Litsea glutinosa extract promotes fracture healing and prevents bone loss via BMP2/SMAD1 signaling.

Estrogen deficiency is one of the main causes for postmenopausal osteoporosis. Current osteoporotic therapies are of high cost and associated with serious side effects. So there is an urgent need for cost-effective anti-osteoporotic agents. Anti-osteoporotic activity of Litsea glutinosa extract (LGE) is less explored. Moreover, its role in fracture healing and mechanism of action is still unknown. In the present study we explore the osteoprotective potential of LGE in osteoblast cells and fractured and ovariectomized (Ovx) mice models. Alkaline phosphatase (ALP), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and mineralization assays revealed that LGE treatment increased osteoblast cell differentiation, viability and mineralization. LGE treatment at 0.01 µg increased the expression of BMP2, PSMAD, RUNX2 and type 1 col. LGE also mitigated RANKL-induced osteoclastogenesis. Next, drill hole injury Balb/C mice model was treated with LGE for 12 days. Micro-CT analysis and Calcein labeling at the fracture site showed that LGE (20 mg/kg) enhanced new bone formation and bone regeneration, also increased expression of BMP2/SMAD1 signaling genes at fracture site. Ovx mice were treated with LGE for 1 month. µCT analysis indicated that the treatment of LGE at 20 mg/kg dose prevented the alteration in bone microarchitecture and maintained bone mineral density and bone mineral content. Treatment also increased bone strength and restored the bone turnover markers. Furthermore, in bone samples, LGE increased osteogenesis by enhancing the expression of BMP2/SMAD1 signaling components and decreased osteoclast number and surface. We conclude that LGE promotes osteogenesis via modulating the BMP2/SMAD1 signaling pathway. The study advocates the therapeutic potential of LGE in osteoporosis treatment.

Psidium guajava: An Insight into Ethnomedicinal Uses, Phytochemistry, and Pharmacology.

BACKGROUND: Psidium guajava (guava) is widely distributed in tropical and subtropical regions and adapted to various environmental conditions. Guava is an important economic fruit widely used as food and folk medicine. It contains flavonoids, alkaloids, tannins, triterpenoids, reducing sugars, essential oils, carotenoids, polyphenols, etc. The presence of triterpenoid acids such as guavacoumaric, ursolic, jacoumaric, guajavanoic, guavenoic, and Asiatic acids helps to develop novel drugs against various diseases. It is used traditionally for medicinal purposes, mainly for antioxidant, antimicrobial, antispasmodic, antidiabetic, anticancer, antiallergy, anti-inflammatory, and hepato-protective properties. OBJECTIVE: The systematic literature study aims to summarize its botanical description, phytochemicals, pharmacological activities, and clinical trials. This review focuses on the plant's chemical composition and scientific approaches to human welfare. METHODS: A systematic literature search was done on Psidium guajava through previous literature and online databases such as Google Scholar, Pubmed, Science Direct, etc., to explain its ethnomedicinal uses, phytochemistry, and pharmacological applications. RESULTS: Previous literature studies of Psidium guajava suggest it can serve as antioxidant, antimicrobial, antispasmodic, antidiabetic, anticancer, anti-allergy, anti-inflammatory, and hepatoprotective effects. Successful clinical trials performed on the plant extracts against infantile rotaviral enteritis and infectious gastroenteritis showed future directions to work with the plant for clinical applications. CONCLUSION: In this review, an attempt is made to show all literature studied, especially in phytochemistry, pharmacology, clinical trials and uses as traditional folk medicine around the world. The leaves have been used by folklore over the years to treat various ailments such as skin ulcers, diarrhoea, vaginal irritation, cough, conjunctivitis, etc. Further studies are required to explore more therapeutic remedies and to develop new medicines for future perspectives.

Renal Transplantation in Patients With Tuberculosis: A Single-center Experience From an Endemic Region.

