Probiotic use in pediatric kidney transplant recipients: What are current practices, and are they evidence-based? A pediatric nephrology research consortium study.

BACKGROUND: Probiotics are living microorganisms that may confer health benefits to their host if administered in sufficient quantities. However, data on the use of probiotics in transplant recipients are scarce. METHOD: This multi-center survey of pediatric nephrologists aimed to examine variations in practice regarding the use of probiotics in pediatric kidney transplant recipients. The survey was conducted via a 10-item questionnaire (developed in Survey Monkey) administered to pediatric nephrologists participating in the Pediatric Nephrology Research Consortium meeting in April 2023. RESULTS: Sixty-four pediatric nephrologists completed the survey. Twenty-seven (42.2%) respondents reported having prescribed probiotics to pediatric kidney transplant recipients. The primary reason for probiotic use was the treatment of antibiotic-associated diarrhea (n = 20), with other reasons including recurrent Clostridium difficile infection (n = 15), general gut health promotion (n = 12), recurrent urinary tract infections (n = 8), and parental request (n = 1). Of those who prescribed probiotics, 48.1% held them during periods of neutropenia and 14.8% during central venous line use. Of the 64 respondents, 20 reported the lack of safety data as a concern for using probiotics in kidney transplant recipients. CONCLUSION: Pediatric nephrologists are increasingly prescribing probiotics to pediatric kidney transplant recipients; nevertheless, substantial practice variations exist. The paucity of safety data is a significant deterrent to probiotic use in this population.

AN IN-DEPTH ASSESSMENT OF THE TUMOR'S IMPACT ON SARCOPENIA.

Loss of muscle mass is a typical symptom of cancer and it is strongly correlated with poor prognosis. Cancer-related Sarcopenia is unresponsive to conventional dietary changes and exercise, in contrast to age-associated muscle atrophy. This particular type of weakness differs from different kinds of muscle loss in that it is triggered by a number of interrelated mechanisms, notably inflammatory processes, abnormal metabolic processes, proteolysis, and autophagy. This research is to examine evidence supporting the theory that tumors have a causal role in causing muscular atrophy. It seeks to investigate the precise regulators that the tumour generates and how they affect the processes that result in muscle waste. The evaluation looks for new directions for further studies and medical treatments. The analysis is based on a thorough examination of the scientific literature and research that shows how tumor and muscle atrophy are related. It concentrates on studies that clarify the numerous strategies by which malignancies cause the loss of muscle. This article highlights particular mechanisms by which these tumor-derived substances affect the development of muscle loss, including inflammatory processes, metabolic disturbance, proteolysis, and autophagy. The discovery of such targets offers hope for the creation of efficient treatment strategies that can enhance the long-term outlook and quality of life of cancer sufferers who are experiencing muscle loss.

Bacteriophages: A possible solution to combat enteropathogenic Escherichia coli infections in neonatal goats.

Due to awareness and benefits of goat rearing in developing economies, goats' significance is increasing. Unfortunately, these ruminants are threatened via multiple bacterial pathogens such as enteropathogenic Escherichia coli (EPEC). In goat kids and lambs, EPEC causes gastrointestinal disease leading to substantial economic losses for farmers and may also pose a threat to public health via the spread of zoonotic diseases. Management of infection is primarily based on antibiotics, but the need for new therapeutic measures as an alternative to antibiotics is becoming vital because of the advent of antimicrobial resistance (AMR). The prevalence of EPEC was established using bfpA gene, uspA gene and Stx1 gene, followed by phylogenetic analysis using Stx1 gene. The lytic activity of the isolated putative coliphages was tested on multi-drug resistant strains of EPEC. It was observed that a PCR based approach is more effective and rapid as compared to phenotypic tests of Escherichia coli virulence. It was also established that the isolated bacteriophages exhibited potent antibacterial efficacy in vitro, with some of the isolates (16%) detected as T4 and T4-like phages based on gp23 gene. Hence, bacteriophages as therapeutic agents may be explored as an alternative to antibiotics in managing public, livestock and environmental health in this era of AMR.

COVID-19 and tobacco cessation: lessons from India.

