Design and evaluation of a chitosan–aprotinin conjugate for the peroral delivery of therapeutic peptides and proteins susceptible to enzymatic degradation

One main barrier for the peroral administration of therapeutic peptides and proteins is the enzymatic barrier, that is mediated by luminally secreted and membrane bound proteolytic enzymes. It was the aim of the study to synthesise, characterise and evaluate a novel polymer–inhibitor conjugate in order to improve the bioavailability of orally-administered peptides and proteins. The trypsin/chymotrypsin inhibitor aprotinin was covalently bound to chitosan. The percentage of the inhibitor in the polymer–inhibitor conjugate (m/m) was determined to be between 1.11 ± 0.36 and 1.92 ± 0.05%. In vitro enzyme assays clearly demonstrated the potential of the novel conjugate to inhibit trypsin and chymotrypsin. Moreover, studies in rats were performed to evaluate the efficacy of the conjugate in vivo. Eight hours after oral administration of tablets containing insulin and the novel chitosan–aprotinin conjugate, the mean blood glucose level decreased to 84 ± 6%. In contrast, the mean blood glucose level in the control group increased to 121 ± 8% of the initial measured blood glucose level. In conclusion it was demonstrated that chitosan–aprotinin conjugate represents a novel and promising tool for the oral administration of therapeutic peptides and proteins susceptible to enzymatic degradation caused by trypsin and chymotrypsin.     

Functional and morphological changes in diabetic macular edema over the course of anti‐vascular endothelial growth factor treatment

Purpose:  To evaluate macular morphology and function in diabetic macular edema (DME) over the course of intravitreal anti‐vascular endothelial growth factor (VEGF) treatment with Ranibizumab. Methods:  A consecutive series of 39 study eyes with centre‐involving DME were included in this study. In all subjects, best‐corrected visual acuity (BCVA) according ETDRS protocol, fluorescein angiography (FA), microperimetric macular sensitivity (MP) and Spectral Domain optical coherence tomography (SD‐OCT) cross‐sectional scans were obtained before treatment and after 3 monthly applied intravitreal Ranibizumab injections. Six different morphological qualities [IS/OS layer integrity, outer nuclear layer (ONL) cysts, ONL cyst size, inner nuclear layer (INL) cysts, blocking phenomenon and subretinal fluid] were graded of each cross‐sectional OCT scan before and over the course of treatment by two experienced graders. Correlation analyses between functional and morphological parameters were obtained. Results:  Mean BCVA increased from 26 ± 14 to 33 ± 13 letters after 3 consecutive monthly applied Ranibizumab injections (p < 0.001). Central retinal thickness (CRT) decreased from 504 ± 144 to 387 ± 122 μm (p < 0.001). Over the course of treatment, IS/OS continuity improved (index: 0.56 ± 0.52 to 0.43 ± 0.49, Z = ?1.415, p = 0.157), ONL cyst prevalence and size decreased significantly (index: 0.61 ± 0.44 to 0.56 ± 0.35, Z = ?3.41, p = 0.001 and 1.75 ± 0.88 to 1.17 ± 1.05, Z = ?4.02, p < 0.001), INL cyst prevalence decreased (index: 0.35 ± 0.52 to 0.28 ± 0.52, Z = ?1.60, p = 0.109), blocking phenomenon did not change significantly (index: 00.12 ± 0.16 to 0.13 ± 0.15, Z = ?0.45, p = 0.656) and subretinal fluid almost disappeared (index: 0.10 ± 0.24 vs. 0.00 ± 0.01, Z = ?2.56, p = 0.011). Correlation analyses revealed highest significant correlations between ONL cyst prevalence and their size and CRT as well as BCVA and MP before treatment and over the course of treatment. Conclusions:  ONL cysts and their size as morphological parameters correlate with retinal function measured with BCVA and microperimetry before and over the course of anti‐VEGF therapy with Ranibizumab in patients with DME.     

Synthesis of Zeolites from Fine-Grained Perlite and Their Application as Sorbents

The hydrothermal alteration of perlite into zeolites was studied using a two-step approach. Firstly, perlite powder was transformed into Na-P1 (GIS) or hydro(xy)sodalite (SOD) zeolites at 100 °C and 24 h using 2 or 5 M NaOH solutions. Secondly, the Si:Al molar ratio of the reacted Si-rich solution was adjusted to 1 by Na-aluminate addition to produce zeolite A (LTA) at 65 or 95 °C and 6 or 24 h at an efficiency of 90 ± 9% for Al and 93 ± 6% for Si conversion. The performance of these zeolites for metal ion removal and water softening applications was assessed by sorption experiments using an artificial waste solution containing 4 mmol/L of metal ions (Me²⁺: Ca²⁺, Mg²⁺, Ba²⁺ and Zn²⁺) and local tap water (2.1 mmol/L Ca²⁺ and 0.6 mmol/L Mg²⁺) at 25 °C. The removal capacity of the LTA-zeolite ranged from 2.69 to 2.86 mmol/g for Me²⁺ (=240–275 mg/g), which is similar to commercial zeolite A (2.73 mmol/g) and GIS-zeolite (2.69 mmol/g), and significantly higher compared to the perlite powder (0.56 mmol/g) and SOD-zeolite (0.88 mmol/g). The best-performing LTA-zeolite removed 99.8% Ca²⁺ and 93.4% Mg²⁺ from tap water. Our results demonstrate the applicability of the LTA-zeolites from perlite for water treatment and softening applications.     