Background: Despite being a common infection in end-stage kidney disease patients, there are no evidence-based guidelines to suggest the ideal time of transplantation in patients on antitubercular therapy (ATT). This study aimed to examine the outcome of transplantation in patients while on ATT compared with those without tuberculosis (TB). Methods: This was a retrospective study. Renal transplant recipients transplanted while on ATT were compared with a 1:1 matched group (for age, sex, diabetic status, and type of induction agent) of patients without TB at the time of transplant. Patient outcomes included relapse of TB and graft and patient survival. Results: There were 71 patients in each group. The mean duration for which ATT was given pretransplant was 3.8 ± 2.47 mo. The average total duration of ATT received was 12.27 ± 1.25 mo. Mortality in both the groups was similar (8.4% in the TB group versus 4.5% in the non-TB group; P = 0.49). None of the surviving patients had recurrence of TB during the follow-up. Death-censored graft survival (98.5% in the TB group versus 97% in the non-TB group; P = 1) and biopsy-proven acute rejection rates (9.86% in the TB group versus 8.45% in the non-TB group; P = 1) were also similar in both the groups. Conclusions: Successful transplantation in patients with end-stage kidney disease on ATT is possible without any deleterious effect on patient and graft survival and no risk of disease recurrence. Multicentric prospective studies are needed.

Madhuca indica: A Review on the Phytochemical and Pharmacological Aspects.

Madhuca indica J.F. Gmel. (family: Sapotaceae), commonly known as Mahua in Indian dialects, occupies the importance as one of the fuel-efficient, energy-saving plant species. Extensive studies showed that the presence of phytochemicals e.g., carbohydrates, fatty acids, flavonoids, saponins, steroids, triterpenoids and glycosidic compounds in the extract of this species. Pharmacologically, it has been used against various disorders in indigenous system of medicine, inckuding antioxidant, anti-inflammatory, anticancer, hepatoprotective, anti-diabetic and wound healing activities. This review highlights various pharmacological activities, phytochemistry and importance of M. indica plant for medicine.

Metabolomics and Network Pharmacology in the Exploration of the Multi-Targeted Therapeutic Approach of Traditional Medicinal Plants.

Metabolomic is generally characterized as a comprehensive and the most copious analytical technique for the identification of targeted and untargeted metabolite diversity in a biological system. Recently, it has exponentially been used for phytochemical analysis and variability among plant metabolites, followed by chemometric analysis. Network pharmacology analysis is a computational technique used for the determination of multi-mechanistic and therapeutic evaluation of chemicals via interaction with the genomes involved in targeted or untargeted diseases. In considering the facts, the present review aims to explore the role of metabolomics and network pharmacology in the scientific validation of therapeutic claims as well as to evaluate the multi-targeted therapeutic approach of traditional Indian medicinal plants. The data was collected from different electronic scientific databases such as Google Scholar, Science Direct, ACS publication, PubMed, Springer, etc., using different keywords such as metabolomics, techniques used in metabolomics, chemometric analysis, a bioinformatic tool for drug discovery and development, network pharmacology, methodology and its role in biological evaluation of chemicals, etc. The screened articles were gathered and evaluated by different experts for their exclusion and inclusion in the final draft of the manuscript. The review findings suggest that metabolomics is one of the recent most precious and effective techniques for metabolite identification in the plant matrix. Various chemometric techniques are copiously used for metabolites discrimination analysis hence validating the unique characteristic of herbal medicines and their derived products concerning their authenticity. Network pharmacology remains the only option for the unique and effective analysis of hundreds of chemicals or metabolites via genomic interaction and thus validating the multi-mechanistic and therapeutic approach to explore the pharmacological aspects of herbal medicines for the management of the disease.

Management strategies and outcomes in renal transplant recipients recovering from COVID-19: A retrospective, multicentre, cohort study.

