Evaluation of the novel folate receptor ligand [18F]fluoro-PEG-folate for macrophage targeting in a rat model of arthritis

Introduction

Detection of (subclinical) synovitis is relevant for both early diagnosis and monitoring of therapy of rheumatoid arthritis (RA). Previously, the potential of imaging (sub)clinical arthritis was demonstrated by targeting the translocator protein in activated macrophages using (R)-[¹¹C]PK11195 and positron emission tomography (PET). Images, however, also showed significant peri-articular background activity. The folate receptor (FR)-β is a potential alternative target for imaging activated macrophages. Therefore, the PET tracer [¹⁸F]fluoro-PEG-folate was synthesized and evaluated in both in vitro and ex vivo studies using a methylated BSA induced arthritis model.

Methods

[¹⁸F]fluoro-PEG-folate was synthesized in a two-step procedure. Relative binding affinities of non-radioactive fluoro-PEG-folate, folic acid and naturally circulating 5-methyltetrahydrofolate (5-Me-THF) to FR were determined using KB cells with high expression of FR. Both in vivo [¹⁸F]fluoro-PEG-folate PET and ex vivo tissue distribution studies were performed in arthritic and normal rats and results were compared with those of the established macrophage tracer (R)-[¹¹C]PK11195.

Results

[¹⁸F]fluoro-PEG-folate was synthesized with a purity >97%, a yield of 300 to 1,700 MBq and a specific activity between 40 and 70 GBq/µmol. Relative in vitro binding affinity for FR of F-PEG-folate was 1.8-fold lower than that of folic acid, but 3-fold higher than that of 5-Me-THF. In the rat model, [¹⁸F]fluoro-PEG-folate uptake in arthritic knees was increased compared with both contralateral knees and knees of normal rats. Uptake in arthritic knees could be blocked by an excess of glucosamine-folate, consistent with [¹⁸F]fluoro-PEG-folate being specifically bound to FR. Arthritic knee-to-bone and arthritic knee-to-blood ratios of [¹⁸F]fluoro-PEG-folate were increased compared with those of (R)-[¹¹C]PK11195. Reduction of 5-Me-THF levels in rat plasma to those mimicking human levels increased absolute [¹⁸F]fluoro-PEG-folate uptake in arthritic joints, but without improving target-to-background ratios.

Conclusions

The novel PET tracer [¹⁸F]fluoro-PEG-folate, designed to target FR on activated macrophages provided improved contrast in a rat model of arthritis compared with the accepted macrophage tracer (R)-[¹¹C]PK11195. These results warrant further exploration of [¹⁸F]fluoro-PEG-folate as a putative PET tracer for imaging (sub)clinical arthritis in RA patients.     

Long-Term Fluctuations in Circalunar Beach Aggregations of the Box Jellyfish Alatina moseri in Hawaii,with Links to Environmental Variability

The box jellyfish Alatina moseri forms monthly aggregations at Waikiki Beach 8–12 days after each full moon, posing a recurrent hazard to swimmers due to painful stings. We present an analysis of long-term (14 years: Jan 1998– Dec 2011) changes in box jellyfish abundance at Waikiki Beach. We tested the relationship of beach counts to climate and biogeochemical variables over time in the North Pacific Sub-tropical Gyre (NPSG). Generalized Additive Models (GAM), Change-Point Analysis (CPA), and General Regression Models (GRM) were used to characterize patterns in box jellyfish arrival at Waikiki Beach 8–12 days following 173 consecutive full moons. Variation in box jellyfish abundance lacked seasonality, but exhibited dramatic differences among months and among years, and followed an oscillating pattern with significant periods of increase (1998–2001; 2006–2011) and decrease (2001–2006). Of three climatic and 12 biogeochemical variables examined, box jellyfish showed a strong, positive relationship with primary production, >2 mm zooplankton biomass, and the North Pacific Gyre Oscillation (NPGO) index. It is clear that that the moon cycle plays a key role in synchronizing timing of the arrival of Alatina moseri medusae to shore. We propose that bottom-up processes, likely initiated by inter-annual regional climatic fluctuations influence primary production, secondary production, and ultimately regulate food availability, and are therefore important in controlling the inter-annual changes in box jellyfish abundance observed at Waikiki Beach.     

Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome

TREX1 constitutes the major 3'-->5' DNA exonuclease activity measured in mammalian cells. Recently, biallelic mutations in TREX1 have been shown to cause Aicardi-Goutieres syndrome at the AGS1 locus. Interestingly, Aicardi-Goutieres syndrome shows overlap with systemic lupus erythematosus at both clinical and pathological levels. Here, we report a heterozygous TREX1 mutation causing familial chilblain lupus. Additionally, we describe a de novo heterozygous mutation, affecting a critical catalytic residue in TREX1, that results in typical Aicardi-Goutieres syndrome.     

