Ureteroplasty with buccal mucosa graft without omental wrap: an effective method to treat ureteral strictures.

PURPOSE: Successful treatment options for ureteral strictures are limited. Surgical options such as ileal interposition and kidney autotransplantation are difficult and associated with morbidity and complications. Techniques such as Boari flap and psoas hitch are limited to distal strictures. Only limited case studies on the success of open buccal mucosa graft (BMG) ureteroplasty exist to this date. The purpose of this study was to evaluate the success of open BMG ureteroplasty without omental wrap. METHODS: In this single-center retrospective study between July 2020 and January 2023, we included 14 consecutive patients with ureteric strictures who were treated with open BMG ureteroplasty without omental wrap. The primary outcome was the success of open BMG ureteroplasty. Further endpoints were complications and hospital readmission. Outcome variables were assessed by clinical examination, kidney sonography, and patient anamnesis. RESULTS: Out of 14 patients, 13 were stricture and ectasia-free without a double-J stent at a median follow-up of 15 months (success rate 93%). No complications were observed at the donor site, and the complication rate overall was low with 3 out of 14 patients (21%) having mild-to-medium complications. CONCLUSIONS: Open BMG ureteroplasty without omental wrap is a successful and feasible technique for ureteric stricture repair.

A novel grading approach predicts worse outcomes in stage pT1 non-muscle-invasive bladder cancer.

OBJECTIVE: To develop a prognostically relevant scoring system for stage pT1 non-muscle-invasive bladder cancer (NMIBC) incorporating tumour budding, growth pattern and invasion pattern because the World Health Organisation grading system shows limited prognostic value in such patients. PATIENTS AND METHODS: The tissue specimens and clinical data of 113 patients with stage pT1 NMIBC who underwent transurethral resection of bladder tumour were retrospectively investigated. Tumour budding, and growth and invasion patterns were evaluated and categorised into two grade groups (GGs). GGs and other clinical and histopathological variables were investigated regarding recurrence-free survival (RFS), progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS) using univariable and multivariable Cox regression analyses. RESULTS: The integration of two tumour budding groups, two growth patterns, and two invasion patterns yielded an unfavourable GG (n = 28; 24.7%) that had a high impact on oncological outcomes. The unfavourable GG was identified as an independent RFS and OS predictor (P = 0.004 and P = 0.046, respectively) and linked to worse PFS (P = 0.001) and CSS (P = 0.001), irrespective of the European Association of Urology risk group. The unfavourable GG was associated with higher rates of BCG-unresponsive tumours (P = 0.006). Study limitations include the retrospective, single-centre design, diverse therapies and small cohort. CONCLUSIONS: We present a morphology-based grading system for stage pT1 NMIBC that correlates with disease aggressiveness and oncological patient outcomes. It therefore identifies a highest risk group of stage pT1 NMIBC patients, who should be followed up more intensively or receive immediate radical cystectomy. The grading incorporates objective variables assessable on haematoxylin and eosin slides and immunohistochemistry, enabling an easy-to-use low-cost approach that is applicable in daily routine. Further studies are needed to validate and confirm these results.

Long-term efficacy of the peptide-based COVID-19 T cell activator CoVac-1 in healthy adults.

OBJECTIVES: T cell immunity is key for the control of viral infections including SARS-CoV-2, in particular with regard to immune memory and protection against arising genetic variants. METHODS: We recently evaluated a peptide-based SARS-CoV-2 T cell activator termed CoVac-1 in a first-in-human trial in healthy adults. Here, we report on long-term safety and efficacy data of CoVac-1 until month 12. RESULTS: CoVac-1 is well tolerated without long-term immune-related side effects and induces long-lasting anti-viral T cell responses in 100% of study participants, with potent expandability of clusters of differentiation (CD4+) and CD8+ T cells targeting multiple different CoVac-1 T cell epitopes. T cell responses were associated with stronger injection site reaction. Beyond induction of T cell immunity, 89% of subjects developed CoVac-1-specific immunoglobulin G antibodies which associated with the intensity of the T cell response, indicating that CoVac-1-specific CD4+ T cells support the induction of B-cell responses. Vaccination with approved COVID-19 vaccines boosted CoVac-1-specific T cell responses. Overall, a low SARS-CoV-2 infection rate (8.3%) was observed. CONCLUSION: Together, a single application of CoVac-1 elicits long-lived and broad SARS-CoV-2-specific T cell immunity, which further supports the current evaluation of our T cell activator in patients with congenital or acquired B-cell defects.

Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency.

T-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT04954469) in 54 patients with congenital or acquired B-cell deficiency receiving one subcutaneous CoVac-1 dose. Immunogenicity in terms of CoVac-1-induced T-cell responses and safety are the primary and secondary endpoints, respectively. No serious or grade 4 CoVac-1-related adverse events have been observed. Expected local granuloma formation has been observed in 94% of study subjects, whereas systemic reactogenicity has been mild or absent. SARS-CoV-2-specific T-cell responses have been induced in 86% of patients and are directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4+ T cells. CoVac-1-induced T-cell responses have exceeded those directed to the spike protein after mRNA-based vaccination of B-cell deficient patients and immunocompetent COVID-19 convalescents with and without seroconversion. Overall, our data show that CoVac-1 induces broad and potent T-cell responses in patients with B-cell/antibody deficiency with a favorable safety profile, which warrants advancement to pivotal Phase III safety and efficacy evaluation. ClinicalTrials.gov identifier NCT04954469.

Two state reactivity (TSR) and hydrogen tunneling reaction kinetics measured in the Co+ mediated decomposition of CH3CHO.

The electronic structure of a transition metal atom allows it to act as a catalytic active site by providing lower energy alternative pathways in chemical transformations. We have identified and kinetically characterized three such pathways in the title reaction. One is an adiabatic pathway that occurs on a single potential energy surface described within the Born-Oppenheimer approximation. A second pathway opens microseconds into the reaction as a portion of the reacting population competitively transitions from triplet to singlet multiplicity to circumvent energetic barriers on the triplet surface. These pathways are single- and two-state reactive (SSR and TSR) where the Co+ cation mediates an oxidative addition/reductive elimination sequence of the CH3CHO molecule. The third observed reaction pathway is the aldehyde hydrogen tunneling through an Eyring barrier to form high-spin products. First-order rate constants for the adiabatic and nonadiabatic energy lowered pathways, and the hydrogen tunneling pathway, are each measured using the single photon initiated dissociative rearrangement reaction (SPIDRR) experimental technique. We believe that this is the first experimental study where such disparate dynamic features (SSR, TSR, and H-tunneling) are disentangled in a system's chemistry, attributing specific rate constant values to each effect and quantifying the various competitions. Moreover, multi-reference CASSCF/CASPT2 calculations indicate that structures with covalent Co-H bonds are present exclusively along the excited singlet surface. This phenomenon significantly reduces these structures' energy relative to their triplet counterparts, thus enabling the surface crossing and spin inversion that cause the observed two-state reactivity.

Body Composition of Patients Undergoing Radical Cystectomy for Bladder Cancer: Sarcopenia, Low Psoas Muscle Index, and Myosteatosis Are Independent Risk Factors for Mortality.

BACKGROUND: We assessed a wide array of body composition parameters to identify those most relevant as prognostic tools for patients undergoing radical cystectomy (RC) due to bladder cancer (BC). METHODS: In this retrospective, single-center study, preoperative computed tomography (CT) scans of 657 patients were measured at the level of the 3rd lumbar vertebra (L3) to determine common body composition indices including sarcopenia, myosteatosis, psoas muscle index (PMI), subcutaneous and visceral fat index (SFI and VFI), visceral-to-subcutaneous fat ratio (VSR), and visceral obesity. Predictors of overall survival (OS) and cancer-specific survival (CSS) were identified in univariate and multivariate survival analysis. RESULTS: Sarcopenia and a low PMI were independently associated with shorter OS (Sarcopenia: HR 1.30; 95% CI 1.02-1.66; p = 0.04 and a low PMI: HR 1.32; 95% CI 1.02-1.70; p = 0.03) and CSS (Sarcopenia: HR 1.64; 95% CI 1.19-2.25; p < 0.01 and a low PMI: HR 1.41; 95% CI 1.02-1.96; p = 0.04). Myosteatosis, measured as decreasing average Hounsfield units of skeletal muscle, was an independent risk factor for OS (HR 0.98; 95% CI 0.97-1.00; p = 0.01) and CSS (HR 0.98; 95% CI 0.96-1.00; p < 0.05). The assessed adipose tissue indices were not significant predictors for OS and CSS. CONCLUSIONS: Sarcopenia, a low PMI, and myosteatosis are independent predictors for OS and CSS in patients undergoing radical cystectomy for bladder cancer.