Background: There is an enormous knowledge gap on management strategies, clinical outcomes, and follow-up after kidney transplantation (KT) in recipients that have recovered from coronavirus disease (COVID-19). Methods: We conducted a multi-center, retrospective analysis in 23 Indian transplant centres between June 26, 2020 to December 1, 2021 on KT recipients who recovered after COVID-19 infections. We analyzed clinical and biopsy-confirmed acute rejection (AR) incidence and used cox-proportional modeling to estimate multivariate-adjusted hazard ratios (HR) for predictors of AR. We also performed competing risk analysis. Additional outcome measures included graft loss, all-cause mortality, waiting time from a positive real-time polymerase test (RT-PCR) to KT, laboratory parameters, and quality of life in follow-up. Findings: Among 372 KT which included 38(10·21%) ABO-incompatible, 12(3·22%) sensitized, 64(17·20%) coexisting donors with COVID-19 history and 20 (5·37%) recipients with residual radiographic abnormalities, the incidence of AR was 34 (9·1%) with 1(0·26%) death censored graft loss, and 4(1·07%) all-cause mortality over a median (interquartile range) follow-up of 241 (106-350) days. In our cox hazard proportional analysis, absence of oxygen requirement during COVID-19 compared to oxygen need [HR = 0·14(0·03-0·59); p-value = 0·0071], and use of thymoglobulin use compared to other induction strategies [HR = 0·17(0·03-0.95); p-value = 0·044] had a lower risk for AR. Degree of Human leukocyte antigen (HLA) DR mismatch had the highest risk of AR [HR = 10.2(1·74-65·83); p-value = 0·011]. With competing risk analysis, with death as a competing event, HLA DR mismatch, and oxygen requirement continued to be associated with AR. Age, gender, obesity, inflammatory markers, dialysis vintage, steroid use, sensitization and ABO-incompatibility have not been associated with a higher risk of AR. The median duration between COVID-19 real time polymerase test negativity to transplant was 88(40-145) days (overall), and ranged from 88(40-137), 65(42-120), 110(49-190), and 127(64-161) days in World Health Organization ordinal scale ≤ 3, 4, 5, and 6-7, respectively. There was no difference in quality of life, tacrolimus levels, blood counts, and mean serum creatinine assessed in patients with a past COVID-19 infection independent of severity. Interpretation: Our findings support that the outcomes of KT after COVID-19 recovery are excellent with absence of COVID-19 sequelae during follow-up. Additionally, there does not seem to be a need for changes in the induction/immunosuppression regimen based on the severity of COVID-19. Funding: Sanofi.

ABO-Incompatible Kidney Transplantation in India: A Single-Center Experience of First Hundred Cases.

Aim: ABO-incompatible (ABOi) kidney transplantation overcomes immunological barrier of blood group incompatibility. There have been very few published experiences of ABOi kidney transplantation from India. We present our single-center experience of the first hundred ABOi kidney transplants. Material and Methods: This is a single-center retrospective study of consecutive first hundred ABOi kidney transplant with at least 6 months of follow-up. Results: During the study period (2011-2020), a total of 121 ABOi kidney transplants were performed. Of these, first hundred patients were analyzed. Median follow-up duration was 33 (10-101) months. Mean recipient and donor age were 41.5 ± 13 and 47.68 ± 11.25 years, respectively. Mean HLA mismatch was 4 ± 1.5. Median baseline anti-blood group antibody titer was 128 (2-1024). Most common recipient blood group was O. Patient and death censored graft survival was 93% and 94%, respectively, at median follow-up of 33 months. Biopsy-proven acute rejection (BPAR) rate was 17% with acute antibody-mediated rejection being 3%. Rate of infection was 37%, most common being urinary tract infection. Conclusion: ABOi kidney transplant patients had acceptable patient and graft survival as well as BPAR rates. With current preconditioning protocol, infection rate was high.

Foreign Bodies in Ear: A Descriptive Study.

Foreign bodies (FB) in the external auditory canal are relative medical emergency. The objective of this study was to describe the types of FB and their complications. Hospital-based descriptive study. This study is done at sub-district hospital Nasirabad (district Ajmer) from period 1 January2016 to 31 May 2020 for period of 3 years 5 months included all patients with foreign body ear. A total of 126 patients were included. All cases were attended by ENT specialist. In our study we concluded that most common incidence is children less than 5 years (63.49%), male:female ratio of 1.33:1, most of the patients present within 24 h of presentation, in maximum cases there is no complications, maximum the foreign body is present in right ear. All cases were attended by ENT specialist. Maximum cases are done in local anaesthesia or no anaesthesia at all, 4 case in light anesthesia and 3 cases referred to nearby higher centre. In this we concluded that foreign body is usually present in less than 5 years of age group. Proper instrumentation and proper skill is required to remove foreign body without any complications.

Grafalon® vs. Thymoglobulin® as an Induction Agent in Renal Transplantation - A Retrospective Study.