Mitochondrial Control Region and Population Genetic Patterns of Nycticebus bengalensis and N. pygmaeus

Bengal slow lorises (Nycticebus bengalensis) and pygmy slow lorises (Nycticebus pygmaeus) are nocturnal which creates difficulties to study them in the field. There is a scarcity of data on them and their population genetics are poorly understood. We sequenced and analyzed a partial fragment in the first hypervariable region of the mitochondrial control region or D-loop HVRI of 21 Nycticebus bengalensis and 119 N. pygmaeus from the boundary between China and Vietnam where they are sympatric. Though the sample size for Nycticebus pygmaeus is much larger, the polymorphism level is much lower than that of N. bengalensis, possibly because of (1) external gene flow from other habitats of N. bengalensis, (2) gene ingression from Sunda slow lorises (N. coucang coucang) to N. bengalensis, (3) a skewed birth sex ratio in N. pygmaeus, and (4) a possible low survival rate of infant N. pygmaeus. Based on genetic comparisons to Nycticebus bengalensis, we propose that N. pygmaeus in southern China and northern Vietnam might have migrated from middle or southern Vietnam recently. Deng Pan and Jing-Hua Chen made equal contributions to the work.     

Early experience with the Venus p‑valve for percutaneous pulmonary valve implantation in native outflow tract

Introduction

The Venus p?valve (MedTech, Shanghai, China) is a self-expanding percutaneous heart valve designed to be implanted in a native patched right ventricle outflow tract. The worldwide clinical experience with this valve is just beginning and the results have so far been encouraging. We present our initial early experience implanting the Venus p?valve in the native right ventricle outflow tract of patients with Tetralogy of Fallot repaired with a transannular patch.

Methods

In 10 selected patients a procedure for percutaneous pulmonary valve implantation was performed using the Venus p?valve. The patients mean age was 32 years (13–57), mean weight 59.6?kg (40–80). All patients had Tetralogy of Fallot with moderate to severe pulmonary regurgitation and an indication for pulmonary valve replacement.

Results

The implantation procedure was successful in all the patients resulting in an immediately functional valve. No procedure-related complications were observed. Follow-up after 12 months (4–21) resulted in an improvement in NYHA class. There was a reduction of the mean right ventricle diastolic volume from 139?ml/m² (105–179) to 78?ml/m² (65–100) and improvement in the regurgitation fraction from 42% (29–58) to 1% (0–5), as seen on routine cardiac magnetic resonance 6 months after the implantation. No stent fractures have been observed so far.

Conclusion

Percutaneous pulmonary valve implantation with the Venus p?valve resulted in a safe and effective procedure. The valve has predictable and sustained functional competence, resulting in clinical improvement in the patients.

     

Molecular cloning and expression of the Streptococcus lactis tagatose 1,6-bisphosphate aldolase gene in Escherichia coli

Abstract A 4.4 kb Eco RI DNA fragment of the Streptococcus lactis H₁ plasmid pDI1 was cloned into the Escherichia coli plasmid pACYC 184. The recombinant plasmid expressed d -tagatose 1,6-bisphosphate aldolase activity in E. coli . Enzyme activity was at the same level as in the original S. lactis host but was not repressed by glucose.     

First Report of Meloidogyne Incognita Infecting Mitragyna Speciosa in the United States

Kratom (Mitragyna speciosa) belongs to the coffee family of Rubiaceae. The tree is native to Southeast Asia and primarily grown in Malaysia, Thailand, and Indonesia. Recently, it has been introduced and cultivated in other countries including the United States. The leaves and extracts of the leaves are used for medicinal and recreational purposes. In February 2022, kratom root and soil samples were submitted to the University of Florida Nematode Assay Laboratory for diagnosis by a commercial grower in Florida. Root galls were observed on the roots. On examination of soil and root samples, it is revealed that high numbers of root-knot nematodes (Meloidogyne sp.) are present. Molecular species identification was performed by a combination of the mitochondria haplotyping and species-specific primer techniques using TRNAH/MHR106 and MORF/MTHIS primer sets and Meloidogyne incognita-specific primers (MIF/MIR). The root-knot nematode infecting kratom is identified as M. incognita by molecular analysis. To our knowledge, this paper is the first report of M. incognita infecting kratom in the United States.