The value of walking: a systematic review on mobility and healthcare costs.

BACKGROUND: The ability to walk is an important indicator of general health and mobility deficits have wide-ranging economic implications. We undertook a systematic review to elucidate the impact of walking parameters on health care costs.  METHODS: Publications reporting on associations between health care costs and walking parameters were identified by a systematic literature search in MEDLINE, Embase, and manual reference screening, following the PRISMA reporting guidelines. First, titles and abstracts were screened by two independent reviewers followed by a review of the full articles if they met the inclusion criteria. Costs were converted to US-Dollars with inflation adjustment for 2021. A narrative synthesis was performed.  RESULTS: Ten studies conducted between 2001 and 2021 fulfilled the inclusion criteria. Assessment of walking ability was carried out via patient reported outcomes, performance tests, or using wearable digital devices. Walking more than one hour per day, a faster walking speed and the ability to walk without impairments are associated with significant lower health care costs. A higher number of steps per day is associated with significant lower costs in two simulation studies, while in the study using a digital device, taking more than 10,000 steps per day is not significantly associated with lower direct costs. The heterogeneity of mobility assessments and of economic analyses both precluded a quantitative synthesis. CONCLUSION: Cross-sectional and observational studies from this systematic review suggest a significant association of better walking performance with lower health care costs. Future health economic research and health technology assessments should use quantifiable mobility outcomes when evaluating new drugs or non-pharmacological interventions.

A new tool for bile duct tissue sampling: ex vivo clinical evaluation of intraductal cryobiopsy for cholangioscopy.

Background and study aims Indeterminate biliary strictures represent a major challenge in clinical diagnostics. Diagnostic yield of radiological, endoscopic imaging and histopathological diagnosis is insufficient. The cryobiopsy technique is a new method for tissue extraction already used in different clinical settings. The aim of this ex vivo clinical study was to investigate feasibility and tissue quality of cryobiopsy in the bile duct. Patients and methods We included 14 patients who underwent pancreaticoduodenectomy. Bile duct samples were taken with either a new prototype cryoprobe or one of two forceps types. Results were analyzed for general feasibility, specimen size, histological assessability as well as representativity of retrieved tissue. Results Feasibility of cholangioscopic forceps was poor compared to gastric biopsy forceps or cryobiopsy. Significantly larger tissue samples were obtained with cryobiopsy (5.6 ±â€Š4.5 mm 2 ) compared to gastric biopsy forceps (3.3 ±â€Š5.1 mm 2 , P  = 0.006). Furthermore, cryobiopsy was superior in histological assessment quality ( P  = 0.02) and concerning representativity ( P  = 0.03). Conclusions Cryobiopsy in the bile duct is feasible and the quality of the obtained tissue is high. Further investigation of bile duct cryobiopsy in vivo is warranted.

Mobility endpoints in marketing authorisation of drugs: what gets the European medicines agency moving?

BACKGROUND: Mobility is defined as the ability to independently move around the environment and is a key contributor to quality of life, especially in older age. The aim of this study was to evaluate the use of mobility as a decisive outcome for the marketing authorisation of drugs by the European Medicines Agency (EMA). METHODS: Fifteen therapeutic areas which commonly lead to relevant mobility impairments and alter the quantity and/or the quality of walking were selected: two systemic neurological diseases, four conditions primarily affecting exercise capacity, seven musculoskeletal diseases and two conditions representing sensory impairments. European Public Assessment Reports (EPARs) published by the EMA until September 2020 were examined for mobility endpoints included in their 'main studies'. Clinical study registries and primary scientific publications for these studies were also reviewed. RESULTS: Four hundred and eighty-four EPARs yielded 186 relevant documents with 402 'main studies'. The EPARs reported 153 primary and 584 secondary endpoints which considered mobility; 70 different assessment tools (38 patient-reported outcomes, 13 clinician-reported outcomes, 8 performance outcomes and 13 composite endpoints) were used. Only 15.7% of those tools distinctly informed on patients' mobility status. Out of 402, 105 (26.1%) of the 'main studies' did not have any mobility assessment. Furthermore, none of these studies included a digital mobility outcome. CONCLUSIONS: For conditions with a high impact on mobility, mobility assessment was given little consideration in the marketing authorisation of drugs by the EMA. Where mobility impairment was considered to be a relevant outcome, questionnaires or composite scores susceptible to reporting biases were predominantly used.