INTRODUCTION: Antihuman thymocyte immunoglobulin, used as an induction agent in renal transplantation, is of two types - thymoglobulin and grafalon (formerly ATG-Fresenius). In this study, we compared outcomes with these two agents. METHODS: This was a single-center retrospective study of patients transplanted from January 2017 to October 2019, who received either grafalon or thymoglobulin induction. Grafalon or thymoglobulin was given at 6 and 3 mg/kg, respectively, followed by standard triple immunosuppression of tacrolimus, MMF, and prednisolone. RESULTS: Median follow up was 22 (3-36) months. Thymoglobulin was given to 255 patients, whereas 78 patients received grafalon. Baseline demographics were similar between the two groups although significantly more patients in the grafalon group received ABO incompatible transplant (15% vs. 4.3%; P = 0.002). Patient survival was similar between the two groups (99% in grafalon vs. 98.8% in thymoglobulin; P = 1.0). Death censored graft survival was also similar (99% in grafalon vs. 100% in thymoglobulin; P = 0.23). Biopsy proven acute rejection (BPAR) was significantly higher in the grafalon group (12.8% vs. 5.1%, P = 0.04). The significance persisted after multivariable regression analysis (P = 0.02). Other outcomes such as infection rate and estimated glomerular filtration rate on last follow up were comparable between the two groups. CONCLUSIONS: Grafalon (6 mg/kg dose) when used as an induction agent was associated with significantly higher rate of BPARs as compared to thymoglobulin (3 mg/kg dose) although with comparable short-term patient and death censored graft survival, graft function, and infection rates.

A Multicenter Cohort Study From India of 75 Kidney Transplants in Recipients Recovered After COVID-19.

BACKGROUND: There is limited current knowledge on feasibility and safety of kidney transplantation in coronavirus disease-19 (COVID-19) survivors. METHODS: We present a retrospective cohort study of 75 kidney transplants in patients who recovered from polymerase chain reaction (PCR)-confirmed COVID-19 performed across 22 transplant centers in India from July 3, 2020, to January 31, 2021. We detail demographics, clinical manifestations, immunosuppression regimen, laboratory findings, treatment, and outcomes. Patients with a previous diagnosis of COVID-19 were accepted after documenting 2 negative severe acute respiratory syndrome coronavirus 2 PCR tests, normal chest imaging with complete resolution of symptom for at least 28 d and significant social distancing for 14 d before surgery. RESULTS: Clinical severity in patients ranged from asymptomatic (n = 17, 22.7%), mild (n = 36.48%), moderate (n = 15.20%), and severe (n = 7.9.3%) disease. Median duration between PCR positive to transplant was 60 d (overall) and increased significantly from asymptomatic, mild, moderate, and severe disease (49, 57, 83, 94 d, P 0.019), respectively. All recipients and donors were asymptomatic with normal creatinine after surgery at a median (interquartile range) follow-up of 81 (56-117) d without any complications relating to surgery or COVID-19. Patient and graft survival was 100%, and acute rejection was reported in 6.6%. CONCLUSIONS: Prospective kidney transplant recipients post-COVID-19 can be considered for transplantation after comprehensive donor and recipient screening before surgery using a combination of clinical, radiologic, and laboratory criteria, careful pretransplant evaluation, and individualized risk-benefit analysis. Further large-scale prospective studies with longer follow-up will better clarify our initial findings. To date, this remains the first and the largest study of kidney transplantation in COVID-19 survivors.

Is it Safe to Be Transplanted From Living Donors Who Recovered From COVID-19? Experience of 31 Kidney Transplants in a Multicenter Cohort Study From India.

