Management of the side-effects of intravenous bisphosphonates: targeting the serum parathyroid hormone elevation.

In their recent review article, Tanvetyanon and Stiff [1] pointedout that hypocalcemia is a frequent side-effect of intravenousbisphosphonates. This adverse event is usually mild and exceptionallysymptomatic, with the principle risk factors being pre-existinghypovitaminosis D, previous parathyroid surgery and intestinalresections. A direct consequence of hypocalcemia     

Expression of rat insulin-like growth factor binding protein-6 in the brain, spinal cord, and sensory ganglia

Insulin-like growth factors (IGFs) are important trophic factors during development as well as in the adult or damaged nervous system. Their trophic actions are modulated by interactions with six distinct IGF binding proteins. The mRNA expression profiles of binding proteins 2, 4 and 5 in the normal developing and adult CNS are well characterized and are shown to have distinctive, non-overlapping distributions. The IGF binding protein-6 (BP6) is also expressed in the CNS, however, details regarding its mRNA expression distribution in the developing and adult nervous system is limited. BP6 has the unique property of preferentially binding the IGF-II ligand. Coupled with the fact that this ligand is the most abundantly expressed IGF in the adult CNS, this suggests that the IGF-II/BP6 complex has a unique role in modulating IGF-II function in the adult brain. In this report the anatomical distribution of BP6 messenger RNA in the developing and adult rat nervous system is presented. In the embryonic animal the CNS expression is tightly restricted to trigeminal ganglia and, relative to the rest of the embryo, this structure has the highest expression. The expression in the forebrain and cerebellum does not occur until after postnatal day 21 and then is primarily associated with GABAergic interneurons. The highest levels of expression in the adult animal are in the hindbrain, spinal cord, cranial ganglia, and dorsal root ganglia. These nuclei in the hindbrain and periphery that express BP6 are all associated with the coordination of sensorimotor function in the cerebellum, which indicates an important role for the BP6/IGF-II complex in the function and maintenance of these systems.     

Mesoporous-silica-coated palladium-nanocubes as recyclable nanocatalyst in C–C-coupling reaction – a green approach

We report the straightforward design of a recyclable palladium-core–silica-shell nanocatalyst showing an excellent balance between sufficient stability and permeability. The overall process – design, catalysis and purification – is characterized by its sustainability and simplicity accompanied by a great recycling potential and ultra high yields in C–C-coupling reactions.

A green approach: in a single-step coating process a mesoporous silica shell was tailored onto palladium-nanocubes. Along with a PEG-matrix this core–shell-nanocatalyst could be recovered after C–C-coupling reactions and reused without any significant decrease in product yield.

