). METHODS: We performed thyroid ultrasound examinations on all 29 XP patients examined from 2011 to 2019 and assessed nodule malignancy using the Thyroid Imaging Reporting and Data System. Thyroid nodule prevalence was also obtained from comparison cohorts. DNA sequencing was performed on thyroid tissue from XP patients who had surgery for thyroid cancer. RESULTS: Thyroid nodules were identified in 18/29 XP patients (62%). The median age of patients with thyroid nodules in our XP cohort (20 years) was younger than that of three comparison groups: 36 years (California study-208 subjects), 48 years (Korean study-24,757 subjects), and 52 years (NIH-682 research subjects). Multiple (2-4) thyroid nodules were found in 12/18 (67%) of the patients with nodules. Autopsy examination revealed follicular adenomas in 4/8 (50%) additional XP patients. DNA sequencing revealed rare mutations in two other XP patients with papillary thyroid cancer. CONCLUSIONS: XP patients have an increased incidence of thyroid nodules at an early age in comparison to the general population. These finding confirm another premature aging feature of XP.

Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

Robotic surgery for thyroid disease.

While conventional open thyroidectomy techniques are the most widely performed thyroid operation, they produce an anterior neck scar that may be difficult to conceal. The endoscopic thyroidectomy was developed to decrease the cosmetic impact on the patient and has the advantage of reducing the incidence of anterior neck hypoesthesia and paresthesia. However, this procedure has some drawbacks, which motivated surgeons to develop a new operation method. Robotic thyroidectomy is a relatively new approach for treating differentiated thyroid cancer. Over the last few years, robotic thyroidectomies have become more common. Robotic thyroidectomies are a feasible, safe alternative for managing thyroid disease that has remarkable functional benefits beyond those of conventional open methods. The applications for robotic thyroidectomy have expanded to include increasingly advanced cases, which will consequently change the thyroid surgery paradigm in the future.

The anteroposterior axis of the tibia in Korean patients undergoing total knee replacement.

The aim of this study was to find anatomical landmarks for rotational alignment of the tibial component in total knee replacement (TKR) in a CT-based study. Pre-operative CT scanning was performed on 94 South Korean patients (nine men, 85 women, 188 knees) with osteoarthritis of the knee joint prior to TKR. The tibial anteroposterior (AP) axis was defined as a line perpendicular to the femoral surgical transepicondylar axis and passing through the centre of the posterior cruciate ligament (PCL). The angles between the defined tibial AP axis and anatomical landmarks at various levels of the tibia were measured. The mean values of the angles between the defined tibial AP axis and the line connecting the anterior border of the proximal third of the tibia to the centre of the PCL was -0.2° (-17 to 14.1, sd 4.1). This was very close to the defined tibial axis, and remained so regardless of lower limb alignment and the degree of tibial bowing. Therefore, AP axis defined as described, is a reliable anatomical landmark for rotational alignment of tibial components.

Clinical applications of platelet-rich plasma in patellar tendinopathy.

Platelet-rich plasma (PRP), a blood derivative with high concentrations of platelets, has been found to have high levels of autologous growth factors (GFs), such as transforming growth factor-ß (TGF-ß), platelet-derived growth factor (PDGF), fibroblastic growth factor (FGF), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). These GFs and other biological active proteins of PRP can promote tissue healing through the regulation of fibrosis and angiogenesis. Moreover, PRP is considered to be safe due to its autologous nature and long-term usage without any reported major complications. Therefore, PRP therapy could be an option in treating overused tendon damage such as chronic tendinopathy. Here, we present a systematic review highlighting the clinical effectiveness of PRP injection therapy in patellar tendinopathy, which is a major cause of athletes to retire from their respective careers.

Intrinsic and integrative properties of substantia nigra pars reticulata neurons.

The GABA projection neurons of the substantia nigra pars reticulata (SNr) are output neurons for the basal ganglia and thus critical for movement control. Their most striking neurophysiological feature is sustained, spontaneous high frequency spike firing. A fundamental question is: what are the key ion channels supporting the remarkable firing capability in these neurons? Recent studies indicate that these neurons express tonically active type 3 transient receptor potential (TRPC3) channels that conduct a Na-dependent inward current even at hyperpolarized membrane potentials. When the membrane potential reaches -60 mV, a voltage-gated persistent sodium current (I(NaP)) starts to activate, further depolarizing the membrane potential. At or slightly below -50 mV, the large transient voltage-activated sodium current (I(NaT)) starts to activate and eventually triggers the rapid rising phase of action potentials. SNr GABA neurons have a higher density of I(NaT), contributing to the faster rise and larger amplitude of action potentials, compared with the slow-spiking dopamine neurons. I(NaT) also recovers from inactivation more quickly in SNr GABA neurons than in nigral dopamine neurons. In SNr GABA neurons, the rising phase of the action potential triggers the activation of high-threshold, inactivation-resistant Kv3-like channels that can rapidly repolarize the membrane. These intrinsic ion channels provide SNr GABA neurons with the ability to fire spontaneous and sustained high frequency spikes. Additionally, robust GABA inputs from direct pathway medium spiny neurons in the striatum and GABA neurons in the globus pallidus may inhibit and silence SNr GABA neurons, whereas glutamate synaptic input from the subthalamic nucleus may induce burst firing in SNr GABA neurons. Thus, afferent GABA and glutamate synaptic inputs sculpt the tonic high frequency firing of SNr GABA neurons and the consequent inhibition of their targets into an integrated motor control signal that is further fine-tuned by neuromodulators including dopamine, serotonin, endocannabinoids, and H2O2.