BACKGROUND: There is lack of data on feasibility and safety of kidney transplants from living donors who recovered from COVID-19. METHODS: Here, we present a retrospective cohort study of 31 kidney transplant recipients (KTR) from living donors who recovered from polymerase chain reaction confirmed COVID-19 across 19 transplant centers in India from July 3, 2020, to December 5, 2020. We detailed demographics, clinical manifestations, immunosuppression regimen, treatment, and outcomes. Donors with a previous diagnosis of COVID-19 were accepted after documenting 2 negative polymerase chain reaction tests with complete symptom resolution for at least 28 days and significant social distancing for 14 days before surgery. RESULTS: COVID-19 clinical severity in donors ranged from completely asymptomatic (71%, n = 22) to mild infection (29%, n = 9). None progressed to moderate or severe stages of the disease in the entire clinical course of home treatment. Patient and graft survival was 100%, respectively, with acute cellular rejection being reported in 6.4% (n = 2) recipient. All recipients and donors were asymptomatic with normal creatinine at median follow-up of 44 days after surgery without any complications relating to surgery and COVID-19. CONCLUSIONS: Our data support safety of proceeding with living donation for asymptomatic individuals with comprehensive donor, recipients screening before surgery, using a combination of clinical, radiologic, and laboratory criteria. It could provide new insights into the management of KTR from living donors who have recovered from COVID-19 in India. To the best of our knowledge, this remains the largest cohort of KTR from living donors who recovered from COVID-19.

Pediatric ABO-incompatible kidney transplantation: Evolving with the advancing apheresis technology: A single-center experience.

Recent literature has endorsed favorable outcomes following ABOi kidney transplantation in pediatric population. Nevertheless, reluctance to pursue an ABOi still remains pervasive. This could be ascribed to various legitimate reasons, namely less extensive pediatric ABOi data, technical difficulties encountered during PP, cost restraints, and concerns regarding higher rates of antibody-mediated rejection, infectious complications, and post-transplant lymphoproliferative disorder as compared to adults. However, given the similar excellent outcomes of both ABOi and ABOc kidney transplantation, clinicians should consider this option sooner if a compatible donor or swap is not available. Here, we describe the outcomes of three pediatric ABOi performed at our institute in India (from 2014 till now), wherein distinct apheresis modalities had been employed in each desensitization protocol, and our techniques evolved with advancing science in apheresis. This case series includes India's first published pediatric ABO-incompatible transplant (Case 2) and the youngest child to undergo ABO-incompatible renal transplant in SAARC nations (Case 3).

Pericardial effusion in children: experience from tertiary care center in northern India.

OBJECTIVE: To describe profile and outcome in children with significant pericardial effusion. METHODS: Hospital records of 25 children admitted with significant pericardial effusion during January 2010 to March 2013 were analyzed. RESULTS: Thirteen (52%) children had tubercular, 6 (24%) had bacterial, 3 viral, 2 recurrent idiopathic and one had malignant pericardial effusion. Only 3 children in our series required surgical drainage. CONCLUSION: Echocardiography guided percutaneous pericardiocentesis and pigtail catheter placement was found to be safe and effective.

Two Indian families with Greig cephalopolysyndactyly with non-syndromic phenotype.

The Greig cephalopolysyndactyly syndrome (GCPS) is a rare, autosomal dominant, pleiotropic, multiple congenital anomaly syndrome. The typical findings include hypertelorism, macrocephaly with frontal bossing, and polysyndactyly. We present two families, with GCPS with a non-syndromic phenotype, without the characteristic craniofacial anomalies and with the presence of complex digital anomalies including various types of polydactyly and syndactyly of the fingers and toes. The cases were proven to be GCPS by mutational analysis of GL13 gene. Our patients support the fact that the phenotypic spectrum of GL13 mutations is broader than that encompassed by the usual clinical diagnostic criteria. Individuals with features of familial polysyndactyly should be screened for mutations in GL13 even if they do not fulfill clinical criteria.

Formononetin reverses established osteopenia in adult ovariectomized rats.

