Small Nerve Fiber Damage and Langerhans Cells in Type 1 and Type 2 Diabetes and LADA Measured by Corneal Confocal Microscopy

PurposeIncreased corneal and epidermal Langerhans cells (LCs) have been reported in patients with diabetic neuropathy. The aim of this study was to quantify the density of LCs in relation to corneal nerve morphology and the presence of diabetic neuropathy and to determine if this differed in patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), and latent autoimmune diabetes of adults (LADA).MethodsPatients with T1DM (n = 25), T2DM (n = 36), or LADA (n = 23) and control subjects (n = 23) underwent detailed assessment of peripheral neuropathy and corneal confocal microscopy. Corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and total, immature and mature LC densities were quantified.ResultsLower CNFD (P < 0.001), CNBD (P < 0.0001), and CNFL (P < 0.0001) and higher LC density (P = 0.03) were detected in patients with T1DM, T2DM, and LADA compared to controls. CNBD was inversely correlated with mature (r = –0.5; P = 0.008), immature (r = –0.4; P = 0.02) and total (r = –0.5; P = 0.01) LC density, and CNFL was inversely correlated with immature LC density (r = –0.4; P = 0.03) in patients with T1DM but not in patients with T2DM and LADA.ConclusionsThis study shows significant corneal nerve loss and an increase in LC density in patients with T1DM, T2DM, and LADA. Furthermore, increased LC density correlated with corneal nerve loss in patients with T1DM.     

Hybrid hollow silica particles: synthesis and comparison of properties with pristine particles

In the past decade, interest in hollow silica particles has grown tremendously because of their applications in diverse fields such as thermal insulation, drug delivery, battery cathodes, catalysis, and functional coatings. Herein, we demonstrate a strategy to synthesize hybrid hollow silica particles having shells made of either polymer-silica or carbon–silica. Hybrid shells were characterized using electron microscopy. The effect of hybrid shell type on particle properties such as thermal and moisture absorption was also investigated.

Hybrid hollow silica particles, which show different properties compared to their pristine counterparts, have been synthesized.