Cluster solver for dynamical mean-field theory with linear scaling in inverse temperature.

Dynamical mean-field theory and its cluster extensions provide a very useful approach for examining phase transitions in model Hamiltonians and, in combination with electronic structure theory, constitute powerful methods to treat strongly correlated materials. The key advantage to the technique is that, unlike competing real-space methods, the sign problem is well controlled in the Hirsch-Fye (HF) quantum Monte Carlo used as an exact cluster solver. However, an important computational bottleneck remains; the HF method scales as the cube of the inverse temperature, ß . This often makes simulations at low temperatures extremely challenging. We present here a method based on determinant quantum Monte Carlo which scales linearly in ß , with a quadratic term that comes in to play for the number of time slices larger than hundred, and demonstrate that the sign problem is identical to HF.

Spatially band-tunable color-cone lasing emission in a dye-doped cholesteric liquid crystal with a photoisomerizable chiral dopant.

This study investigates a spatially band-tunable color-cone lasing emission (CCLE) based on a dye-doped cholesteric liquid crystal with a photoisomerizable chiral dopant (IBM). Experimental results show that the lasing band of the formed CCLE of the cell with a photoinduced pitch gradient can be spatially tuned among various color regions by adjusting the pumped position of the cell. The spatially band tunability of the laser results from the UV-irradiation-induced decrease of the helical twisting power of IBM via trans-->cis isomerization, accordingly shrinking the pitch of the cholesteric-liquid-crystal host. The total spatially tunable wavelength range for the laser exceeds 100 nm.

All-optically controllable random laser based on a dye-doped polymer-dispersed liquid crystal with nano-sized droplets.

This study elucidates for the first time an all-optically controllable random laser in a dye-doped polymer-dispersed liquid crystal (DDPDLC) with nano-sized LC droplets. Experimental results demonstrate that the lasing intensity of the random laser can be controlled to decrease by increasing irradiation time/intensity of one green beam, and increase by increasing the irradiation time of one red beam. The all-optical controllability of the random laser is attributed to the green (red)-beaminduced isothermal nematic-->isotropic (isotropic-->nematic) phase transition in LC droplets by trans-->cis (cis-->trans back) isomerization of azo dyes. This isomerization may decrease (increase) the difference between the refractive indices of the LC droplets and the polymer, thereby increasing (decreasing) the diffusion constant (or transport mean free path), subsequently decreasing the scattering strength and, thus, random lasing intensity.

Immunocytochemical identification of proteins involved in dopamine release from the somatodendritic compartment of nigral dopaminergic neurons.

We examined the somatodendritic compartment of nigral dopaminergic neurons by immunocytochemistry and confocal microscopy, with the aim of identifying proteins that participate in dopamine packaging and release. Nigral dopaminergic neurons were identified by location, cellular features and tyrosine hydroxylase immunoreactivity. Immunoreactive puncta of vesicular monoamine transporter type 2 and proton ATPase, both involved in the packaging of dopamine for release, were located primarily in dopaminergic cell bodies, but were absent in distal dopaminergic dendrites. Many presynaptic proteins associated with transmitter release at fast synapses were absent in nigral dopaminergic neurons, including synaptotagmin 1, syntaxin1, synaptic vesicle proteins 2a and 2b, synaptophysin and synaptobrevin 1 (VAMP 1). On the other hand, syntaxin 3, synaptobrevin 2 (VAMP 2) and SNAP-25-immunoreactivities were found in dopaminergic somata and dendrites Our data imply that the storage and exocytosis of dopamine from the somatodendritic compartment of nigral dopaminergic neurons is mechanistically distinct from transmitter release at axon terminals utilizing amino acid neurotransmitters.

Color cone lasing emission in a dye-doped cholesteric liquid crystal with a single pitch.