OBJECTIVE: Formononetin (Formo) prevents ovariectomy (Ovx)-induced bone loss in rats. However, there are no reports on the curative effects of Formo. The objective of this study was to investigate the ability of Formo in restoring trabecular microarchitecture and promoting new bone formation in osteopenic rats. METHODS: Adult Sprague-Dawley rats were ovariectomized and left for 90 days for osteopenia to develop. After 90 days, Formo (10.0 mg kg d) was given orally for the next 12 weeks to Ovx rats in a therapeutic protocol. Sham-operated, Ovx + vehicle, and Ovx + parathyroid hormone (PTH) groups served as controls. Trabecular microarchitecture, osteoid formation, bone turnover/resorption markers, and bone osteoprotegerin-to-receptor activator for nuclear κB ligand ratio were studied. One-way analysis of variance was used to test significance of effects. RESULTS: Formo treatment significantly restored the lost trabecular microarchitecture in the femurs and tibia of osteopenic Ovx rats and promoted new bone formation. Formo was devoid of any uterine estrogenicity. Serum levels of type I collagen N-terminal propeptide, which is a reliable marker of bone formation, were increased in Ovx rats treated with Formo compared with Ovx + vehicle group, and the levels were comparable with those in the sham group. Formo prevented the Ovx-induced increase in bone turnover markers, including serum osteocalcin and urinary type I collagen degradation product. Furthermore, Formo-treated Ovx rats had an increased bone osteoprotegerin-to-receptor activator for nuclear κB ligand ratio compared with the Ovx + vehicle group. CONCLUSIONS: Daily oral administration of Formo for 12 weeks has a substantial anabolic effect, thus raising the possibility of its use in postmenopausal osteoporosis.

Predictors of acute kidney injury post-cardiopulmonary bypass in children.

OBJECTIVE: To investigate the incidence, implicating factors and outcome of acute kidney injury (AKI) after cardiopulmonary bypass (CPB) in patients admitted to a pediatric cardiothoracic intensive care unit (ICU). DESIGN: A retrospective review study. SETTING: A 10-bed cardiothoracic ICU. PATIENTS: One hundred and twenty-four children (<18 years of age) admitted to the cardiothoracic ICU following CPB between January 2007 and December 2009. METHODS: Age, sex, diagnosis, baseline and post-surgery hemoglobin, total leukocyte count, platelet count and biochemistry were recorded. Baseline and postoperative urea (mg/dl), creatinine (mg/dl), urine output (ml/kg/h) and inotrope dose were also recorded daily. The duration of CPB was noted. Postoperative cardiac, renal, hepatic, neurologic and respiratory dysfunctions were recorded. RESULTS: Seven (5%) children developed AKI stage I, five children (4%) developed AKI stage II and two children developed AKI stage III (2%). All patients with AKI had a longer stay in hospital and increased mortality. Two children required dialysis for AKI and none developed chronic renal impairment. All patients with AKI stage III died during the ICU stay. Using stepwise regression, younger age (<1 year), weight <10 kg, pump failure, sepsis and duration of CPB >90 min were significant risk factors identified for developing AKI. CONCLUSIONS: AKI is common and occurred in 11% of our patients following CPB; however, AKI requiring renal replacement therapy is uncommon.

Methoxylated isoflavones, cajanin and isoformononetin, have non-estrogenic bone forming effect via differential mitogen activated protein kinase (MAPK) signaling.

Following a lead obtained from stem-bark extract of Butea monosperma, two structurally related methoxyisoflavones; cajanin and isoformononetin were studied for their effects in osteoblasts. Cajanin had strong mitogenic as well as differentiation-promoting effects on osteoblasts that involved subsequent activation of MEK-Erk and Akt pathways. On the other hand, isoformononetin exhibited potent anti-apoptotic effect in addition to promoting osteoblast differentiation that involved parallel activation of MEK-Erk and Akt pathways. Unlike genistein or daidzein, none of these two compounds appear to act via estrogen receptors in osteoblast. Once daily oral (by gavage) treatment for 30 consecutive days was given to recently weaned female Sprague-Dawley rats with each of these compounds at 10.0 mg kg(-1) day(-1) dose. Cajanin increased bone mineral density (BMD) at all skeletal sites studied, bone biomechanical strength, mineral apposition rate (MAR) and bone formation rate (BFR), compared with control. BMD levels at various anatomic positions were also increased with isoformononetin compared with control however, its effect was less potent than cajanin. Isoformononetin had no effect on the parameters of bone biomechanical strength although it enhanced MAR and BFR compared with control. Isoformononetin had very mild uterotrophic effect, whereas cajanin was devoid of any such effect. Our data suggest that cajanin is more potent than isoformononetin in accelerating peak bone mass achievement. To the best of our knowledge, this work represents the first attempt to elucidate structure-activity relationship between the two methoxylated isoflavones regarding their effects in osteoblasts and bone formation.