Oral Iron Replacement Normalizes Fibroblast Growth Factor 23 in Iron-Deficient Patients With Autosomal Dominant Hypophosphatemic Rickets

Autosomal dominant hypophosphatemic rickets (ADHR) is caused by mutations impairing cleavage of fibroblast growth factor 23 (FGF23). FGF23 gene expression increases during iron deficiency. In humans and mice with the ADHR mutation, iron deficiency results in increased intact FGF23 concentrations and hypophosphatemia. We conducted a prospective open label pilot clinical trial of oral iron replacement over 12 months in ADHR patients to test the hypothesis that oral iron administration would normalize FGF23 concentrations. Eligibility criteria included: FGF23 mutation; and either serum iron <50 μg/dL; or serum iron 50 to 100 μg/dL combined with hypophosphatemia and intact FGF23 >30 pg/mL at screening. Key exclusion criteria were kidney disease and pregnancy. Oral iron supplementation started at 65 mg daily and was titrated based on fasting serum iron concentration. The primary outcome was decrease in fasting intact FGF23 by ≥20% from baseline. Six adults (three male, three female) having the FGF23-R176Q mutation were enrolled; five completed the 12-month protocol. At baseline three of five subjects had severely symptomatic hypophosphatemia (phosphorus <2.5 mg/dL) and received calcitriol with or without phosphate concurrent with oral iron during the trial. The primary outcome was met by 4 of 5 (80%) subjects all by month 4, and 5 of 5 had normal intact FGF23 at month 12. Median (minimum, maximum) intact FGF23 concentration decreased from 172 (20, 192) pg/mL at baseline to 47 (17, 78) pg/mL at month 4 and 42 (19, 63) pg/mL at month 12. Median ferritin increased from 18.6 (7.7, 82.5) ng/mL at baseline to 78.0 (49.6, 261.0) ng/mL at month 12. During iron treatment, all three subjects with baseline hypophosphatemia normalized serum phosphorus, had markedly improved symptoms, and were able to discontinue calcitriol and phosphate. Oral iron repletion normalized FGF23 and phosphorus in symptomatic, iron-deficient ADHR subjects. Thus, the standard approach to ADHR should include recognition, treatment, and prevention of iron deficiency. © 2019 American Society for Bone and Mineral Research.     

Asymptomatic prostatic inflammation in men with clinical BPH and erectile dysfunction affects the positive predictive value of prostate-specific antigen

ObjectiveTo test the hypothesis that sexual dysfunction in elderly men with benign prostatic hyperplasia leads to prostatic inflammation, diagnosed by prostatic fluid interleukin-8 (IL-8), which lowers the positive predictive value of prostate-specific antigen (PSA).MethodsOverall, 160 men with lower urinary tract symptoms between 50 and 75 years of age with an elevated PSA level of more than 4 ng/ml with normal digital rectal examination and 50 age-matched controls with normal PSA level were prospectively evaluated for prostatic fluid IL-8 levels. Erectile dysfunction was measured by self-administered questionnaire of the Sexual Health Inventory for Men. Total and free serum PSA levels and IL-8 in prostatic fluid were measured 6 to 8 weeks after a course of 400 mg of ofloxacin and 20 mg of piroxicam given daily for 2 weeks. Transrectal ultrasonography–guided biopsy was done only when PSA level did not decrease less than 4 ng/ml.ResultsMean ages of patients and controls were 63.18 (standard deviation [SD]±7.10) and 60.18 (SD+6.02) years, respectively. Mean concentration of IL-8 in prostatic fluid of the patients was significantly higher, i.e., 6678 pg/ml (SD±1985.7) than in control, i.e., 1543 pg/ml (SD±375.7) (P<0.001). Following anti-inflammatory treatment, there was a significant decrease in the mean level of IL-8 from baseline to 5622 pg/ml (SD±1870.66) (P<0.001). Corresponding to this, a significant decrease was noted in total PSA levels to less than 4 ng/ml in 105 (65.62%) patients. Men with the highest levels of IL-8 had a greater degree of erectile dysfunction.ConclusionMen with symptomatic benign prostatic hyperplasia and erectile dysfunction had significant inflammation of the prostate to cause spurious rise in PSA level resulting in an unnecessary biopsy.     

