Nanoparticle-Mediated Multiple Modulation of Bone Microenvironment To Tackle Osteoarthritis.

Development of nanomedicines that can collaboratively scavenge reactive oxygen species (ROS) and inhibit inflammatory cytokines, along with osteogenesis promotion, is essential for efficient osteoarthritis (OA) treatment. Herein, we report the design of a ROS-responsive nanomedicine formulation based on fibronectin (FN)-coated polymer nanoparticles (NPs) loaded with azabisdimethylphoaphonate-terminated phosphorus dendrimers (G4-TBP). The constructed G4-TBP NPs-FN with a size of 268 nm are stable under physiological conditions, can be specifically taken up by macrophages through the FN-mediated targeting, and can be dissociated in the oxidative inflammatory microenvironment. The G4-TBP NPs-FN loaded with G4-TBP dendrimer having intrinsic anti-inflammatory property and FN having both anti-inflammatory and antioxidative properties display integrated functions of ROS scavenging, hypoxia attenuation, and macrophage M2 polarization, thus protecting macrophages from apoptosis and creating designed bone immune microenvironment for stem cell osteogenic differentiation. These characteristics of the G4-TBP NPs-FN lead to their effective treatment of an OA model in vivo to reduce pathological changes of joints including synovitis inhibition and cartilage matrix degradation and simultaneously promote osteogenic differentiation for bone repair. The developed nanomedicine formulation combining the advantages of both bioactive phosphorus dendrimers and FN to treat OA may be developed for immunomodulatory therapy of different inflammatory diseases.

Sevelamer reverses liver fibrosis by deactivation of hepatic stellate cells.

Liver fibrosis is a chronic liver disease characterized by a progressive wound healing response caused by chronic liver injury. Currently, there are no approved clinical treatments for liver fibrosis. Sevelamer is used clinically to treat hyperphosphatemia and has shown potential therapeutic effects on liver diseases. However, there have been few studies evaluating the therapeutic effects of sevelamer on liver fibrosis, and the specific mechanisms are still unclear. In this study, we investigated the antifibrotic effects of sevelamer-induced low inorganic phosphate (Pi) stress in vitro and in vivo and analyzed the detailed mechanisms. We found that low Pi stress could inhibit the proliferation of activated hepatic stellate cells (HSCs) by promoting apoptosis, effectively suppressing the migration and epithelial-mesenchymal transition (EMT) of hepatic stellate cells. Additionally, low Pi stress significantly increased the antioxidant stress response. It is worth noting that low Pi stress indirectly inhibited the activation and migration of HSCs by suppressing transforming growth factor ß (TGF-ß) expression in macrophages. In a rat model of liver fibrosis, oral administration of sevelamer significantly decreased blood phosphorus levels, improved liver function, reduced liver inflammation, and increased the antioxidant stress response in the liver. Our study revealed that the key mechanism by which sevelamer inhibited liver fibrosis involved binding to gastrointestinal phosphate, resulting in a decrease in blood phosphorus levels, the downregulation of TGF-ß expression in macrophages, and the inhibition of HSC migration and fibrosis-related protein expression. Therefore, our results suggest that sevelamer-induced low Pi stress can attenuate hepatic stellate cell activation and inhibit the progression of liver fibrosis, making it a potential option for the treatment of liver fibrosis and other refractory chronic liver diseases.

Black Phosphorus Flake-Enabled Wireless Neuromodulation for Epilepsy Treatment.

Epilepsy is a prevalent and severe neurological disorder and generally requires prolonged electrode implantation and tether brain stimulation in refractory cases. However, implants may cause potential chronic immune inflammation and permanent tissue damage due to material property mismatches with soft brain tissue. Here, we demonstrated a nanomaterial-enabled near-infrared (NIR) neuromodulation approach to provide nongenetic and nonimplantable therapeutic benefits in epilepsy mouse models. Our study showed that crystal-exfoliated photothermal black phosphorus (BP) flakes could enhance neural activity by altering the membrane capacitive currents in hippocampus neurons through NIR photothermal neuromodulation. Optical stimulation facilitated by BP flakes in hippocampal slices evoked action potentials with a high spatiotemporal resolution. Furthermore, BP flake-enabled NIR neuromodulation of hippocampus neural circuits can suppress epileptic signals in epilepsy model mice with minimal invasiveness and high biocompatibility. Consequently, nanomaterial-enabled NIR neuromodulation may open up opportunities for nonimplantable optical therapy of epilepsy in nontransgenic organisms.

Biochemical markers of iron status and iron accumulation in peritoneal dialysis patients treated with ferric citrate.