In contrast to bulk materials, metal-nanocyrstals (NC) possess unique physical and chemical properties. Both, nano-scale and geometry can dictate their optical, electronic and catalytic behavior.^1–3 Consequently, nanomaterials have been implemented already in various fields like medicine,⁴ sensing,⁵ nano-electronics⁶ and organic synthesis.⁷ Smart strategies for a sustainable usage of limited resources such as precious metals and hydrocarbons are inevitable due to the consistently growing population and economy.^8–10 Generally, catalysis gives rise to novel and energy-saving synthetic routes. However, homogeneous catalysis is not widely used in industrial processes, due to the need of mostly toxic ligands and the costly purification along with a restricted reusability potential.^11–13 Heterogeneous catalysis based on the utilization of metal nanocrystals overcomes most of these limitations. Caused by its high surface-to-volume ratio, catalytic activities are drastically increased in comparison to bulk materials. However, the most common disadvantage in NC-based catalysis lies in the occurrence of aggregates during the reaction, which leads to a decrease of the catalytic active surface. Several studies were already presented in literature to delay that phenomenon using micelle-like- or core–shell-nanostructures as potential nanocatalytic systems.^14–20 However, these surfactants or shells are either potentially harmful for the environment or very step-inefficient to produce. Other approaches used the deposition of small NCs in a mesoporous support which offers a large active surface area.^21–24 In this context, it is crucial to find an adequate balance between permeability for small organic molecules and the overall stability of the nanocatalyst. Overcoming these obstacles can contribute to a sustainable supply of drugs and other organic substances.In the present work palladium-nanocubes (Pd-NCubes) were fabricated in aqueous solution using cetyltrimethyl-ammoniumbromide (CTAB) as surfactant. The procedure is adapted from a previously published study.^25,26 The respective transmission electron microscopy (TEM) image and the selected area electron diffraction (SAED) pattern of the as-obtained Pd-NCubes are depicted in Fig. S1.^† The SAED confirms the single-crystallinity of Pd-NCubes bound by {100}-facets. TE micrographs of Pd-NCubes revealed an average edge-length of (18 ± 2) nm (for histogram see Fig. S2^†). The formation of polyhedra and nanorods was found to be less than 1%.To the best of our knowledge, there is no procedure reported that showed the direct fabrication of a mesoporous silica (mSi) shell tailored on Pd-NCs. However, Matsuura et al. demonstrated a single-step coating approach of CTAB-capped gold-nanorods and CdSe/ZnS quantum dots obtaining a mesoporous silica shell.²⁷ The pores were determined to be 4 nm in width with 2 nm thick walls. Since the Pd-NCubes are covered by CTAB, already no surfactant exchange is necessary. Consequently, this procedure could be directly transferred to the as-obtained Pd-NCubes (∼10¹⁵ particles per L) of this study using tetraethyl orthosilicate (TEOS) as silica precursor in an alkaline solution. Here, CTAB serves as organic template for the formation of the mesoporous silica shell.TE micrographs of individual Pd-mSi-nanohybrids are depicted in Fig. 1 showing a spherical silica coating with a thickness of (17 ± 2) nm (for histogram see Fig. S3^†). The porosity is essential to ensure that vacant coordination sites on the palladium-core are present and accessible for catalysis. In contrast to other multistep approaches, pores are formed in situ with no additional etching step necessary.^28,29 This avoids the usage of harmful etching agents such as fluorides or ammonia.³⁰ The silica shell then served as platform for further surface modification using two different PEG-silanes (M_n = 5000 g mol⁻¹ and M_n = 20 000 g mol⁻¹). TE microscopy did not reveal any changes in the structure of the PEG functionalized Pd-mSi-nanohybrids opposed to the unfunctionalized nanocatalyst, since the contrast of polymer is too low (see Fig. S4^†). However, dynamic light scattering (DLS) measurements in diluted aqueous solutions proved an increased hydrodynamic radius with increasing molecular weight of the PEG-chain grafted onto the silica shell (see Fig. 2). These results provide evidence that only individual nanostructures are formed while no larger aggregates are present.Open in a separate windowFig. 1Exemplary TE micrographs of Pd-mSi-nanohybrids.Open in a separate windowFig. 2DLS results along the different stages of the hierarchal fabrication process of the nanocatalyst.The successful functionalization of the Pd-mSi-nanohybrid with PEG provides the dispersibility for the overall nanocatalyst in a PEG matrix. Due to its lack of toxicity and its simple recovery, caused by its melting point at ∼50 °C, PEG is considered as a “green” reaction medium.³¹ It has already been shown that PEG can act as suitable solvent for both homogeneous and heterogeneous catalysis.