OBJECTIVES: The Government of India prohibited the sale of tobacco products during the COVID-19 lockdown to prevent the spread of the SARS-CoV-2 virus. This study assessed the tobacco cessation behaviour and its predictors among adult tobacco users during the initial COVID-19 lockdown period in India. METHODS: A cross-sectional study was conducted with 801 adult tobacco users (both smoking and smokeless tobacco) in two urban metropolitan cities of India over a 2-month period (July to August 2020). The study assessed complete tobacco cessation and quit attempts during the lockdown period. Logistic and negative binomial regression models were used to study the correlates of tobacco cessation and quit attempts, respectively. RESULTS: In total, 90 (11.3%) tobacco users reported that they had quit using tobacco after the COVID-19 lockdown period. Overall, a median of two quit attempts (interquartile range 0-6) was made by tobacco users. Participants with good knowledge on the harmful effects of tobacco use and COVID-19 were significantly more likely to quit tobacco use (odds ratio [OR] 2.2; 95% confidence interval [CI] 1.2-4.0) and reported more quit attempts (incidence risk ratio 5.7; 95% CI 2.8-11.8) compared to those with poor knowledge. Participants who had access to tobacco products were less likely to quit tobacco use compared to those who had no access (OR 0.3; 95% CI 0.2-0.5]. CONCLUSIONS: Access restrictions and correct knowledge on the harmful effects of tobacco use and COVID-19 can play an important role in creating a conducive environment for tobacco cessation among users.

Assessment of plaque vulnerability in carotid atherosclerotic plaques using contrast-enhanced ultrasound.

Background: Atherosclerotic carotid plaques are one of the most important causes of stroke. Apart from the severity of stenosis, there are certain plaque characteristics such as neovascularization and, surface ulceration which makes a plaque vulnerable. This study was performed to study the plaque characteristics using contrast-enhanced ultrasound (CEUS) and evaluate their association with presence of ischemic cerebrovascular symptoms in these patients. Methods: This study included patients presenting at a tertiary care center, having carotid plaques causing >60% stenosis. CEUS was performed for assessment of intraplaque neovascularity and plaque surface characteristics. These plaque features were then evaluated for their association with presence of ischemic cerebrovascular symptoms in patients. Results: Sixty plaques were studied in 50 patients. Thirty-two plaques were associated with ischemic cerebrovascular symptoms. On CEUS, intraplaque neovascularization was seen in 38 of the 60 plaques studied (63.3%). There was statistically significant association of intraplaque neovascularity and plaque surface characteristics with presence of ischemic cerebrovascular symptoms. Conclusion: CEUS allows better characterization of plaque surface characteristics and also depicts plaque neovascularization, which helps in determining the plaque vulnerability. It should be used as an adjunct to ultrasound and doppler assessment of carotid plaques.

YouTube as a source of patient information for transrectal ultrasound-guided biopsy of the prostate.

AIM: To assess the quality of YouTube videos explaining transrectal ultrasound (TRUS)-guided biopsies of the prostate. MATERIALS AND METHODS: A search of YouTube was made for the terms "TRUS", "TRUS biopsy", "transrectal ultrasound", and "prostate biopsy". Videos were selected from the first 10 pages of results and reviewed by three authors against criteria based on written information from the British Association of Urological Surgeons. They were given a qualitative rating based on how well they provided information on factors such as preparation for the procedure, mechanism of the procedure and possible side effects. Data were also collected on view count, country of origin, likes, and dislikes. RESULTS: A total of 41 videos were reviewed, with no videos achieving an "excellent" rating, 32 being rated as "very poor", and only one rated as "good". Despite the poor-quality information, 39 of the videos were from healthcare organisations or individual surgeons. Videos often lacked specific information, or were targeted at healthcare professionals instead of patients. CONCLUSION: The information about TRUS-guided prostate biopsies on YouTube was not of a sufficiently high standard to allow patients to make informed decisions. Healthcare professionals hence have a duty to point patients towards adequate sources of reputable information online. Furthermore, there remains an opportunity to produce high-quality, informative, patient-focussed medical YouTube videos.

Improved joint health in subjects with severe haemophilia A treated prophylactically with recombinant factor VIII Fc fusion protein.

INTRODUCTION: Joint arthropathy is the long-term consequence of joint bleeding in people with severe haemophilia. AIM: This study assessed change in joint health over time in subjects receiving recombinant factor VIII Fc fusion protein (rFVIIIFc) prophylaxis. METHODS: ALONG is the phase 3 pivotal study in which the benefit of rFVIIIFc as a prophylactic treatment for bleeding control was shown in previously treated severe haemophilia patients ≥12 years of age (arm 1: 25-65 IU/kg every 3-5 days, arm 2: 65 IU/kg weekly and arm 3: episodic). After completing ALONG, subjects had the option to enrol into the extension study (ASPIRE). This interim, post hoc analysis assessed changes in joint health over ~2.8 years in these patients. RESULTS: Forty-seven subjects had modified Haemophilia Joint Health Score (mHJHS) data at A-LONG baseline, ASPIRE baseline and ASPIRE Year 1 and Year 2. Compared with A-LONG baseline (23.4), mean improvement at ASPIRE Year 2 was -4.1 (95% confidence interval [CI], -6.5, -1.8; P = .001). Regardless of prestudy treatment regimen, subjects showed continuous improvement in mHJHS from A-LONG baseline through ASPIRE Year 2 (prestudy prophylaxis: -2.4, P = .09; prestudy episodic treatment: -7.2, P = .003). Benefits were seen in subjects with target joints (-5.6, P = .005) as well as those with severe arthropathy (-8.8, P = .02). The mHJHS components with the greatest improvement at ASPIRE Year 2 were swelling (-1.4, P = .008), range of motion (-1.1, P = .03) and strength (-0.8, P = .04). CONCLUSIONS: Prophylaxis with rFVIIIFc may improve joint health over time regardless of prestudy prophylaxis or episodic treatment regimens.