BACKGROUND: Hyperphosphataemia is a common complication of kidney disease. Current dialysis techniques do not provide enough phosphorus clearance, hence the need to use phosphorus binders. Treatment options include calcium carbonate, calcium acetate, lanthanum carbonate, sevelamer hydrochloride and iron-based binders. Patients receiving peritoneal dialysis (PD) with sustained elevated ferritin levels exceeding 800 ng/mL are at a higher risk of death. We identify PD patients treated with iron-based binders and compare ferritin and risk of iron accumulation to patients treated with non-iron-based binders. METHODS: All records of patients receiving PD at Emory dialysis centres until 30 October 2021 were reviewed for phosphorus binders. Basic demographics and laboratory data were time-referenced to the days on treatment with a particular binder. Patients were followed until discontinuation of the phosphorus binder, death, transplant, transfer to another dialysis provider or censoring at 36 months after medication was started. RESULTS: Compared to calcium acetate and sevelamer, ferric citrate utilisation in PD patients resulted in a sustained increase in ferritin. The proportion of patients with a ferritin equal to or greater than 800 ng/dL and transferrin saturation greater than 40% increased over time in patients treated with ferric citrate and was higher during the second and third year of follow-up compared to baseline values and to patients treated with calcium acetate or sevelamer. Two patients (7%) treated with ferric citrate developed clinically significant haemosiderosis. CONCLUSIONS: Use of ferric citrated in PD resulted in significant iron accumulation as judged by ferritin levels.

Protective effect of activated charcoal against progression of chronic kidney disease: A randomized clinical study.

Chronic kidney disease (CKD) is a non-reversible and progressive disease affecting the kidneys, significantly impacting global public health. One of the complications of chronic kidney disease is impaired intestinal barrier function, which may allow harmful products such as urea to enter the bloodstream and cause systemic inflammation. This study aimed to investigate whether supplementation with activated charcoal could reduce uremic toxins in patients with end-stage renal disease (ESRD). The study was a randomized clinical trial conducted at the Dialysis Center of al Diwaniyah Medical Hospital in the Diwaniyah Governorate. Eighty-two patients with ESRD on regular hemodialysis were enrolled, with 15 patients receiving oral supplementation with activated charcoal in addition to standard care and 13 patients receiving only standard care. Blood samples were collected at baseline and after eight weeks, and several biomarkers were measured, including estimated glomerular filtration rate (eGFR), creatinine, urea, phosphorus, albumin, and indoxyl sulfate. The results showed a significant reduction in both serum urea and serum phosphorus levels after eight weeks of oral-activated charcoal treatment. However, the other biomarkers were not affected by the treatment. In conclusion, the use of oral-activated charcoal for eight weeks in Iraqi patients undergoing maintenance hemodialysis improved urea and phosphorus levels.

Linear growth of children with X-linked hypophosphatemia treated with burosumab: a real-life observational study.

To assess the long-term efficacy of burosumab for pediatric patients with X-linked hypophosphatemia, focusing on linear growth. This multi-center retrospective study included 35 pediatric patients who began treatment with burosumab between January 2018 and January 2021. We collected clinical data, anthropometric measurements, laboratory results, and Rickets Severity Score (RSS), from 2 years prior to treatment initiation and up to 4 years after. Burosumab was initiated at a mean age of 7.5 ± 4.4 years (range 0.6-15.9), with a mean initial dose of 0.8 ± 0.3 mg/kg, which was subsequently increased to 1.1 ± 0.4 mg/kg. The patients were followed for 2.9 ± 1.4 years (range 1-4) after initiating burosumab. Serum phosphorus levels increased from 2.7 ± 0.8 mg/dl at burosumab initiation to 3.4 ± 0.6 mg/dl after 3 months and remained stable (p < 0.001). Total reabsorption of phosphorus increased from 82.0 ± 6.8 to 90.1 ± 5.3% after 12 months of treatment (p = 0.041). The RSS improved from 1.7 ± 1.0 at burosumab initiation to 0.5 ± 0.6 and 0.3 ± 0.6 after 12 and 24 months, respectively (p < 0.001). Both height z-score and weight z-score improved from burosumab initiation to the end of the study: from - 2.07 ± 1.05 to - 1.72 ± 1.04 (p < 0.001) and from - 0.51 ± 1.12 to - 0.11 ± 1.29 (p < 0.001), respectively. Eight children received growth hormone combined with burosumab treatment. Height z-score improved among those who received growth hormone (from - 2.33 ± 1.12 to - 1.94 ± 1.24, p = 0.042) and among those who did not (from - 2.01 ± 1.01 to - 1.66 ± 1.01, p = 0.001). CONCLUSION:  Burosumab treatment in a real-life setting improved phosphate homeostasis and rickets severity and enhanced linear growth. WHAT IS KNOWN: • Compared to conventional therapy, burosumab treatment has been shown to increase serum phosphate levels and reduce the severity of rickets. • The effect of burosumab on growth is still being study. WHAT IS NEW: • Height z-score improved between the start of burosumab treatment and the end of the study (-2.07 ± 1.05 vs. -1.72 ± 1.04, p < 0.001). • Eight children received burosumab combined with growth hormone treatment without side effects during the concomitant treatments.