This work investigates a novel color cone lasing emission (CCLE) based on a one-dimensional photonic crystal-like dye-doped cholesteric liquid crystal (DDCLC) film with a single pitch. The lasing wavelength in the CCLE is distributed continuously at 676.7-595.6 nm, as measured at a continuously increasing oblique angle relative to the helical axis of 0-50 degrees . This work demonstrates that lasing wavelength coincides exactly with the wavelength at the long wavelength edge of the CLC reflection band at oblique angles of 0-50 degrees . Simulation results of dispersion relations at different oblique angles using Berreman's 4X4 matrix method agrees closely with experimental results. Some unique and important features of the CCLE are identified and discussed.

Band-tunable color cone lasing emission based on dye-doped cholesteric liquid crystals with various pitches and a pitch gradient.

This study elucidates, for the first time, a novel band-tunable color cone lasing emission (CCLE) based on dye-doped cholesteric liquid crystal (DDCLC) films with various pitches. For several CLC cells with different pitches it was shown experimentally that the lasing band on the CCLE can be tuned among various color regions measured within different angular ranges. Some important features of the tunable CCLE are also identified and discussed. A spatially band-tunable color cone laser, based on a single DDCLC with a gradient pitch, is developed as a real application.

Cyclooxygenase polymorphisms and risk of cardiovascular events: the Atherosclerosis Risk in Communities (ARIC) study.

Cyclooxygenase-derived prostaglandins modulate cardiovascular disease risk. We genotyped 2212 Atherosclerosis Risk in Communities study participants (1,023 incident coronary heart disease (CHD) cases; 270 incident ischemic stroke cases; 919 non-cases) with available DNA for polymorphisms in PTGS1 and PTGS2. Using a case-cohort design, associations between genotype and CHD or stroke risk were evaluated using proportional hazards regression. In Caucasians, the reduced function PTGS1 -1006A variant allele was significantly more common among stroke cases compared to non-cases (18.2 versus 10.6%, P=0.027). In African Americans, the reduced function PTGS2 -765C variant allele was significantly more common in stroke cases (61.4 versus 49.4%, P=0.032). No significant relationships with CHD risk were observed. However, aspirin utilization appeared to modify the relationship between the PTGS2 G-765C polymorphism and CHD risk (interaction P=0.072). These findings suggest that genetic variation in PTGS1 and PTGS2 may be important risk factors for the development of cardiovascular disease events. Confirmation in independent populations is necessary.

Manganese does not alter the severe neurotoxicity of MPTP.

We utilized a mice model of Parkinsonism: (1) to evaluate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity; and (2) to evaluate whether manganese (Mn) exposure can affect MPTP-induced neurotoxicity. A 2 x 3 experimental design (MPTP x+/- Mn) was as follows: SS, MPTP(-) x Mn(-); SLMn, MPTP(-) x low Mn(+); SHMn, MPTP(-) x high Mn(+); MpS, MPTP(+) x Mn(-); MpLMn, MPTP(+) x low Mn(+); MpHMn, MPTP(+) x high Mn(+). We administered MPTP (30 mg/kg per day) to male C57BL/6 mice intraperitoneally, once a day for 5 days. Subsequently, mice were treated with either 2 or 8 mg/kg of MnCl(2).4H(2)O intraperitoneally, once a day for 3 weeks. Blood and striatal Mn levels were elevated in the Mnexposed groups. The number of tyrosine hydroxylase (TH)-immunoreactive (ir) neurons in the substantia nigra pars compacta were decreased significantly in the MPTP-exposed groups. The densities of TH-ir axon terminals in caudate-putamen (CPU) were significantly decreased in the MPTP-treated groups. However, Mn treatment did not affect MPTP neurotoxicity. The densities of glial fibrillary acidic protein (GFAP)-ir astrocytes in the CPU or globus pallidus were significantly increased in the MPTP-treated groups. Concentrations of dopamine in the striatum were decreased significantly in the MPTP-exposed groups only, but Mn had no effect.

Pallidal control of substantia nigra dopaminergic neuron firing pattern and its relation to extracellular neostriatal dopamine levels.

