Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours

PURPOSE: Diethylenetriamine-pentaacetic acid (DTPA)-coupled minigastrins are unsuitable for therapeutic application with the available beta-emitting radiometals due to low complex stability. Low tumour-to-kidney ratio of the known radiopharmaceuticals is further limiting their potency. We used macrocyclic chelators for coupling to increase complex stability, modified the peptide sequence to enhance radiolytic stability and studied tumour-to-kidney ratio and metabolic stability using (111)In-labelled derivatives. METHODS: Gastrin derivatives with decreasing numbers of glutamic acids were synthesised using (111)In as surrogate for therapeutic radiometals for in vitro and in vivo studies. Gastrin receptor affinities of the (nat)In-metallated compounds were determined by receptor autoradiography using (125)I-CCK as radioligand. Internalisation was evaluated in AR4-2J cells. Enzymatic stability was determined by incubating the (111)In-labelled peptides in human serum. Biodistribution was performed in AR4-2J-bearing Lewis rats. RESULTS: IC(50) values of the (nat)In-metallated gastrin derivatives vary between 1.2 and 4.8 nmol/L for all methionine-containing derivatives. Replacement of methionine by norleucine, isoleucine, methionine-sulfoxide and methionine-sulfone resulted in significant decrease of receptor affinity (IC(50) between 9.9 and 1,195 nmol/L). All cholecystokinin receptor affinities were >100 nmol/L. All (111)In-labelled radiopeptides showed receptor-specific internalisation. Serum mean-life times varied between 2.0 and 72.6 h, positively correlating with the number of Glu residues. All (111)In-labelled macrocyclic chelator conjugates showed higher tumour-to-kidney ratios after 24 h (0.37-0.99) compared to (111)In-DTPA-minigastrin 0 (0.05). Tumour wash out between 4 and 24 h was low. Imaging studies confirmed receptor-specific blocking of the tumour uptake. CONCLUSIONS: Reducing the number of glutamates increased tumour-to-kidney ratio but resulted in lower metabolic stability. The properties of the macrocyclic chelator-bearing derivatives make them potentially suitable for clinical purposes.

The effect of pulsed jet lavage in vertebroplasty on injection forces of polymethylmethacrylate bone cement, material distribution, and potential fat embolism: a cadaver study

STUDY DESIGN: In vitro testing of vertebroplasty techniques including pulsed jet-lavage for fat and marrow removal in human cadaveric lumbar and thoracic vertebrae. OBJECTIVE: To develop jet-lavage techniques for vertebroplasty and investigate their effect on cement distribution, injection forces, and fat embolism. SUMMARY OF BACKGROUND DATA: The main complications of cement vertebroplasty are cement leakage and pulmonary fat embolism, which can have fatal consequences and are difficult to prevent reliably by current vertebroplasty techniques. METHODS: Twenty-four vertebrae (Th8-L04) from 5 osteoporotic cadaver spines were grouped in triplets depending on bone mineral density (BMD). Before polymethylmethacrylate (PMMA) vertebroplasty, a pulsatile jet-lavage for removal of intertrabecular fat and bone marrow was performed in 2 groups with 8 specimens each, performing radial and axial irrigation from the biopsy needles. One hundred mL of Ringer solution were injected through 1 pedicle and regained by low vacuum via the contralateral pedicle. Eight control vertebrae were not irrigated. All specimens underwent standardized PMMA cement augmentation injecting 20% of the vertebral volume. Injection forces, cement distribution, and extravasations were quantified. RESULTS: All irrigation solution could be retrieved with the vacuum applied. A Kruskal-Wallis test revealed significantly higher injection forces of the control group as compared with the irrigated groups (P = 0.021). Dilatation of the syringe at forces above 300 N occurred in 75% of the untreated compared with 12.5% of the lavaged specimens. CT distribution analysis showed more homogenous cement distribution of the cement and significantly less extravasation in the irrigated specimens. CONCLUSION: The developed lavage technique for vertebroplasty showed to be feasible and reproducible. The reduction of injection forces would allow the use of more viscous PMMA cement lowering the risk for cement embolization and results in a safer procedure. The wash-out of bone marrow and the possible reduction of pulmonary fat embolism have to be verified with in vivo models.

Isolation of Nicoletella semolina from Equine Tracheal Washes

The aim of the present study was to describe the prevalence of Nicoletella semolina in equine airways and its relationships with cytological evaluation of tracheal wash (TW). Samples were collected in the framework of routine bacteriological diagnostics of equine TW between May 2010 and June 2011. N semolina has been isolated, along with either common pathogens or contaminants, from 19 (1.8%) of the 1,054 TW samples. Median TW neutrophil counts (87.0%) in specimens from N semolina-positive horses were significantly different from those from N semolina-“negative” horses (52.0%). The data presented in this report may suggest considering such bacteria in horses clinically suffering from airway inflammation.