A dual-nanozyme-loaded black phosphorus multifunctional therapeutic platform for combined photothermal/photodynamic/starvation cancer therapy.

The typical hypoxia of tumor microenvironments seriously affects the efficacy of starvation therapy (ST) and photodynamic therapy (PDT). Therefore, it is of great significance to prepare a multimodal combined therapy nanocomposite with the ability to relieve tumor hypoxia. It is an effective method to release oxygen into the tumor microenvironment using a nanoenzyme. In this work, two-dimensional black phosphorus nanosheets (BPNSs) were used as photothermal reagents and photosensitized agents due to the unique physical properties and also used as nano-carriers for the in situ reduction deposition of Au nanoparticles and fragmented MnO2 coatings. Finally, polyethylene glycol was introduced to obtain the nanocomposite BP@Au@MnO2-PEG (i.e., AMGP). In the tumor microenvironment, MnO2 can catalyze endogenous H2O2 to produce oxygen, improving the effect of ST and PDT. H2O2 generated via the catalytic oxidation of glucose by Au nanoparticles can continue to be used as the substrate catalyzed by MnO2. Meanwhile, black phosphorus nanosheets have excellent photothermal properties for photothermal treatment. The results of in vitro and in vivo experiments indicated that AMGP nanocomposites have good combined antitumor efficacies and biosafety.

Black Phosphorus Nanosheets Grafted with Gold Nanorods and Carbon Nanodots for Synergistic Antitumor Therapy.

Synergetic photothermal/photodynamic/chemotherapy receives significant attention for precise in vivo cancer treatment. Despite plenty of encouraging photosensitizers explored, integrated nanoagents with multiple functions are still highly desired. In this study, novel nanocomposites coupling black phosphorus (BP) nanosheets, gold nanorods (AuNRs), carbon nanodots (CDs), and doxorubicin (Dox) are prepared. The nanoagents exhibit high antitumor activity on account of their broad light absorption, excellent catalytic ability, and significant photothermal and photodynamic effects. CDs not only emit bright fluorescence for accurate diagnosis and guiding of tumor treatment but also catalyze the generation of ROS for photodynamic therapy (PDT). The released Dox induces apoptosis of cells and increases the levels of H2O2 to promote PDT. AuNRs are the main photothermal therapy (PTT) material that converts light into heat. Moreover, BP can be used to enhance both PTT and PDT efficiencies, and the two therapy modes can be cooperatively reinforced. It is also found that the local immune microenvironment of the tumors is activated. The strategy makes good use of the features of each component. Satisfactory antitumor phenomena are well confirmed by in vitro and in vivo results. This study provides new insights into enhanced synergetic therapy, highlighting the great utility of BP-based nanoagents in the field of nanomedicine.

Milk Calcium and Phosphorus in Ugandan Women with HIV on Tenofovir-Based Antiretroviral Therapy.

BACKGROUND: Breastfed infants depend on human milk calcium and phosphorus for bone mineral accretion and growth. We reported greater mobilization of bone mineral and delayed skeletal recovery in lactating Ugandan women with HIV initiated on tenofovir-based antiretroviral therapy during pregnancy compared to HIV-uninfected counterparts in the Gumba Study. However, it is unknown if these disruptions in maternal bone metabolism affect milk mineral concentrations. RESEARCH AIM: To compare concentrations and patterns of change in milk calcium and phosphorus between lactating women with and without HIV. METHODS: A longitudinal observational study was conducted to compare milk mineral concentrations between women with HIV receiving tenofovir-based ART and uninfected women in the Gumba Study. Milk collected at 2, 14, 26, and 52 weeks lactation was analyzed for calcium and phosphorus. Sodium and potassium were measured at 2 and 14 weeks to detect sub-clinical mastitis. Differences in milk composition between 84 women with HIV and 81 uninfected women were investigated. RESULTS: Women with HIV had higher milk calcium than uninfected women at 14 weeks. The percent difference was +10.2% (SE = 3.0, p = .008) and there was a tendency to greater values at 2 and 26 weeks. Milk calcium decreased in both groups during lactation (p ≤ .001) but was more pronounced in women with HIV. The magnitude of change within individuals in the 1st year of lactation from 2 to 52 weeks was -28.3% (SE 3.9) versus -16.5% (SE 3.5), p for interaction = .05. Differences in milk phosphorus and calcium-to-phosphorus ratio were smaller and mostly not significant. CONCLUSIONS: Participants with HIV on tenofovir-based antiretroviral therapy had altered milk mineral composition. Studies are needed to investigate mechanisms and health implications for the woman and infant.