^32–34 Consequently, further experiments were performed using only the Pd-mSi-nanohybrid functionalized with PEG-silane having an average molecular weight of M_n = 5000 g mol⁻¹ (PEG-5k). For catalytic reactions, Pd-mSi-PEG-5k was dispersed in a PEG matrix (PEG-2000, M_n = 2000 g mol⁻¹) and charged into a Teflon centrifuge tube. Using only one tube for the reaction and the product separation avoids an additional transfer step and prevents any loss of the nanocatalyst between reaction cycles (see recycling Scheme 1). Here, the C–C-coupling between ethyl acrylate and p-iodoanisole served as model Heck-reaction to prove the catalytic activity of the designed catalyst (4.4 mol% overall Pd conc. equal to ca. 0.3 mol% surface-available Pd; conc. is determined by ICP-MS measurements, see Table S1^†). Sodium phosphate was used as base providing the largest product yield when compared to other bases, such as Na₂CO₃, K₂CO₃ and K₃PO₄. Once the catalysis was performed and the PEG-2000 was cooled down, diethyl ether was added to extract the product and separated from the reaction medium via centrifugation.Open in a separate windowScheme 1Recycling process of the Pd-mSi-PEG-5k-nanocatalyst and PEG-2000 as solvent after the Heck-reaction between ethyl acrylate and p-iodoanisole to form ethyl p-methoxycinnamate.To exclude any suspended compounds from the desired product, the mixture was passed through a PTFE-filter. Et₂O was removed in vacuo without the need of column chromatography. Comparing the ¹H-NMR spectra of the as-obtained product with the educts indicate a yield of 98% with only small amounts of PEG-2000 present (identified by the signal at ∼3.6 ppm, < 1 weight-%). The results show that both educts and the base Na₃PO₄ are able to diffuse through the mesoporous silica shell to the palladium core (see Fig. 3). A detailed ¹H-NMR signal assignment of the product is given in Fig. S5.^†Open in a separate windowFig. 3 ¹H-NMR spectra of the educts ethyl acrylate (top) and p-iodoanisole (center) and the product ethyl p-methoxycinnamate (bottom).After recovering the reaction mixture containing Pd-mSi-PEG-5k and PEG-2000, seven further Heck-reaction-cycles were conducted under the same conditions. Results obtained from ¹H-NMR and gravimetry indicate no significant decrease in catalytic activity (see ¹H-NMR spectra in Fig. 4). Along the eight Heck-reactions, product yields were determined between 94% and 99%. Only small traces of p-iodoanisole (identified by the signal at ∼6.75 ppm) were still present while ethyl acrylate could be fully removed in vacuo. The yields obtained after each cycle are displayed in Fig. 5. ICP-MS measurements of the catalysis product were performed to determine the palladium leaching out of the catalytic system. The results are displayed in Table S1^† indicating that leaching is strongly suppressed since the overall Pd-content in the product ranges from 0.3–5.7 ng, only. This corresponds to 0.002–0.044 ppm palladium with respect to the product mass. The data are in good agreement with the high product yields along the eight Heck-reactions. To trace the evolution of the nanocatalyst along the cycles, TE micrographs were taken after the 1^st and the 8^th Heck-cycle (see Fig. 6). It can be seen that the cubical structure of the palladium vanishes during the first reaction (left TEM image). Inside the silica shell spherical palladium particles were formed. An explanation for this rearrangement lies in the suggested Heck-mechanism.³⁵ Here, a Pd²⁺-species forms after the oxidative addition of the p-iodoanisole which can desorb from the Pd-NCube. Once the reductive elimination of the product occurs the Pd⁰-species is generated again that can re-deposit on the palladium-core.²¹ Since the spherical geometry possesses the lowest free surface energy, globules were eventually formed.³ The mesoporous silica shell is not affected significantly by the catalysis and the rearrangement of the palladium. The porosity appears to stay intact, enabling the penetration of further small organic molecules. Control experiments were performed to validate whether these observations are based on either a thermally or a chemically induced rearrangement process of the palladium core. Therefore, only the nanocatalyst was dispersed in PEG-2000 and heated at 110 °C for 24 h without any conducted catalysis reaction. TEM results showed no changes in the structure of neither the palladium core nor the silica shell (see Fig. S6^†). After the 8^th reaction, no core–shell-nanostructures could be detected anymore via TEM. Only small randomly shaped Pd-nanoparticles (≤20 nm) were found indicating a slow leaching of the palladium out of the silica shell. However, no larger aggregates were formed (see right TE micrograph in Fig. 6) which explains the continuously high catalytic activity.Open in a separate windowFig. 4 ¹H-NMR spectra of the product ethyl p-methoxycinnamate after the 1^st Heck-reaction (bottom) up to the 8^th reaction (top).Open in a separate windowFig. 5Conversions of ethyl p-methoxycinnamate obtained via NMR and gravimetry after each respective Heck-reaction (1–8).Open in a separate windowFig. 6TE micrographs of the Pd-mSi-PEG-5k-nanocatalyst taken after the 1^st (left) and the 8^th Heck-reaction (right).     