The phenotype of adverse drug effects: Do emergency visits due to adverse drug reactions look different in older people? Results from the ADRED study.

AIMS: Older patients in particular suffer from adverse drug reactions (ADR) when presenting in the emergency department. We aimed to characterise the phenotype of those ADRs, to be able to recognise an ADR in older patients. METHODS: Cases of ADRs in emergency departments collected within the multicentre prospective observational study (ADRED) were analysed (n = 2215). We analysed ADR-associated diagnoses, symptoms and their risk profiles. We present frequencies and odds ratios (OR) with 95% confidence intervals for adults (18-64 years) compared to older adults (≥65 years; young-old 65-79, old-old ≥80 years) and regression coefficients (B) for each year of age. RESULTS: Most prominent differences were seen for drug-associated confusion, dehydration, and bradycardia (OR 6.70 [1.59-28.27], B .054; OR 6.02 [2.41-15.03], B .081, and 4.82 [2.21-10.54], B .040), more likely seen in older adults. Bleedings were reported in all age groups, but gastrointestinal bleedings occurred with more than doubled chance in older adults (OR 2.46 [1.77-3.41], B .030), likewise did other bleedings such as haemorrhage from respiratory passages (OR 2.89 [1.37-6.11], B.036). Falls were more likely in older adults (OR 2.84 [1.77-4.53], B .030), while dizziness was frequent in both age groups. CONCLUSION: Our data point to differences in symptoms of ADRs between adults and older individuals, with dangerous drug-associated phenomena in the older adult such as bleedings or falls. Physicians should consider drug-associated origins of symptoms in older adults with an increased risk for serious health problems.

Personalising drug safety-results from the multi-centre prospective observational study on Adverse Drug Reactions in Emergency Departments (ADRED).

PURPOSE: Adverse drug reactions (ADR) account for 5 to 7% of emergency department (ED) consultations. We aimed to assess medication risk profiles for ADRs leading to ED visits. METHODS: We analysed medication intake and patient demographics in a prospective multi-centre observational study collecting ADR cases in four large EDs in Germany. Odds ratios (OR) were calculated to relate drug classes taken to those suspicious for an ADR after a causality assessment. RESULTS: A total of 2215 cases of ED visits due to ADRs were collected. The median age of the cohort was 73 years; in median, six co-morbidities and an intake of seven drugs were documented. Antineoplastic/immunomodulating agents had the highest OR for being suspected for an ADR (OR 20.45, 95% CI 14.54-28.77), followed by antithrombotics (OR 2.94, 95% CI 2.49-3.47), antibiotics (OR 2.65, 95% CI 1.78-3.95), systemic glucocorticoids (OR 2.43, 95% CI 1.54-3.82) and drugs affecting the central nervous system (CNS), such as antipsychotics (OR 2.36, 95% CI 1.46-3.81), antidepressants (OR 2.10, 95% CI 1.57-2.83), antiparkinsonian medication (OR 2.11, 95% CI 1.15-3.84), opioids (OR 1.79, 95% CI 1.26-2.54) and non-opioid analgesics (OR 1.32, 95% CI 1.01-1.72). CONCLUSIONS: Patients experiencing ADRs leading to ED visits are commonly old, multi-morbid and multi-medicated. CNS drugs may be more relevant than prior expected. With calculating ORs, we could replicate involvement of antineoplastic agents, antithrombotics, antibiotics, systemic glucocorticoids and non-opioid analgesics as frequently suspected for ADRs in EDs. TRIAL REGISTRATION: DRKS-ID: DRKS00008979.