Rattus norvegicus infectados com Trypanosoma cruzi: efeitos clínicos do tratamento com Lycopodium clavatun e phosphorus ultradiluídos / Rattus norvegicus infected with Trypanosoma cruzi: clinical effects of treatment with highly diluted Lycopodium clavatun and phosphorus / Rattus norvegicus infectado con Trypanosoma cruzi: efectos clínicos del tratamiento con Clavatun licopodio altamente diluido y fósforo

A doença de Chagas causada pelo parasita Trypanosoma cruzi acomete milhões de pessoas no mundo e não conta com um medicamento de ação efetiva para o seu tratamento etiológico. As drogas disponíveis, o nifurtimox e o benznidazol possuem índices de cura baixos com efeitos colaterais e toxidade que dificultam a adesão dos pacientes à terapia. Este fato impulsiona a busca por alternativas de tratamento que sejam mais efetivas e menos agressivas. Sendo assim, este trabalho teve como objetivo a avaliação dos efeitos clínicos apresentados por Rattus norvergicus infectados por T. cruzi e tratados com soluções ultradiluídas de Lycopodium clavatum ou Phosphorus. O estudo envolveu 93 ratos com quarenta e cinco dias de idade infectados intraperitonealmente com 5x106 formas tripomastigotas sanguíneos da cepa Y de T. cruzi, distribuídos nos grupos: Sadio SD (n=13) - controle não infectado e não tratado, grupo CI (n=27) - controle infectado e tratado com solução hidroalccólica 7% (etanol ­ água), grupo LY diluição 1:1x1026 (n=27) - infectado e tratado com Lycopodium, grupo PH diluição 1:1x1026 (n=26) - infectado e tratado com Phosphorum. Os animais foram avaliados clinicamente através dos parâmetros peso, temperatura, consumo de água e ração, quantidade de excretas, diâmetro e comprimento intestinal, aspecto da pelagem e consistência das fezes. Este estudo mostrou que os parâmetros utilizados foram importantes para a definição clínica da infecção de Rattus novergicus, linhagem Wistar pelo T. cruzi. Mostrou que os medicamentos LY e PH apresentam efeitos benéficos na evolução da clínica dos animais tratados. A utilização de Lycopodium clavatum e Phosphorus diluídos na proporção de 1:1x1026, apresentaram efeitos diferentes. Oito e seis parâmetros de quatorze analisados mostraram efeitos positivos para LY e PH, respectivamente. Os parâmetros consumo de água e ração, quantidade de excretas, diarreia, alopecia difusa e comprimento intestinal apresentaram diferenças significativas em relação ao controle infectado mostrando que mais estudos são necessários com o uso de medicamentos ultradiluídos na infecção pelo T. cruzi.

Chagas disease caused by the parasite Trypanosoma cruzi affects millions of people worldwide and does not have an effective drug for its etiological treatment. The available drugs, nifurtimox and benznidazole, have low cure rates with side effects and toxicity that make it difficult for patients to adhere to therapy. This fact drives the search for treatment alternatives that are more effective and less aggressive. Therefore, this work aimed to evaluate the clinical effects presented by Rattus norvergicus infected by T. cruzi and treated with ultradiluted solutions of Lycopodium clavatum or Phosphorus. The study involved 93 forty five day old rats intraperitoneally infected with 5x106 blood trypomastigotes forms of the Y strain of T. cruzi, distributed in the following groups: Healthy SD (n=13) - non-infected and untreated control, CI group (n =27) - infected control and treated with 7% hydroalcoholic solution (ethanol ­ water), LY group dilution 1:1x1026 (n=27) - infected and treated with Lycopodium, PH group dilution 1:1x1026 (n=26) - infected and treated with Phosphorum. The animals were clinically evaluated through the parameters weight, temperature, water and feed consumption, amount of excreta, intestinal diameter and length, coat appearance and feces consistency. This study showed that the parameters used were important for the clinical definition of infection of Rattus novergicus, Wistar lineage by T. cruzi. It showed that LY and PH drugs have beneficial effects on the clinical evolution of treated animals. The use of Lycopodium clavatum and Phosphorus diluted in the ratio of 1:1x1026, showed different effects. Eight and six parameters out of fourteen analyzed showed positive effects for LY and PH, respectively. The parameters water and feed consumption, amount of excreta, diarrhea, diffuse alopecia and intestinal length showed significant differences in relation to the infected control, showing that more studies are needed with the use of ultradiluted drugs in T. cruzi infection.