Dalfampridine in patients with downbeat nystagmus—an observational study

We investigated the effects of dalfampridine, the sustained-release form of 4-aminopyridine, on slow phase velocity (SPV) and visual acuity (VA) in patients with downbeat nystagmus (DBN) and the side effects of the drug. In this proof-of-principle observational study, ten patients received dalfampridine 10 mg bid for 2 weeks. Recordings were conducted at baseline, 180 min after first administration, after 2 weeks of treatment and after 4 weeks of wash-out. Mean SPV decreased from a baseline of 2.12 deg/s ± 1.72 (mean ± SD) to 0.51 deg/s ± 1.00 180 min after first administration of dalfampridine 10 mg and to 0.89 deg/s ± 0.75 after 2 weeks of treatment with dalfampridine (p < 0.05; post hoc both: p < 0.05). After a wash-out period of 1 week, mean SPV increased to 2.30 deg/s ± 1.6 (p < 0.05; post hoc both: p < 0.05). The VA significantly improved during treatment with dalfampridine. Also, 50 % of patients did not report any side effects. The most common reported side effects were abdominal discomfort and dizziness. Dalfampridine is an effective treatment for DBN in terms of SPV. It was well-tolerated in all patients.

Should the standard dimethyl sulfoxide concentration be reduced? Results of a European Group for Blood and Marrow Transplantation prospective noninterventional study on usage and side effects of dimethyl sulfoxide.

BACKGROUND Dimethyl sulfoxide (DMSO) is essential for the preservation of liquid nitrogen-frozen stem cells, but is associated with toxicity in the transplant recipient. STUDY DESIGN AND METHODS In this prospective noninterventional study, we describe the use of DMSO in 64 European Blood and Marrow Transplant Group centers undertaking autologous transplantation on patients with myeloma and lymphoma and analyze side effects after return of DMSO-preserved stem cells. RESULTS While the majority of centers continue to use 10% DMSO, a significant proportion either use lower concentrations, mostly 5 or 7.5%, or wash cells before infusion (some for selected patients only). In contrast, the median dose of DMSO given (20 mL) was much less than the upper limit set by the same institutions (70 mL). In an accompanying statistical analysis of side effects noted after return of DMSO-preserved stem cells, we show that patients in the highest quartile receiving DMSO (mL and mL/kg body weight) had significantly more side effects attributed to DMSO, although this effect was not observed if DMSO was calculated as mL/min. Dividing the myeloma and lymphoma patients each into two equal groups by age we were able to confirm this result in all but young myeloma patients in whom an inversion of the odds ratio was seen, possibly related to the higher dose of melphalan received by young myeloma patients. CONCLUSION We suggest better standardization of preservation method with reduced DMSO concentration and attention to the dose of DMSO received by patients could help reduce the toxicity and morbidity of the transplant procedure.

What's in a name? Inflammatory airway disease in racehorses in training

The term 'inflammatory airway disease' (IAD) is often used to describe the syndrome of lower airway inflammation that frequently affects young racehorses in training around the world. In practice, this inflammation is generally diagnosed using a combination of endoscopic tracheal examination, including grading of amounts of mucus present and tracheal wash sampling. However, a recent consensus statement from the American College of Veterinary Internal Medicine concluded that bronchoalveolar lavage (BAL) sampling, rather than tracheal wash (TW) sampling, is required for cytological diagnosis of IAD and that tracheal mucus is not an essential criterion. However, as BAL is a relatively invasive procedure that is not commonly used on racing yards, this definition can only be applied routinely to a biased referral population. In contrast, many practitioners continue to diagnose IAD using endoscopic tracheal examination and sampling. We argue that, rather than restricting the use of the term IAD to phenotypes diagnosed by BAL, it is important to distinguish in the literature between airway inflammation diagnosed by BAL and that identified in the field using TW sampling. We suggest the use of the term brIAD for the former and trIAD for the latter. It is essential that we continue to endeavour to improve our understanding of the aetiology, pathogenesis and clinical relevance of airway inflammation identified in racehorses in training using tracheal examination and sampling. Future studies should focus on investigations of the component signs of airway inflammation.

Effectiveness of meticillin-resistant Staphylococcus aureus decolonization in long-term haemodialysis patients: a systematic review and meta-analysis.

BACKGROUND Chronic haemodialysis patients are a high-risk population for meticillin-resistant Staphylococcus aureus (MRSA) colonization, which is a precursor of infection. AIM To summarize the effect of nasal (± whole-body wash) MRSA decolonization in haemodialysis patients by means of a systematic review and meta-analysis. METHODS We identified eligible studies using Medline, Embase, the Cochrane database, clinicaltrials.org, and conference abstracts investigating the success of MRSA decolonization in haemodialysis patients. For the statistical analysis, we used Stata 13 to express study-specific proportions with 95% confidence intervals. A likelihood ratio test was used to assess inter-study heterogeneity. FINDINGS Six published prospective cohort studies and one study described in a conference abstract met our inclusion criteria. From 1150 haemodialysis patients enrolled in these studies, MRSA was isolated from nasal swabs of 147 (12.8%) patients. Six of the trials used mupirocin nasal ointment and combined it with chlorhexidine body washes for decolonization. The most widely used protocol was a five-day course of mupirocin nasal ointment application three times a day, and chlorhexidine body wash once daily. The pooled success rate of decolonization was 0.88 (95% confidence interval: 0.75-0.95). A likelihood ratio test of the fixed versus the random-effects model showed significant inter-study heterogeneity (P = 0.047). Four of seven studies determined subsequent MRSA infections in 94 carriers overall, two (2%) of which experienced infection. CONCLUSION The use of mupirocin together with whole-body decolonization is highly effective in eradicating MRSA carriage in haemodialysis patients. The current literature, however, is characterized by a lack of comparative effectiveness studies for this intervention.