The Impact of CYP3A4*22 on Tacrolimus Pharmacokinetics and Outcome in Clinical Practice at a Single Kidney Transplant Center.

Background: Although there is evidence that the CYP3A4*22 variant should be considered in tacrolimus dosing in renal transplantation, its impact beyond tacrolimus dose requirements remains controversial. Methods: In a cohort of 121 kidney transplant recipients, we analyzed the CYP3A4*1B, CYP3A4*22, and CYP3A5*3 alleles and the ABCB1 variants 1236C>T, 2677G>T/A, and 3435C>T for their impact on exposure and dose requirement. Relevant clinical outcome measures such as acute rejection within the first year after transplantation, delayed graft function, and renal function at discharge (estimated glomerular filtration rate) were evaluated. Results: Extensive metabolizer (n = 17, CYP3A4*1/*1 carriers with at least one CYP3A5*1 allele) showed significantly higher tacrolimus dose requirement (P = 0.004) compared with both intermediate metabolizer (IM, n = 93, CYP3A5*3/*3 plus CYP3A4*1/*1 or CYP3A4*22 carriers plus one CYP3A5*1 allele), and poor metabolizer (n = 11, CYP3A4*22 allele in combination with CYP3A5*3/*3) after onset of therapy. Significantly higher dose requirement was observed in CYP3A5 expressers (P = 0.046) compared with non-expressers again at onset of therapy. Using the log additive genetic model, the area under the curve for the total observation period up to 16 days was significantly associated with the CYP3A5*3 genotype (P = 3.34 × 10-4) as well as with the IM or extensive metabolizer phenotype (P = 1.54 × 10-4), even after adjustment for multiple testing. Heterozygous carriers for CYP3A4*22 showed significantly higher areas under the curve than the CYP3A4*1/*1 genotype in the second week post-transplantation (adjusted P = 0.016). Regarding clinical outcomes, acute rejection was significantly associated with human leukocyte antigen mismatch (≥3 alleles; OR = 12.14, 95% CI 1.76, 525.21, P = 0.019 after correction for multiple testing). Graft recipients from deceased donors showed higher incidende of delayed graft function (OR 7.15, 95% CI 2.23, 30.46, adjusted P = 0.0008) and a lower estimated glomerular filtration rate at discharge (P = 0.0001). Tested CYP3A4 or CYP3A5 variants did not show any effects on clinical outcome parameters. ABCB1 variants did neither impact on pharmacokinetics nor on clinical endpoints. Conclusion: At our transplantation center, both CYP3A5*3 and, to a lesser extent, CYP3A4*22 affect tacrolimus pharmacokinetics early after onset of therapy with consequences for steady-state treatment in routine clinical practice.

REACH alternative testing strategy for skin sensitization in practice: Fact or fiction?

From October 2016 the REACH Regulation requires an alternative testing strategy for skin sensitization. The current paper describes our experience when putting into practice the REACH alternative testing strategy with a modification for 50 industrial chemicals in total, including mono-constituents, multi-constituents and UVCBs. For mono- and multi-constituents, a tiered approach was followed starting with an in silico (Derek Nexus) assessment, DPRA and KeratinoSens™ assay, followed by a weight of evidence conclusion based on the generated data, or further testing using the U-SENS™ assay. For UVCBs testing started with the KeratinoSens™ assay followed by the U-SENS™ assay if additional relevant information could be gained for an overall conclusion. From the 50 substances tested, for 46% a conclusion on skin sensitization potential and potency could be drawn based on the non-animal testing strategy; however, 54% of the substances still needed to be studied in vivo due to discordant results from non-animal testing or the need for reliable potency data. Important issues with the currently available, validated non-animal methods are the lack or comparability of skin metabolism and lack of potency indication, which is present in the in vivo assays. Skin sensitization testing for UVCBs and multi-constituents is still in a grey area, as neither the in chemico, in vitro assays, and in vivo LLNA have been validated for UVCBs and multi-constituents.

Tacrolimus Suppositories in Therapy-Resistant Ulcerative Proctitis.