The firing patterns of dopaminergic neurons in vivo are strongly modulated by afferent input. The principal GABAergic inputs to the dopaminergic neurons of the substantia nigra originate from neurons of the neostriatum, globus pallidus and substantia nigra pars reticulata. It has previously been shown that the firing pattern of nigral dopaminergic neurons can be manipulated by pharmacologically induced excitation or inhibition of the globus pallidus with relatively little effect on firing rate. We used this technique to explore the relation between the firing pattern of dopaminergic neurons and extracellular dopamine levels in the neostriatum in vivo. Specifically, we tested whether an increase in burst firing in dopaminergic neurons produced by increased pallidal activity led to increased extracellular dopamine levels in the neostriatum. Single unit extracellular recording combined with simultaneous microdialysis was used to measure the firing rates and patterns of dopaminergic neurons and extracellular striatal dopamine levels, respectively, during bicuculline-induced excitation of the globus pallidus. Pallidal excitation resulted in a marked increase in burst firing in dopaminergic neurons along with only a slight increase in firing rate, but produced a significant elevation (approximately 45%) in neostriatal dopamine levels. These data suggest that afferent-induced burst firing in dopaminergic neurons leads to an increase in extracellular dopamine levels in the neostriatum when compared with less bursty patterns with similar overall firing rates.

CYP2C9 genotype as a predictor of drug disposition in humans.

Discovery of genetic polymorphisms in CYP2C9 has stimulated numerous in vitro and in vivo studies evaluating the influence of CYP2C9 genotype on metabolic activity and drug disposition. CYP2C9*2 (Arg144Cys) and *3 (Ile359Leu) have been the most widely studied alleles. They are present in approximately 10-15% and 5-10% of white populations, respectively, and are even less frequent in black and Asian populations. The CYP2C9*2 and *3 alleles have been consistently associated with lower intrinsic clearance compared with CYP2C9*1 in vitro; however, the magnitude of these differences appears to be highly substrate-specific. In addition, multiple human studies have demonstrated significant associations between CYP2C9 genotype and the disposition of substrates such as warfarin, phenytoin and various sulfonylureas, angiotensin II receptor blockers and non-steroidal antiinflammatory agents. Individuals carrying the CYP2C9*2 and *3 alleles also have lower warfarin and phenytoin daily dose requirements, and appear more susceptible to adverse events during the initiation of therapy. Collectively, these findings suggest that CYP2C9 genotype-guided dosing may be clinically useful and warrants prospective investigation.

Surface-assisted photoalignment in dye-doped liquid-crystal films.

This study examines the surface-assisted photoalignment effect of dye-doped liquid-crystal films having a homogeneous alignment. Observations made using a polarizing optical microscope, a scanning electronic microscope, and an atomic force microscope confirm that the morphology of laser-induced surface-adsorbed dyes at the command surface strongly affects the orientation of liquid crystals (LC's) in a manner that depends significantly on the intensity and duration of the pumping. In weak-intensity regime, a homogeneous and fine layer of adsorbed dyes competes with a layer of ripple structure in reorienting LC's. These two effects dominantly cause LC's to reorient perpendicular and parallel to the polarization direction of the pump beam in the early and late stages, respectively. In the high-intensity regime, rough and inhomogeneous ribbonlike adsorbents produced by rapid and random aggregation and adsorption form on the top of the preformed microgrooves, reorienting LC's irregularly. This surface morphology does not enable photoalignment.

Modulation of the contractile and biosynthetic activity of chondrocytes seeded in collagen-glycosaminoglycan matrices.

Studies have demonstrated that articular chondrocytes can express the gene for alpha-smooth muscle actin (SMA) and can contract porous polymeric matrices employed for tissue engineering, thereby altering the pore structure and distorting the shape of the scaffold. The objectives of this study were to determine whether an agent known to disrupt microfilament organization in chondrocytes could reduce this contractility and to assess whether there was an association between the contractile behavior of chondrocytes and their biosynthetic activity. Staurosporine, an antibiotic known to inhibit protein kinase C and disrupt cytoskeletal structure, was used as the agent to modulate the chondrocytic phenotype and contractile and biosynthetic activity of serially passaged adult canine chondrocytes seeded in type 1 collagen-glycosaminoglycan scaffolds. Cells in monolayer culture treated with as little as 3 nM staurosporine for 4 days contained type II procollagen, whereas few cells in the untreated control cultures demonstrated type II procollagen synthesis. Treatment with staurosporine also led to a decrease in the amount of SMA synthesized by the cells. Consistent with this decreased expression of the contractile actin isoform, cells cultured in the collagen-glycosaminoglycan scaffolds and treated with 5 nM staurosporine contracted the scaffold significantly less than untreated cells (15% diameter contraction by treated cells, compared with more than 50% contraction by untreated cells). The staurosporine-treated cells were biosynthetically active, displaying higher rates of protein and glycosaminoglycan synthesis, as indicated by rates of incorporation of [(3)H]proline and [(35)S]sulfate, respectively, compared with untreated cells. The long-held notion that changes in cytoskeletal structure influence phenotypic characteristics of cultured chondrocytes may now be extended to relate expression of a specific muscle actin isoform to certain cell processes. Moreover, the finding that chondrocytes with a lower level of expression of SMA and reduced contractility display higher rates of biosynthesis warrants further study.