La enfermedad de Chagas causada por el parásito Trypanosoma cruzi afecta a millones de personas en todo el mundo y no cuenta con un fármaco eficaz para su tratamiento etiológico. Los fármacos disponibles, nifurtimox y benznidazol, presentan bajas tasas de curación con efectos secundarios y toxicidad que dificultan la adherencia terapéutica de los pacientes. Este hecho impulsa la búsqueda de alternativas de tratamiento más eficaces y menos agresivas. Por lo tanto, este trabajo tuvo como objetivo evaluar los efectos clínicos presentados por Rattus norvergicus infectados por T. cruzi y tratados con soluciones ultradiluidas de Lycopodium clavatum o Fósforo. En el estudio participaron 93 ratas de cuarenta y cinco días de edad infectadas intraperitonealmente con 5x106 formas tripomastigotes sanguíneas de la cepa Y de T. cruzi, distribuidos en los siguientes grupos: SD sano (n=13) - control no infectado y no tratado, grupo CI (n =27) - control infectado y tratado con solución hidroalcohólica al 7% (etanol - agua), grupo LY dilución 1:1x1026 (n=27) - infectado y tratado con Lycopodium, grupo PH dilución 1:1x1026 (n=26) - infectado y tratado con Phosphorum. Los animales fueron evaluados clínicamente mediante los parámetros peso, temperatura, consumo de agua y pienso, cantidad de excrementos, diámetro y longitud intestinal, aspecto del pelaje y consistencia de las heces. Este estudio demostró que los parámetros utilizados eran importantes para la definición clínica de la infección de Rattus novergicus, linaje Wistar por T. cruzi. Demostró que los fármacos LY y PH tienen efectos beneficiosos en la evolución clínica de los animales tratados. El uso de Lycopodium clavatum y Phosphorus diluidos en la proporción de 1:1x1026, mostró efectos diferentes. Ocho y seis parámetros de los catorce analizados mostraron efectos positivos para LY y PH, respectivamente. Los parámetros consumo de agua y pienso, cantidad de excretas, diarrea, alopecia difusa y longitud intestinal mostraron diferencias significativas en relación al control infectado, mostrando que son necesarios más estudios con el uso de fármacos ultradiluidos en la infección por

Homeopatia em trombocitopenia canina: relato de caso / Homeopathy in canine thrombocytopenia: case report

Hemoparasitoses constituem-se de enfermidades cosmopolitas que são causadas por parasitos intracelulares obrigatórios de células sanguínea. Os mais frequentemente encontrados nos cães são a babesiose, erliquiose e anaplasmose. O tratamento consiste no uso de antibiótico do grupo das tetraciclinas, sendo a doxiciclina o medicamento mais indicado. O objetivo deste relato de caso é descrever o tratamento homeopático em um cão da raça shih-tzu, senil (8 anos de idade), cardiopata com trombocitopenia discreta secundário a hemoparasitose ­ ehrlichiose. O medicamento homeopático repertorizado foi Phosphorus 30 cH 3 glóbulos 2x ao dia por 3 dias. Foi administrado também a Calcarea Carbonica 6 cH 3 glóbulos 2x ao dia por 7 dias. Tal sucesso terapêutico foi atingido em 3 dias de tratamento, com melhora laboratorial da trombocitopenia e do quadro de dispnéia. Este estudo contribui com pesquisas existentes a caráter de novos tratamentos para a ehrlichiose canina.

Hemoparasitoses are cosmopolitan diseases that are caused by obligate intracellular parasites of blood cells. The most frequently found in dogs are babesiosis, ehrlichiosis and anaplasmosis. Treatment consists of the use of antibiotics from the tetracycline group, with doxycycline being the most indicated medication. The objective of this case report is to describe the homeopathic treatment in a dog of the shih-tzu breed, senile (8 years old), heart disease with mild thrombocytopenia secondary to hemoparasitosis - ehrlichiosis. The repertorized homeopathic medicine was Phosphorus 30 cH 3 globules 2x a day for 3 days. Calcarea Carbonica 6 cH 3 globules was also administered twice a day for 7 days. Such therapeutic success was achieved in 3 days of treatment, with laboratory improvement of thrombocytopenia and dyspnea. This study contributes to existing research on new treatments for canine ehrlichiosis.

2D Hetero-Nanoconstructs of Black Phosphorus for Breast Cancer Theragnosis: Technological Advancements.