In the past decade, hollow particles have attracted a great deal of interest because of their unique properties (e.g., high surface area, low density, and encapsulated cavity) compared with their dense counterparts. Hollow particles of several materials, including polymers, silica, titania, carbon, and zinc oxide have been reported.^1–9 Among these, hollow silica particles have attracted great attention from scientists because of their low material cost; well understood chemistry; and potential applications in widespread areas such as thermal insulation, drug delivery, energy storage, phase change encapsulation, catalysis, and superhydrophobic coatings.^10–18 Hollow silica particles can be synthesized using various approaches, such as by employing polymer micelles, immiscible solvent emulsions, inorganic or polymer (e.g., polystyrene) particles, and bacterial or virus cells as templates; by etching solid silica particles; or by spray pyrolysis.^19–25 Polymer micelles or emulsions provide very small particles, but making larger particles and tuning particle size are challenges in this approach. Similarly, the obtained particles typically fuse with one another, and achieving individually separated particles is a challenging task. Inorganic template etching is a time-consuming process, and in many cases, rudiments of inorganic templates remain in the hollow particle cavity if etching is incomplete. Unconventional techniques such as spray drying are inexpensive, but particle size control is difficult. The use of polystyrene particles as templates is attracting much attention because polystyrene particles can be synthesized at low cost with controlled sizes. Polystyrene particle-based synthesis of hollow silica particles involves three steps: (1) synthesis of polystyrene particles, (2) deposition of silica shells on polystyrene particles, and (3) removal of the polystyrene core by burning or dissolving to obtain hollow silica particles.Synthesis of hollow silica particles having shells made of silica alone (pristine hollow particles) is well reported. Some previous efforts have been made to attach surfactant molecules to the surfaces of mesoporous (not hollow) hollow particles. For example, Zhang et al.²⁶ first made porous silica particles by using cetyltrimethylammonium bromide (CTAB) as the template. In the next step, sodium carbonate-based etching was used to create cavities inside the porous particles, thus leading to porous-hollow silica particles. Then, 3-mercaptopropyl-trimethoxysilane (MPTS) was used to attach thiol-group ending surfactants to the surface. Similarly, Ribeiro et al.²⁷ coated solid silica particles with poly(butyl methacrylate) to make superhydrophobic coatings. Similarly, hollow polymer particles have been reported by depositing a polymer layer around solid silica particles, followed by etching the silica core. The same hollow polymer particles were also converted to hollow carbon particles by pyrolysis of polymer.^28,31 However, in this work, shell is made of a single material – polymer or carbon.^28,31 To the best of our knowledge, no work has reported hollow particles with a hybrid shell – shell made of two layers of different materials (inner layer: silica and outer layer: polymer or carbon). Additionally, no previous report has investigated the effect of such an additional layer on the properties of the hollow silica particles. We envisage that such additional layers can change the properties, such as stability against moisture and thermal conductivity, of pristine hollow silica particles.We report the synthesis of hybrid hollow silica particles, characterize these hybrid particles, and compare their properties with the properties of pristine hollow silica particles. Our investigations reveal that by changing the coating material, several intrinsic properties of hollow silica particles can be modified.Hollow silica particles were synthesized by modifying previously reported strategies based on the use of polystyrene particles (synthesis details in ESI S1^†) as a template.¹ For synthesizing hollow silica particles, in a typical experiment, 0.25 g of polystyrene particles were mixed into 100 mL of ethanol/water (ethanol 80 mL, water 20 mL). A suitable amount of tetraethyl orthosilicate was added to make complete shells around the polystyrene particles. To increase the TEOS hydrolysis, 28–30% of ammonium hydroxide was used as a catalyst. Fig. 1a depicts a schematic of hollow particle formation. Fig. 1b shows an SEM image of the polystyrene particles used as templates, and Fig. 1c shows a transmission electron microscope (TEM) image of polystyrene core-silica shell particles. Fig. 1d shows an SEM and Fig. 1e shows a high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) image of hollow silica particles obtained after burning the polystyrene core by keeping the sample at 550 °C for 4 h.Open in a separate windowFig. 1(a) Schematic showing synthesis of hollow silica particles. (b) SEM image of polystyrene particles. (c) TEM image of polystyrene core coated with silica shell (core–shell). (d) SEM and (e) HAADF-STEM image of hollow silica particles.There are several polymers that can be used to form coatings on silica.^28–31 Among these, the use of resorcinol is well studied.^28,31 In a typical experiment, 0.25 g of hollow particles (0.25 g) were mixed in water (100 mL). Ammonium hydroxide (28–30%, 500 μL), resorcinol (0.1 g), and formaldehyde (150 μL) were added to this reaction mixture. The reaction was allowed to proceed overnight (≈16 h) to completion. Expected mechanism for polymer coating formation is explained in ESI S3.^†Fig. 2a shows a schematic of the process used to make a polymer (polyresorcinol) coating on a silica shell. Fig. 2b shows low-magnification (i) and high-magnification (ii) TEM images of polymer-coated hollow silica particles. The polymer coating can be clearly seen (light in contrast) around the silica shell (dense in contrast). Though TEM imaging confirmed the presence of a polymer coating on the surface of the silica, to further confirm the formation of the coating, we applied electron energy loss spectroscopy (EELS). Energy dispersive X-ray (EDX) imaging is easy to use and is a readily available technique for analysing materials; however, EDX has a very low sensitivity to low-atomic-weight elements such as carbon and oxygen. Therefore, it was not a suitable technique for confirming the polymer presence. In contrast, EELS is known for its high sensitivity to low-atomic-weight elements (e.g., carbon and oxygen). Fig. 2c shows scanning HAADF-STEM (i) and EELS (ii) images of the polymer-silica hybrid shell. The coating was quite uniform, with some thicker areas on the free surfaces of particles and some thinner areas at the joints in aggregated particles (ESI S2^†). Therefore, if individual uniform coatings are required, the original hollow particle samples must be properly disaggregated.Open in a separate windowFig. 