BACKGROUND: Ulcerative proctitis may often be managed with topical salicylates or steroids alone, but in some patients, symptoms are persistent and severe. We analyzed the efficacy of tacrolimus suppositories in patients who had proven refractory to combined topical and systemic treatment. METHODS: In this retrospective analysis, ulcerative colitis activity index (CAI), side effects, co-medication and drug levels were assessed in 43 patients with distal ulcerative colitis who received suppositories containing 2 mg of tacrolimus b.i.d. as add-on medication. RESULTS: A total of 23 patients with ulcerative proctitis presented to follow-up within ≤50 days (mean 27.0 days) after suppositories were started. A decrease in CAI (from 8.0 to 5.5 points) was observed and 52.3% reached clinical remission (CAI ≤4). In total, 43 patients were available for analysis, of whom 9 had inflammation of the sigmoid colon as well. For the entire cohort, the median treatment duration was 76 days; 60% were in remission on the last documented visit. Serum measurements revealed a substantial tacrolimus level with a mean of 5.5 ng/mL. We observed one case of mild reversible acute kidney injury. CONCLUSIONS: In ulcerative proctitis, adding tacrolimus suppositories can be an effective and safe option when topical mesalazine, corticoid formulations and concomitant oral or parenteral medications have failed.

Impact of NUDT15 genetics on severe thiopurine-related hematotoxicity in patients with European ancestry.

PURPOSE: Severe hematotoxicity in patients with thiopurine therapy has been associated with genetic polymorphisms in the thiopurine S-methyltransferase (TPMT). While TPMT genetic testing is clinically implemented for dose individualization, alterations in the nudix hydrolase 15 (NUDT15) emerged as independent determinant of thiopurine-related hematotoxicity. Because data for European patients are limited, we investigated the relevance of NUDT15 in Europeans. METHODS: Additionally to TPMT phenotyping/genotyping, we performed in-depth Sanger sequencing analyses of NUDT15 coding region in 107 European patients who developed severe thiopurine-related hematotoxicity as extreme phenotype. Moreover, genotyping for NUDT15 variants in 689 acute lymphoblastic leukemia (ALL) patients was performed. RESULTS: As expected TPMT was the main cause of severe hematotoxicity in 31% of patients, who were either TPMT deficient (10%) or heterozygous carriers of TPMT variants (21%). By comparison, NUDT15 genetic polymorphism was identified in 14 (13%) patients including one novel variant (p.Met1Ile). Six percent of patients with severe toxicity carried variants in both TPMT and NUDT15. Among patients who developed toxicity within 3 months of treatment, 13% were found to be carriers of NUDT15 variants. CONCLUSION: Taken together, NUDT15 and TPMT genetics explain ~50% of severe thiopurine-related hematotoxicity, providing a compelling rationale for additional preemptive testing of NUDT15 genetics not only in Asians, but also in Europeans.

Influence of NOD2 Variants on Trichuris suis ova Treatment Outcome in Crohn's Disease.

A recent randomized study of whipworm Trichuris suis ova (TSO) in ileal Crohn's disease failed to demonstrate a clinical benefit compared to placebo after 12 weeks. Nonetheless, it has recently been shown that the spontaneous small intestinal inflammatory changes in Nod2-/- (Nucleotide-binding oligomerization domain 2) mice could be substantially ameliorated when these mice were colonized by Trichuris muris. Those and complementary epidemiologic findings in humans lead to the hypothesis that helminths may be advantageous only in patients carrying defective NOD2 variants. Thus, 207 participants of the TSO trial were retrospectively genotyped for six functional NOD2 genetic variants to evaluate whether the treatment outcome differed in patients carrying NOD2 variants. We observed no significant association of the NOD2 variants or their haplotypes with clinical outcome after TSO treatment.

Modelling the fracture-healing process as a moving-interface problem using an interface-capturing approach.

We present a novel numerical model of the fracture-healing process using interface-capturing techniques, a well-known approach from fields like fluid dynamics, to describe tissue growth. One advantage of this method is its direct connection to experimentally observable parameters, including tissue-growth velocities. In our model, osteogenesis, chondrogenesis and revascularisation are triggered by mechanical stimuli via mechano-transduction based on previously established hypothesis of Claes and Heigele. After experimentally verifying the convergence of the numerical method, we compare the predictions of our model with those of the already established Ulm bone-healing model, which serves as a benchmark, and corroborate our results with existing animal experiments. We demonstrate that the new model can predict the history of the interfragmentary movement and forecast a tissue evolution that appears similar to the experimental results. Furthermore, we compare the relative tissue concentration in the healing domain with outcomes of animal experiments. Finally, we discuss the possible application of the model to new fields, where numerical simulations could also prove beneficial.