As per global cancer statistics of 2020, female breast cancer is the most commonly diagnosed cancer and also the foremost cause of cancer death in women. Traditional treatments include a number of negative effects, making it necessary to investigate novel smart drug delivery methods and identify new therapeutic approaches. Efforts for developing novel strategies for breast cancer therapy are being devised worldwide by various research groups. Currently, two-dimensional black phosphorus nanosheets (BPNSs) have attracted considerable attention and are best suited for theranostic nanomedicine. Particularly, their characteristics, including drug loading efficacy, biocompatibility, optical, thermal, electrical, and phototherapeutic characteristics, support their growing demand as a potential substitute for graphene-based nanomaterials in biomedical applications. In this review, we have explained different platforms of BP nanomaterials for breast cancer management, their structures, functionalization approaches, and general methods of synthesis. Various characteristics of BP nanomaterials that make them suitable for cancer therapy and diagnosis, such as large surface area, nontoxicity, solubility, biodegradability, and excellent near-infrared (NIR) absorption capability, are discussed in the later sections. Next, we summarize targeting approaches using various strategies for effective therapy with BP nanoplatforms. Then, we describe applications of BP nanomaterials for breast cancer treatment, which include drug delivery, codelivery of drugs, photodynamic therapy, photothermal therapy, combined therapy, gene therapy, immunotherapy, and multidrug resistance reversal strategy. Finally, the present challenges and future aspects of BP nanomaterials are discussed.

[FGF23 tumor induced osteomalacia].

Tumor induced osteomalacia is a rare acquired disease. The cause is a mesenchymal tumor secreting fibroblast growth factor 23 (FGF23). An excessive amount of FGF 23 disrupts the metabolism of phosphorus and vitamin D, which leads to severe paraneoplastic syndrome, manifested in the form of multiple fractures, severe pain in the bones and generalized myopathy. With oncogenic osteomalacia, a complete cure is possible with radical resection of the tumor. Unfortunately, localization, small size of formations and rare frequency of occurrence lead to the fact that the disease remains unrecognized for a long time and leads to severe, disabling consequences. A step-by-step approach to diagnosis improves treatment outcomes. First, a thorough anamnesis is collected, then functional visualization is performed and the diagnosis is confirmed by anatomical visualization of the tumor. After that, the method of choice is a surgical treatment. If resection is not possible, then conservative therapy with active metabolites of vitamin D and phosphorus salts is indicated. New therapeutic approaches, such as the antibody to FGF23 or the pan-inhibitor of receptors to FGF, are actively developing. This article provides an overview of modern approaches to the diagnosis and treatment of this disease.

New treatments for rare bone diseases: hypophosphatemic rickets/osteomalacia.

Phosphorus is one of the most abundant minerals in the human body; it is required to maintain bone integrity and mineralization, in addition to other biological processes. Phosphorus is regulated by parathyroid hormone, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], and fibroblast growth factor 23 (FGF-23) in a complex set of processes that occur in the gut, skeleton, and kidneys. Different molecular mechanisms - overproduction of FGF-23 by tumors responsible for oncogenic osteomalacia, generation of an FGF-23 mutant that is resistant to cleavage by enzymes, and impaired FGF-23 degradation due to a reduction in or loss of the PHEX gene - can lead to FGF-23-stimulating activity and the consequent waste of urinary phosphate and low levels of 1,25(OH)2D3. Conventional treatment consists of multiple daily doses of oral phosphate salts and vitamin D analogs, which may improve radiographic rickets but do not normalize growth. Complications of the conventional long-term treatment consist of hypercalcemia, hypercalciuria, nephrolithiasis, nephrocalcinosis, impaired renal function, and potentially chronic kidney disease. Recently, burosumab, an antibody against FGF-23, was approved as a novel therapy for children and adults with X-linked hypophosphatemia and patients with tumor-induced osteomalacia. Burosumab showed good performance in different trials in children and adults. It increased and sustained the serum phosphorus levels, decreased the rickets severity and pain scores, and improved mineralization. It offers a new perspective on the treatment of chronic and disabling diseases.

A Systematic Review and Meta-analysis of Efficacy and Safety of Calcimimetic Agents in the Treatment of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease.

BACKGROUND: Some reports have pointed out that calcimimetics agents are effective in the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD) patients, but there is no detailed description of the advantages and disadvantages of calcimimetics agents of SHPT in CKD patients. We tried to pool the published data to verify the effectiveness of calcimimetics agents and to compare the advantages and disadvantages of cinacalcet compared with control in the treatment of SHPT in CKD patients. METHODS: We included eligible studies of published papers from January 1st, 2000 to December 31st, 2020 in Medline, Pubmed and Web of science databases, and the data were extracted for this meta-analysis. RESULTS: Twenty-seven studies were eligible, and all the included studies were randomized controlled trials (RCT) including patients treated with long-term dialysis. The results indicated that calcimimetic agents can reduce the parathyroid hormone (PTH, pg/ml) level (WMD = -178.22, 95% CI: -238.57, -117.86, P < 0.00001), calcium (Ca, mg/dl) level (WMD = -0.71, 95% CI: -0.86, -0.55, P < 0.00001), phosphorus (P, mg/dl) level (WMD = -0.32, 95% CI: -0.55, -0.08, P = 0.008), calcium-phosphorus product level (WMD = -7.73, 95% CI: -9.64, -5.82, P < 0.00001). Calcimimetic agents increased the bone alkaline phosphatase (BSAP, ng/ml) levels and rate of achieving target PTH, and reduced osteocalcin levels and the rate of parathyroidectomy. Calcimimetic agents increased the total adverse events' rate, the rate of hypocalcemia and gastrointestinal side effects (nausea, vomiting, abdominal pain and diarrhea), but there was no significant difference in serious adverse events between the calcimimetic agent group and control group. CONCLUSION: Calcimimetic agents can reduce the PTH level, Ca level, P level, calcium-phosphorus product level and do not increase serious adverse events.