Recombinant factor VIII Fc fusion protein for immune tolerance induction in patients with severe haemophilia A with inhibitors-A retrospective analysis.

INTRODUCTION: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources. AIM: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors. METHODS: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI. RESULTS: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported. CONCLUSIONS: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI.

Characteristics, outcomes, prognostic factors and treatment of patients with T-cell prolymphocytic leukemia (T-PLL).

BACKGROUND: T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL. PATIENTS AND METHODS: We reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016. RESULTS: One hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin < 9.3 g/dl, lactate dehydrogenase (LDH) ≥ 1668 IU/l, white blood cell ≥ 208 K/l and ß2M ≥ 8 mg/l had significantly inferior OS and patients with hemoglobin < 9.3 g/dl had inferior progression-free survival (PFS). In multivariate analysis, we identified that presence of pleural effusion [hazard ratio (HR) 2.08 (95% CI 1.11-3.9); P = 0.02], high LDH (≥ 1668 IU/l) [HR 2.5 (95% CI 1.20-4.24); P < 0.001)], and low hemoglobin (< 9.3 g/dl) [HR 0.33 (95% CI 0.14-0.75); P = 0.008] were associated with shorter OS. Fifty-five previously untreated patients received treatment with an alemtuzumab-based regimen (42 monotherapy and 13 combination with pentostatin). Overall response rate, complete remission rate (CR) for single-agent alemtuzumab and alemtuzumab combined with pentostatin were 83%, 66% and 82%, 73% respectively. In patients who achieved initial CR, stem cell transplantation was not associated with longer PFS and OS. CONCLUSION: Outcomes in T-PLL remain poor. Multicenter collaborative effort is required to conduct prospective studies.

Mood, stress and longevity: convergence on ANK3.

Antidepressants have been shown to improve longevity in C. elegans. It is plausible that orthologs of genes involved in mood regulation and stress response are involved in such an effect. We sought to understand the underlying biology. First, we analyzed the transcriptome from worms treated with the antidepressant mianserin, previously identified in a large-scale unbiased drug screen as promoting increased lifespan in worms. We identified the most robust treatment-related changes in gene expression, and identified the corresponding human orthologs. Our analysis uncovered a series of genes and biological pathways that may be at the interface between antidepressant effects and longevity, notably pathways involved in drug metabolism/degradation (nicotine and melatonin). Second, we examined which of these genes overlap with genes which may be involved in depressive symptoms in an aging non-psychiatric human population (n=3577), discovered using a genome-wide association study (GWAS) approach in a design with extremes of distribution of phenotype. Third, we used a convergent functional genomics (CFG) approach to prioritize these genes for relevance to mood disorders and stress. The top gene identified was ANK3. To validate our findings, we conducted genetic and gene-expression studies, in C. elegans and in humans. We studied C. elegans inactivating mutants for ANK3/unc-44, and show that they survive longer than wild-type, particularly in older worms, independently of mianserin treatment. We also show that some ANK3/unc-44 expression is necessary for the effects of mianserin on prolonging lifespan and survival in the face of oxidative stress, particularly in younger worms. Wild-type ANK3/unc-44 increases in expression with age in C. elegans, and is maintained at lower youthful levels by mianserin treatment. These lower levels may be optimal in terms of longevity, offering a favorable balance between sufficient oxidative stress resistance in younger worms and survival effects in older worms. Thus, ANK3/unc-44 may represent an example of antagonistic pleiotropy, in which low-expression level in young animals are beneficial, but the age-associated increase becomes detrimental. Inactivating mutations in ANK3/unc-44 reverse this effect and cause detrimental effects in young animals (sensitivity to oxidative stress) and beneficial effect in old animals (increased survival). In humans, we studied if the most significant single nucleotide polymorphism (SNP) for depressive symptoms in ANK3 from our GWAS has a relationship to lifespan, and show a trend towards longer lifespan in individuals with the risk allele for depressive symptoms in men (odds ratio (OR) 1.41, P=0.031) but not in women (OR 1.08, P=0.33). We also examined whether ANK3, by itself or in a panel with other top CFG-prioritized genes, acts as a blood gene-expression biomarker for biological age, in two independent cohorts, one of live psychiatric patients (n=737), and one of suicide completers from the coroner's office (n=45). We show significantly lower levels of ANK3 expression in chronologically younger individuals than in middle age individuals, with a diminution of that effect in suicide completers, who presumably have been exposed to more severe and acute negative mood and stress. Of note, ANK3 was previously reported to be overexpressed in fibroblasts from patients with Hutchinson-Gilford progeria syndrome, a form of accelerated aging. Taken together, these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and longevity/aging, that may be biomarkers as well as targets for preventive or therapeutic interventions. Drug repurposing bioinformatics analyses identified the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol as potential longevity promoting compounds, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and sirolimus/rapamycin. Intriguingly, some of our top candidate genes for mood and stress-modulated longevity were changed in expression in opposite direction in previous studies in the Alzheimer disease. Additionally, a whole series of others were changed in expression in opposite direction in our previous studies on suicide, suggesting the possibility of a "life switch" actively controlled by mood and stress.