Venous drainage patterns in a case of pseudotumor cerebri following unilateral radical neck dissection

We report the extracranial venous ultrasound findings in a case of pseudotumor cerebri (PTC) following unilateral radical neck dissection (rND). PTC is known to be a rare complication following bilateral rND, and is caused by venous outflow obstruction. Single cases of PTC have been reported after unilateral rND, and are thought to be due to resection of the dominant internal jugular vein (IJV) in the presence of a hypoplastic or aplastic contralateral transverse sinus. Our patient developed PTC despite prominent flow in the contralateral IJV as shown by venous ultrasound. No compensatory increase in flow in the vertebral veins was observed, as confirmed by digital subtraction angiography. We conclude that the physiological collateral function of the vertebral venous system and deep neck veins was insufficient and contributed to global venous outflow obstruction in our case of unilateral rND.     

Integration of Oncology and Palliative Care: A Systematic Review

Background.

Both the American Society of Clinical Oncology and the European Society for Medical Oncology strongly endorse integrating oncology and palliative care (PC); however, a global consensus on what constitutes integration is currently lacking. To better understand what integration entails, we conducted a systematic review to identify articles addressing the clinical, educational, research, and administrative indicators of integration.

Materials and Methods.

We searched Ovid MEDLINE and Ovid EMBase between 1948 and 2013. Two researchers independently reviewed each citation for inclusion and extracted the indicators related to integration. The inter-rater agreement was high (κ = 0.96, p < .001).

Results.

Of the 431 publications in our initial search, 101 were included. A majority were review articles (58%) published in oncology journals (59%) and in or after 2010 (64%, p < .001). A total of 55 articles (54%), 33 articles (32%), 24 articles (24%), and 14 articles (14%) discussed the role of outpatient clinics, community-based care, PC units, and inpatient consultation teams in integration, respectively. Process indicators of integration include interdisciplinary PC teams (n = 72), simultaneous care approach (n = 71), routine symptom screening (n = 25), PC guidelines (n = 33), care pathways (n = 11), and combined tumor boards (n = 10). A total of 66 articles (65%) mentioned early involvement of PC, 18 (18%) provided a specific timing, and 28 (28%) discussed referral criteria. A total of 45 articles (45%), 20 articles (20%), and 66 articles (65%) discussed 8, 4, and 9 indicators related to the educational, research, and administrative aspects of integration, respectively.

Conclusion.

Integration was a heterogeneously defined concept. Our systematic review highlighted 38 clinical, educational, research, and administrative indicators. With further refinement, these indicators may facilitate assessment of the level of integration of oncology and PC.     

Response of proopiomelanocortin and gonado- or lactotroph systems to in-vitro fertilisation procedures stress

Objective

To analyse for the first time the response of the corticotroph-type and the melanotroph-type pituitary proopiomelanocortin (POMC) system with regard to in-vitro fertilisation (IVF) treatment using self-developed highly specific non-cross-reacting radioimmunoassay.

Study design

Setting: University hospital. Patients: A total of 28 patients undergoing IVF oocyte retrieval. Cross sectional exploratory study, one factorial design with repeated measurements on one factor, non-parametric tests. Blood was collected before anaesthesia (t_A) (n = 28) and immediately after oocyte retrieval (t_B) (n = 28). Main outcome measure(s): β-endorphin immunoreactive material (IRM), acetyl-N-β-endorphin IRM, β-lipotropin IRM, ACTH, cortisol, estradiol, progesterone, prolactin, luteinizing hormone, and follicle-stimulating hormone. For determination of authentic β-endorphin [β-endorphin (1–31)] a highly specific two-site fluid phase immunoprecipitation radioimmunoassay was developed, which did not cross-react with any β-endorphin derivative or any other opioid peptide tested.

Results

No response of acetyl-N-β-endorphin IRM and of authentic β-endorphin (1–31) was observed to oocyte retrieval in contrast to a significant increase of corticotroph-type proopiomelanocortin derivatives. A significant rise in prolactin plasma concentration indicates a pronounced lactotroph response to oocyte retrieval stress. No significant correlation between POMC derivates and prolactin and between POMC derivatives and gonadotropins or sexual steroids except for ACTH and progesterone and for β-endorphin IRM and estradiol was observed.

Conclusion

IVF treatment stress led to significant corticotroph-type POMC and lactotroph responses, but not to responses of authentic β-endorphin or melanotroph-type POMC in women undergoing oocyte retrieval.     

Ischias und Bandscheibenvorfall

Ohne Zusammenfassung     

Extensively drug-resistant (XDR) Neisseria gonorrhoeae causing possible gonorrhoea treatment failure with ceftriaxone plus azithromycin in Austria,April 2022

We describe a gonorrhoea case with ceftriaxone plus high-level azithromycin resistance. In April 2022, an Austrian heterosexual male was diagnosed with gonorrhoea after sexual intercourse with a female sex worker in Cambodia. Recommended treatment with ceftriaxone (1 g) plus azithromycin (1.5 g) possibly failed. Worryingly, this is the second strain in an Asian Neisseria gonorrhoeae genomic sublineage including high-level azithromycin-resistant strains that developed ceftriaxone resistance by acquisition of mosaic penA-60.001. Enhanced resistance surveillance and actions are imperative to prevent spread.