Clinical evaluation of an HIV-1 and HCV assay and demonstration of significant reduction of the HCV detection window before seroconversion

BACKGROUND: One HIV-1 and HCV assay simultaneously detects HIV-1 and HCV RNA (Procleix, Chiron Corp.). The main intended use of the assay is the testing of blood and blood products in blood banking. STUDY DESIGN AND METHODS: To evaluate the clinical sensitivity of the assay, 164 anti-HIV-1+ and 160 anti-HCV+ patients of different viral load were tested. The assay specificity was determined in 1000 HIV-1- and HCV-seronegative blood donors. The ability of the assay to detect different HCV genotypes was investigated in a total of 40 patients of different genotypes (1-4). Furthermore, to investigate the reduction of the HCV window phase before seroconversion, serial samples of 25 hemodialysis patients who seroconverted to anti-HCV were also tested. RESULTS: The assay detected all 60 HIV-1-infected patients with a viral load of greater than 50 copies per mL and 48 of 104 patients with a viral load of less than 50 copies per mL. Moreover, all 60 patients with an HCV RNA load of greater than 521 IU per mL and 7 of 100 patients with a viral load of less than 50 IU per mL tested positive. The assay specificity was found to be 100 percent. In addition, all 40 patients of different HCV genotypes were successfully detected. Finally, the median time that the assay detected HCV infection before second- and third-generation anti-HCV assay was found to be 183 and 91 days, respectively. CONCLUSION: The assay sensitivity and specificity, its ability to detect different HCV genotypes, and the significant reduction of window period of HCV infection further support its use for improving the safety of blood and blood products.     

Big Events in Greece and HIV Infection Among People Who Inject Drugs

Big Events are processes like macroeconomic transitions that have lowered social well-being in various settings in the past. Greece has been hit by the global crisis and experienced an HIV outbreak among people who inject drugs. Since the crisis began (2008), Greece has seen population displacement, inter-communal violence, cuts in governmental expenditures, and social movements. These may have affected normative regulation, networks, and behaviors. However, most pathways to risk remain unknown or unmeasured. We use what is known and unknown about the Greek HIV outbreak to suggest modifications in Big Events models and the need for additional research.     

Future trends of HCV-related cirrhosis and hepatocellular carcinoma under the currently available treatments

Summary. The epidemic of hepatitis C virus (HCV) infection is a major public health issue. We conducted a comprehensive analysis to estimate future HCV-related morbidity and mortality, using a model which is the first to take into account currently available treatments. We reconstructed the incident infections per year in the past that progressed to chronic hepatitis C (CHC) in Greece. Then, the natural history of the disease was simulated in subcohorts of newly infected subjects in the presence or absence of treatment using yearly estimates of the number of treated patients obtained from national databases. Annual estimates of the incidence and prevalence of CHC by fibrosis stage, hepatocellular carcinoma (HCC) and mortality were obtained up to 2030. The current proportion of naïve CHC patients receiving treatment in Greece is 1.2% per year. Treatment of 1.2–10% of naïve CHC patients per year would reduce the cumulative number of incident cirrhosis and HCC cases from 2002 to 2030 by 10.8–39.4% and 12.8–39.8%, respectively and decrease the number of prevalent cirrhosis and HCC cases in 2030 by approximately 17–48% compared with the number estimated under the assumption of no treatment. Approximately 17 cirrhosis cases or six HCC cases or 10 premature deaths would be prevented for every 100 treated patients. However, the prevalent cirrhotic/HCC cases because of HCV and HCV-related deaths would not plateau until 2030. Despite the introduction of effective treatment, HCV-related morbidity and mortality will likely increase during the next 20–30 years in Greece. Intensive primary prevention efforts coupled with increased access to the currently available treatments are necessary to control the chronic consequences of HCV epidemic.     

A Kinetic Investigation of the Initialization of Catalyzed Chain Growth of Styrene: The Reaction of Cp*2ZrCl2 with Dibenzylmagnesium

The system Cp*₂ZrCl₂ and dibenzyl magnesium in toluene, which is a model system for initialization in the catalyzed chain growth (CCG) of styrene using a bifunctional organometallic chain transfer agent, is studied via time‐resolved NMR spectroscopy. Based on these data, a mechanism of initialization is proposed. The experimental concentration profiles of the individual species can successfully be modeled to the proposed kinetic scheme. Refined kinetic coefficients of high significance can be obtained by applying analytical methods using pseudo‐first‐order rate approximations. It is found that the adduct of the Zr catalyst and the Mg compound only slowly transforms via a ligand exchange reaction, yielding the alkylated Zr species. The temperature dependence of these reactions indicates a high reaction barrier of this type of rearrangement, which constitutes the core reaction of CCG in terms of molecular‐weight control.