Current therapeutic options for the treatment of secondary hyperparathyroidism in end-stage renal disease patients treated with hemodialysis: a 12-month comparative study.

AIM: The aim of the study was to investigate the effect of a new calcimimetic, Etelcalcetide, on secondary hyperparathyroidism and its effects in end-stage renal disease (ESRD) patients treated with hemodialysis (HD) compared with hemodialysis (HD) patients not treated with calcimimetics. MATERIALS AND METHODS: The cohort study included 203 ESRD patients with secondary hyperparathyroidism (SHPT) who received HD treatment. Total number patients were randomly to two groups. The main group (n=71) included HD patients treated by new calcimimetic Etelcalcetide. The historical group (n=132) was evaluated retrospectively and included patients who had SHPT but did not receive calcimimetic treatment. Serum levels of phosphorus, calcium and parathyroid hormone were compared for 12 months. The primary endpoint of the study was death from any cause, surrogates - cases of fractures, parathyroidectomy, death from cardiovascular (CV) events. RESULTS: The dose of Etelcalcetide changed monthly and averaged 8.58±1.79 mg. The dynamics of parathormone (PTH) indicators showed that the decrease in PTH levels by 30% from basal occurred after 3 months of treatment in 39 (54.9%) and 12 (9.1%) patients of the main group and historical group, respectively (p<0.0001). At the end of the study, the target PTH level reached in 52 (73.2%) patients in the main group and only 14 (10.6%) in the comparison group (p<0.0001). In addition to the decrease in serum PTH content, in the main group of patients, there was also a decrease in serum calcium and phosphorus levels. During the time to be analyzed, 36 deaths were reported, 61.1% of which were fatal CV events. The proportion of CV events in the mortality structure is more than 70% higher in the historical group than in the group of patients treated with Etelcalcetide, and is 69,2% vs 40,0%, respectively. The frequency of fractures is almost three times higher in the historical than in the main group of patients. The proportion of patients who required parathyroidectomy was significantly more than three times higher in the historical group than in the main group (p<0,05). CONCLUSIONS: In a prospective study, we demonstrated the high efficacy of Etelcalcetide in the treatment of SHPT in hemodialysis patients. Treatment of SHPT with the inclusion of Etelcalcetide is accompanied by improved clinical outcomes such as the incidence of bone fractures, cardiovascular morbidity and mortality.

Proximal tubular dysfunction related to tenofovir in people living with HIV/AIDS: a pharmacogenetic study.

OBJECTIVES: The purpose of this case-control study was to verify the association between single nucleotide polymorphisms (SNPs) in genes encoding drug transporters related to tenofovir disoproxil fumarate (TDF) and proximal renal tubular dysfunction (PRTD), and the association between PRTD and clinical characteristics. METHODS: The 'cases' met the diagnostic criteria for PRTD, determined by the presence of two or more of the following abnormalities: non-diabetic glycosuria, metabolic acidosis, increased uric acid and phosphorus excretion, decreased tubular phosphorus reabsorption and ß2-microglobulinuria. We analyzed eight SNPs in ABCC2, ABCC4, ABCC10 and SLC28A2 genes. Genotyping was performed using real-time PCR. RESULTS: Of the 204 people living with HIV, 38 (18.6%) met the criteria for diagnosis of PRTD and 131 were male (64.2%), with a mean age of 49 years and a history of previous antiretroviral therapy for an average of 5 years. In the multivariate analysis, older individuals, TDF use, protease inhibitor, antihypertensives and anticonvulsants were associated with a risk of developing PRTD. Increased excretion of ß2microglobulin was associated with the A/G genotype of rsCC8187710 from ABCC2 ( P = 0.003) and the following genotypes of ABCC4 SNPs: A/G from rs1059751 ( P = 0.023), G/G from rs1059751 ( P = 0.030) and C/C of rs3742106 ( P = 0.041). The increase in the fraction of excreted phosphorus was associated with the C/T genotype of SNCC rsP40037 from ABCC2 ( P = 0.0041). CONCLUSIONS: The results indicate an important relationship between SNPs associated with these markers and changes in proximal renal tubule function, and thus support their use as biomarkers for the early detection of PRTD risk.