2(a) Schematic showing the polymer coating process. (b) TEM images of polymer-coated silica particles. (c) HAADF-TEM (i) and EELS S map (ii) showing polymer and silica layers of hybrid shell.Additionally, we demonstrated the formation of hybrid hollow silica particles with outer layers made of carbon and inner layers made of silica. To form a carbon layer on a silica shell, the initial polymer coating was sintered in an inert atmosphere (argon) at 550 °C for 4 h. Fig. 3a shows a schematic of polymer layer conversion to a carbon layer. Under these conditions, polymer converts into carbon instead of being completely oxidized into carbon dioxide and water. After heating under an inert atmosphere, brown polymer-coated particles changed to black carbon-coated particles. Separate carbon (outer) and silica (inner) layers were observed in TEM (Fig. 3b) and EELS images (Fig. 3c).Open in a separate windowFig. 3(a) Schematic showing conversion of polymer coating to carbon coating. (b) TEM images of carbon-coated particles. (c) EELS element map showing the carbon layer on a silica shell.In addition to making hybrid shell hollow particles, we investigated whether the coating affected the properties (e.g., thermal conductivity and moisture absorption) of the pristine hollow silica particles. We measured the thermal conductivity of pristine, polymer-coated, and carbon-coated particles. The results showed that polymer-coated particles had the lowest thermal conductivity and carbon-coated particles had the highest thermal conductivity of the three types. The Fig. 4 plot shows the thermal conductivities of the three types of particles, and respective insets show photos of corresponding particle samples. More details of the measurements are provided in ESI-S3.^† As expected, the polymer silica particles had lower thermal conductivity (0.022 ± 0.002 W m⁻¹ K⁻¹) than pristine hollow particles (0.024 ± 0.002 W m⁻¹ K⁻¹), whereas carbon-coated particles had higher thermal conductivity (0.036 ± 0.004 W m⁻¹ K⁻¹) than both the pristine and the polymer-coated particles. This information provides a new tool to achieve or tune thermal properties of hollow silica particles as desired. For example, for high-thermal-insulation materials, polymer-coated particles are ideal; whereas carbon-coated particles are more suitable where somewhat higher thermal conductivity, but hydrophobicity is required. We were expecting that a carbon coating will increase electrical conductivity of hollow particles, however, we observed that even carbon coated particles had an electrical resistance in the megaOhm range, i.e., behave as electrically insulators (measurement details in ESI S3^†). Although the thermal conductivity of polymer-coated or carbon-coated hollow silica particles can be further modified by modifying the coating thickness, in the present work, we did not investigate the effect of coating thickness on thermal conductivity in detail. We expect the thinner the coating, the lower the thermal conductivity will be. We observed in both the polymer- and carbon-coated particles that the coatings were not uniform. Some particles had thick and others thin coatings, indicating that coating nucleation was not uniform, and the coatings may have begun forming earlier on some particles than on others. We observed that carbon–silica hollow particles are hydrophobic in nature, staying afloat on water for several hours (ESI Fig. S4^†) and mixing in water only after vigorous stirring. It appears that, with stirring, water molecules enter the hollow particle cavities through the pores present in the carbon and silica shells and wet the inner parts of the cavities, thus causing the particles to mix in water.Open in a separate windowFig. 4Effect of different types of coatings on the thermal conductivity of hollow silica particles. Insets show the photos of respective particles.Additionally, we compared the moisture absorption properties of pristine hollow silica particles with those of polymer- and carbon-coated hollow silica particles (Fig. 5). Moisture absorption/desorption experiments were performed using a dual vapor gravimetric sorption analyser. We observed that polymer-coated particles absorbed less humidity compared with pristine particles at the same relative humidity. However, both materials had similar isotherm profiles in which the moisture adsorption capacity increased at relatively higher moisture concentrations. The carbon-coated particles, on the other hand, showed a completely different isotherm behaviour: an immediate increase in adsorption capacity was observed between 30% and 50% relative humidity. A sharp increase in moisture absorption at higher relative humidity (between 30–50%) appears due to the entry of water vapors inside the particles because of porous nature of carbon layer. Similar shape of isotherms for pristine and polymer coated particles indicates that both of these particles had similar surface groups (–OH), but lower absorption in polymer coated particles compared to pristine particles indicates that its surface has a small number of moisture absorbing groups (–OH) compared to pristine particles. The hysteresis between adsorption and desorption isotherms was found to be minimal, indicating that the samples had similar performance for adsorption or desorption process. We expect this information to be helpful for applications such as developing water-stable coatings or insulation materials by using hollow silica particles.Open in a separate windowFig. 5Effect on moisture adsorption and desorption process. Plot showing behaviour of hollow particles under different relative humidity conditions for pristine and coated samples.     