Unlocked nucleic acid modified primer-based enzymatic polymerization assay: towards allele-specific genotype detection of human platelet antigens

Accurate detection of single nucleotide polymorphisms (SNPs) is paramount for the appropriate therapeutic intervention of debilitating diseases associated with SNPs. However, in some cases current nucleic acid probes fail to detect allele-specific mutations, for example, human platelet antigens, HPA-15a (TCC) and HPA-15b (TAC) alleles associated with neonatal alloimmune thrombocytopenia. Towards this, it is necessary to develop a novel assay for detection of allele-specific mutations. In this study, we investigated the potential of unlocked nucleic acid (UNA)-modified primers in SNP detection utilising an enzymatic polymerisation-based approach. Our results of primer extension and asymmetric polymerase chain reaction by KOD XL DNA polymerase revealed that UNA-modified primers achieved excellent allele-specificity in discriminating the human platelet antigen DNA template, whereas the DNA control primers were not able to differentiate between the normal and mutant alleles, demonstrating the scope of this novel UNA-based enzymatic approach as a robust methodology for efficient detection of allele-specific mismatches. Although further evaluation is required for other disease conditions, we firmly believe that our findings offer a great promise for the diagnosis of neonatal alloimmune thrombocytopenia and other SNP-related diseases.

We investigated the potential of UNA-modified primers for mismatch recognition capabilities using enzymatic polymerisation approach. Efficient allele-specific discrimination was achieved with the UNA-modified primers unlike the DNA primers.     

Outcomes of junctional ectopic tachycardia ablation in adult population—a multicenter experience

Purpose

Idiopathic junctional ectopic tachycardia (JET) is typically refractory to antiarrhythmic agents. Catheter ablation for JET is feasible but is associated with high risk of unintended atrioventricular (AV) block. There is limited data on the appropriate procedural technique and clinical outcomes with catheter ablation for idiopathic JET in adults.

Methods

This is a multicenter, retrospective study of all adult patients (age?≥?18 years) who underwent catheter ablation for idiopathic JET. Patient, procedural characteristics, and long-term outcomes were evaluated.

Results

Fifteen patients [radiofrequency ablation (RF)?=?14 and cryoablation?=?1) were treated with catheter ablation. The median age was 58 years with 67% males. All patients underwent mapping of the right atrium and the aortic cusps prior to energy delivery. The location of earliest activation in relation to the atrioventricular (AV) node was postero-superior in 73% (11/15), posterior in 13% (2/15), and superior in 13% (2/15) respectively. Acute success was 100%. Arrhythmia recurrence occurred in 53% (8/15) all of whom underwent a repeat ablation. High-grade AV block requiring permanent pacemaker occurred in 20% (3/15). At 12-month follow-up in the redo-ablation group, 37.5% (3/8) had recurrence of the arrhythmia two of which underwent a third ablation procedure.

Conclusion

Catheter ablation of idiopathic JET in adults is associated with a high rate of recurrence requiring multiple procedures and high risk of AV block requiring a permanent pacemaker. Mapping and ablation of the non-coronary cusp can be considered as the arrhythmia was controlled in 3 patients with no inadvertent AV block.

     

Pure phase synthesis of Cu3PS4 and Cu6PS5Cl for semiconductor applications

We have achieved the first reported pure phase synthesis of two new nanoparticle materials, Cu₃PS₄ and Cu₆PS₅Cl. We have achieved this through learning about the potential reaction pathways that CuCl₂, P₂S₅, and 1-dodecanethiol can take. This study has shown that the key variable to control is the state of the phosphorus source when the CuCl₂ is added. If P₂S₅ is added together with the CuCl₂ to dodecanethiol then the reaction will follow a path to Cu₃PS₄, but if it is dissolved in dodecanethiol prior to the addition to CuCl₂ then the reaction will produce Cu₆PS₅Cl. The formation of these two different phases can occur simultaneously, yet we have found sets of conditions that manipulate the reaction system to form each phase exclusively. These nanoparticles could have broad semiconductor or solid electrolyte applications.

We have achieved the first reported pure phase synthesis of two new nanoparticle materials, Cu₃PS₄ and Cu₆PS₅Cl.