Abalone-Inspired Adhesive and Photo-Responsive Microparticle Delivery Systems for Periodontal Drug Therapy.

Antibiotics provide promising strategies for treating periodontitis, while their delivery and controllable release with desired oral retention remain challenging. Here, inspired by the unique suction-cup structures of abalones, a novel adhesive and photo-responsive microparticle (MP) delivery system is developed to treat periodontitis through microfluidic electrospray technology. Such MPs are generated by quickly ionic cross-linking of sodium alginate together with photo-curing of poly(ethylene glycol) diacrylate of the distorted microfluidic droplets during their high-speed dropping into calcium chloride solution. Attributing to their unique concave structures, the abalone-inspired MPs exhibit desired underwater adhesion ability and stability under running water. In addition, due to the loading of antibiotics minocycline hydrochloride and near-infrared (NIR)-responsive black phosphorus during their fabrication, the resultant MPs can not only eradicate bacteria directly, but also realize a controllable and effective drug release upon NIR irradiation. Based on these features, it is demonstrated from in vivo periodontitis that the abalone-inspired MPs are firmly adhesive and can controlled-release drugs on the tooth, and thus have outstanding antibacterial efficacy against Porphyromonas gingivalis. These results indicate the particular values of the abalone-inspired MPs for oral-related disease treatment.

Early calcium and phosphorus supplementation in VLBW infants to reduce metabolic bone disease of prematurity: a quality improvement initiative.

OBJECTIVE: To reduce the incidence of metabolic bone disease (MBD) among very low birthweight (VLBW) infants admitted to neonatal intensive care unit from baseline of 35% by 50% over 2 years by implementing a quality improvement (QI) initiative. METHODS: A multidisciplinary QI team used evidence-based interventions and the healthcare improvement model to reduce MBD rate in VLBW infants. The specific interventions included routine enteral supplementation of calcium and phosphorus using Human Milk Fortifier (HMF) to expressed breast milk by day 14 of life (Plan/Do/Study/Act (PDSA) cycle 1), parenteral and early enteral supplementation of calcium and phosphorus (PDSA cycles 2 and 3). We included VLBW infants admitted within the study period at birth and excluded babies with congenital malformations, skeletal disorders and those who died before 2 weeks of age. Compliance with adding HMF by day 14, compliance with adding calcium and phosphorus in total parenteral nutrition (TPN) from day 1 of life and compliance with starting HMF when the baby reached 100 mL/kg/day of feeds were used as process indicators. The incidence of MBD was used as an outcome indicator during the study. The incidence of MBD was tracked using the Statistical Process Control methodology. RESULTS: The baseline MBD rate in 2015 was 35%. After the first PDSA cycle, 20% developed MBD (p=0.02). The same was sustained for a period of 1 year with the rate of 22%. After the second and third PDSA cycles, there was a drop in the MBD rate to 17%, and sustained for 3 months with 21%. CONCLUSION: Implementation of QI initiatives decreased the MBD rate from 35% to <20%. Early parenteral calcium and phosphorus supplementation in TPN and optimising enteral supplementation with multicomponent fortifiers appear to have significant reduction in the incidence of MBD.

Meta-Analysis of Effects of Nutritional Intervention Combined with Calcium Carbonate D3 Tablets on Bone Mineral Density, Bone Metabolism, and Curative Effect in Patients with Osteoporosis.

To investigate the changes in bone mineral density, bone metabolism, and efficacy of nutritional intervention combined with calcium carbonate D3 tablets in patients with osteoporosis, a RevMan 5.2 software meta-analysis was conducted in this study. According to the therapeutic direction of nutritional intervention combined with calcium carbonate D3 tablets for osteoporosis patients, relevant literature were searched in Wanfang Medical, CNKI, VIP, and PubMed literature databases at home and abroad. Keywords included bone mineral density, bone metabolism, blood calcium (Ca), blood phosphorus (P), osteocalcin (OC), bone mineral density (BMD), serum alkaline phosphatase (ALP), efficacy, osteoporosis, and nutritional intervention. Literature that met the criteria were deleted, and meta-analysis was performed using RevMan 5.2 software. The results indicate that a total of 10 Chinese literature were included. Compared with the monotherapy group, the clinical efficacy, osteocalcin, BMD, alkaline phosphatase, calcium, and phosphorus were significantly higher in the combination group (P < 0.05). Based on calcium carbonate D3, treatment combined with nutritional intervention can enhance the clinical efficacy, bone metabolism, and bone mineral density of patients with osteoporosis, and nutritional intervention combined with calcium carbonate D3 tablets is a feasible program to promote the recovery of patients with osteoporosis.