Gender-specific differences in muscle-invasive bladder cancer: the concept of sex steroid sensitivity

Purpose

To describe the role of sex steroid-dependent growth of muscle-invasive bladder cancer (MIBC) and the role of single-nucleotide polymorphisms (SNP) located on chromosome 8q24 as a molecular explanation for gender-specific differences in the incidence and outcome of MIBC.

Methods

A detailed, non-systematic analysis was performed for articles and reviews investigating the role of sex steroids in the development and progression of MIBC between 2000 and 2012.

Results

Localized MIBCs overexpress the androgen receptor (AR), whereas in lymph node-positive stages, loss of AR expression has been found. High-risk SNPs of genes on chromosome 8q24, that is, the rs2294008 of prostate stem cell antigen (PSCA) gene, have been linked with increased susceptibility for MIBC. The PSCA gene possesses an androgen-responsive element (ARE) in its promoter region. Recent studies suggest that loss of AR responsiveness to the PSCA promoter may result in the induction of an androgen-independent mechanism, that is, the insulin-like growth factor-binding protein 2 signalling pathway—a key event in the development of hormone-independent prostate cancer—and this may increase the metastatic potential. In females, it can be hypothesized that due to the altered androgen levels, these mechanisms may be initiated earlier during tumor progression in females and result in inferior survival compared to males.

Conclusion

Muscle-invasive bladder cancer (MIBC) is a sex steroid-dependent tumor. AREs in the promoter region of high-risk genes may drive tumor progression and result in loss of androgen responsiveness, which eventually leads to the activation of androgen-independent processes forming the metastatic potential. The determination of the AR status in cystectomy specimens additionally offers new adjuvant approaches after cystectomy.     

Inducible displacements of the cup and the femoral head during active range of motion: Dynamic RSA studies of cemented total hip replacements

We evaluated changes in position of the femoral head relative to the cup and of the cup relative to the pelvis in total hip replacement patients during hip motion 2 years postoperatively. Two patient groups with nine patients in each group were studied. Hip motions, translations of the femoral head center, and cup displacements were recorded with dynamic radiostereometric examination (RSA, 2 exposures/s) during abduction in Group 1 and with use of static RSA exposures at increasing flexion of the hip in Group 2. Conventional radiographic examinations were used to evaluate any radiolucent lines around the cups at 2 years. During active abduction the femoral head center moved medially (median 0.04 mm) and the cup tilted anteriorly (median 0.09 mm). Increments in radiolucent lines at 2 years correlated to medial femoral head penetration, posterior tilt, and retroversion of the cup at 20° of abduction. The extension of radiolucent lines at 2 years showed a positive correlation with proximal inducible displacement of the cup and posterior translation of the femoral head center at maximum hip flexion. Our observations may be of value in understanding the pathogenesis of the loosening process and may be used to facilitate the development of prosthetic designs that optimize hip kinematics. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1686–1693, 2013     

Strumpell's Disease in a Family with Hereditary Focal Segmental Glomerulosclerosis

Strumpell's familial spastic paraplegia is a rare hereditary disease, clinically characterized by progressive disturbance of gait. Focal Segmental Glomerulosclerosis (FSGS) is a frequent glomerulopathy, with an extremely rare familial subtype. The cases of two brothers with Strumpell's disease are reported, who also developed glomerular renal disease, most probably familial FSGS. The genetics of the two disorders, Strumpell's paraplegia and familial FSGS, are discussed, together with the possibility of a parallel transmission.