There is a need to explore new thin film photovoltaic absorbers, as many of the current thin film technologies have challenges associated with them. The high efficiency materials such as CuIn_xGa_1−xSe₂ (ref. 1–5) and CdTe,^6–8 require the use of the less-abundant elements indium and tellurium. To rectify this short coming, materials that use earth abundant elements such as Cu₂ZnSnSe₄ (CZTSe)^9,10 and amorphous-Si^11–13 have been explored. This class of materials has been unable to reach the efficiencies of the CuIn_xGa_1−xSe₂ and CdTe cells that are necessary to become an economic alternative to fossil fuel based energy. Specifically in the case for CZTSe, the issue is caused by intrinsic defect formation, leading to band tails in the material.^14–17 This defect is caused by the zinc on copper site (Cu_Zn) and the accompanying copper on zinc (Zn_Cu) site.^18,19 This is due to the similar sizes of the Cu¹⁺ and the Zn²⁺ ions.Because of the uncertainties regarding the limitations and future of previously developed earth abundant materials for solar cells, it is necessary to investigate new materials that avoid the pitfalls that have hampered the previous technologies. It has been proposed to use a Cu₃–V–VI₄ (V = P, As, Sb; VI = S, Se) structured material to address these issues.^20–28 This class of materials uses earth abundant cations to allow for production on a terawatt scale. They also avoid the cation switching that has hampered the efficiencies of CZTSe devices, due to the mismatch between the sizes of V⁵⁺ and Cu¹⁺ cations.Some work examining the phosphorus member of the Cu₃–V–VI₄ material family and its potential use as a solar absorber material has been reported in the literature. The reported calculations have estimated that the band gap of the selenide material is within the ideal range of 1.0–1.5 eV, and they have potential for the power conversion efficiencies to be greater than that of CuInSe₂. Experimental studies have confirmed the band gap of Cu₃PSe₄ to be 1.35 eV.²² On the other hand, Cu₃PS₄ with a higher band gap is a potential candidate for a top cell in a tandem cell. Both of the materials have shown a photoelectric response,^22,23 and could be attractive materials for photovoltaic devices.In the past, crystals of Cu₃PS₄ have been synthesized either using chemical vapor transport and temperatures in excess of 850 °C for long periods of time such as 24 hours^20,29 or heating elemental powders of copper, phosphorus and sulfur in sealed evacuated fused silica tubes at high temperatures for extended time periods.^22,27,30 While these techniques produce crystals of Cu₃PS₄ that could be used for fundamental characterization, they are not suitable for fabrication of thin films of Cu₃PS₄. There is a need to pursue and develop new solution based techniques for the synthesis of Cu₃PS₄, if it is to be competitive with other thin film technologies. Using nanoparticles as a method for forming thin films has been employed for a variety of other materials for PV applications.^1,9,31,32The previous solution-based method, to synthesize Cu₃PS₄ nanoparticles has faced significant obstacles.²³ This method is based on reducing both copper and phosphorus to a neutral state and reacting them together to form Cu₃P nanoparticles. These nanoparticles are then reacted with thiourea in a separate reaction. While this procedure does produce Cu₃PS₄ nanoparticles, they are not pure phase. There is the presence of a phosphorus rich phase that is altering the composition and effecting the photoluminescence. If Cu₃PS₄ nanoparticles are to be used a precursor to a solar absorber, they will need to be free of any contaminants that could adversely affect a final film.For this contribution we have examined copper–phosphorus–sulfide system. This material can occur in two main phases, the Cu₃PS₄ enargite phase and the Cu₇PS₆ argyrodite phase. The argyrodite structure also has a chloride phase compound Cu₆PS₅Cl. The enargite phase is of more interest for photovoltaic applications, as either a top material for a multi-junction device or for use in high band gap electronic devices.Argyrodites, while they may not be useful as solar absorbers, have been explored for use as solid electrolytes.^33–35 Cu₆PS₅Cl has been of particular interest due to its high performance and copper mobility.^36,37 This material has shown better conductivities than other materials in the same family. In a similar case to the enargite materials, synthesis of the argyrodites is done in sealed ampule or vacuum based methods.^34–37     

Potential and Prospects of Shikonin Production Enhancement in Medicinal Plants

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - Plants are a rich source of valuable chemicals that are used as herbal and modern medicines. Shikonin, a...