CLPFFD-PEG functionalized NIR-absorbing hollow gold nanospheres and gold nanorods inhibit ß-amyloid aggregation.

Gold nanoparticles with specific optical properties in combination with the CLPFFD peptide that exhibits selectivity for ß-amyloid (Aß) aggregates are promising photothermal absorbers for application in Alzheimer's disease therapy. We report on hollow gold nanospheres (HAuNS) and gold nanorods (AuNR), which exhibit strong plasmonic near infrared (NIR) absorbance in the optical window of biological tissue and which are functionalized with CLPFFD in two different ways. Therefore the peptide was either directly bound to the particle surface or indirectly to a particle-protecting polyethylene glycol (PEG) ligand shell, thereby reducing the CLPFFD density on the surfaces of both types of particles. Fully PEGylated particles were used for comparison. The effects on cell viability and the fundamental suitability of the HAuNS and AuNR conjugates as photothermal absorbers to inhibit Aß-fibrillation are analysed in vitro. The positive influence of the use of PEG ligands on the reduced cytotoxicity of the conjugates and on the Aß-disaggregation is discussed.

Ion specific effects on the immobilisation of charged gold nanoparticles on metal surfaces.

Since the pioneering work of F. Hofmeister, Arch. Exp. Pathol. Pharmakol., 1888, 24, 247, ion specific effects have been steadily reported in the context of colloidal or protein stabilisation in electrolyte solutions. Although the observed effects are omnipresent in chemistry and biology, their origin is still under ferocious discussion. Here, we report on ion specific effects affecting the self-assembly of amine and carboxylic acid functionalised gold nanoparticles on metal surfaces as well as in electrolyte solution as a function of the monovalent cations Li+, Na+, K+ and Cs+. Mercaptooctanoic acid and 1,8-amine-octanethiol functionalised gold nanoparticles were adsorbed on structured AuPd/Pt substrates under addition of the respective chloride salts. Furthermore, the influence of the same salts on the salt induced aggregation of these AuNP was investigated. Our results demonstrate that the assembly processes on the metal surface as well as in electrolyte solution are influenced by the addition of different cations. We attribute the observed effects to ion pairing of the functional end groups with the added cations. With these findings we introduce a new parameter to control the self-assembly of 2D AuNP arrays on solid supports or of 3D AuNP networks in solution, which could be of relevance for the fabrication of new tailor-made functional materials or for biomedical applications.

Gold nanoparticles stabilized with ßcyclodextrin-2-amino-4-(4-chlorophenyl)thiazole complex: A novel system for drug transport.

While 2-amino-4-(4-chlorophenyl)thiazole (AT) drug and thiazole derivatives have several biological applications, these compounds present some drawbacks, such as low aqueous solubility and instability. A new complex of ßCD-AT has been synthesized to increase AT solubility and has been used as a substrate for the deposit of solid-state AuNPs via magnetron sputtering, thus forming the ßCD-AT-AuNPs ternary system, which is stable in solution. Complex formation has been confirmed through powder X-ray diffraction and 1D and 2D nuclear magnetic resonance. Importantly, the amine and sulfide groups of AT remained exposed and can interact with the surfaces of the AuNPs. The complex association constant (970 M-1) has been determined using phase solubility analysis. AuNPs formation (32 nm average diameter) has been studied by UV-Visible spectroscopy, transmission/scanning electron microscopy and energy-dispersive X-ray analysis. The in vitro permeability assays show that effective permeability of AT increased using ßCD. In contrast, the ternary system did not have the capacity to diffuse through the membrane. Nevertheless, the antibacterial assays have demonstrated that AT is transferred from ßCD-AT-AuNPs, being available to exert its antibacterial activity. In conclusion, this novel ßCD-AT-AuNPs ternary system is a promising alternative to improve the delivery of AT drugs in therapy.