The impact of ocular trauma during the Nepal earthquake in 2015.

BACKGROUND: Nepal was struck by a massive earthquake on the 25th April 2015 and major aftershock on the 12th of May 2015, resulting in widespread devastation with a death toll in the thousands. The burden of ocular trauma resulting from the recent earthquakes in Nepal has not been described thus far. The aim of this study was to determine the types of ocular injuries sustained in the earthquake in Nepal and its management in Tilganga Institute of Ophthalmology (TIO) in Gaushala, Kathmandu. METHODS: This is a hospital-based retrospective study of patients presenting to TIO following repeated earthquake. Variables that were recorded included patients' presenting symptoms and time to presentation, visual acuities at presentation and at follow-up, diagnosis of ocular injury and surgery performed. RESULTS: There were 59 cases of earthquake victims visiting TIO, Gaushala, Kathmandu from April 2015 to July 2015, with 64 affected eyes due to 5 cases of bilateral involvement. The majority of patients were from the district Sindhupalchowk (14 cases, 23.7%), which was the epicenter of the main earthquake. The average duration between the earthquake and presentation was 13 · 9 days (range 1-120 days). Closed globe injury was most frequent (23 cases), followed by open globe injuries (8 cases). While 24 patients (38%) initially presented with a visual acuity <3/60 in their affected eye, 15 patients (23%) had a visual acuity of <3/60 on follow-up. A variety of surgical treatments were required including anterior and posterior segment repair. CONCLUSIONS: Immediate management of ocular trauma is critical in order to prevent blindness. Characterizing the burden of earthquake-related ocular trauma will facilitate planning for service provision in the event of a future earthquake in Nepal, or in countries, which are similarly at risk of having natural disasters.

The Mysterious Case of Dyspnea.

INTRODUCTION: Dehiscence of a mitral valve annuloplasty ring is a rare occurrence that often manifests as mitral regurgitation and heart failure. We present a case of mitral ring dehiscence which was initially unrecognized by standard 2-dimensional transthoracic echocardiography (2D TTE); and 2-dimensional transesophageal echocardiography (2D TEE);. CASE: A 65-year-old woman was referred to Cardiology clinic for evaluation of dyspnea. Her history included tobacco abuse, atrial fibrillation status post pulmonary vein isolation, nonischemic cardiomyopathy, and prior mitral valve repair with annuloplasty ring for rheumatic valvular disease. She had been asymptomatic post-surgery. Physical examination, cardiac rhythm and initial ischemic workup were unremarkable. Pulmonary function tests revealed moderate emphysematous type obstructive lung disease. A 2D TTE demonstrated moderate mitral regurgitation with normal left ventricular function. In right heart catheterization, large v waves were noted and 2D TEE also revealed severe mitral regurgitation. On 2D TEE, the mitral valve annuloplasty ring was visible above the native anterior mitral valve leaflet. Color Doppler flow estimated the effective regurgitation orifice area of 0.4cm2 using the proximal isovelocity surface area method and regurgitant volume of 58 cc, consistent with severe mitral regurgitation. A "floating mitral ring" and dehiscence measuring 1 cm in diameter were seen on high resolution three-dimensional reconstruction resulting from the detachment of the ring from the weakened posterior annulus. Based on these findings patient was referred to cardiothoracic surgeon for re-do mitral valve surgery. DISCUSSION: This was a perplexing case as the patient's dyspnea could be explained by many disease processes including atrial fibrillation, mitral regurgitation and chronic obstructive lung disease. The standard imaging modalities did not help us to formulate a diagnosis. 3D TEE provided invaluable and unparalleled information of mitral valve pathology. Annuloplasty ring dehiscence is a well described complication of mitral valve repair and should always be considered in symptomatic patients.

Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach.

Worldwide, one person dies every 40 seconds by suicide, a potentially preventable tragedy. A limiting step in our ability to intervene is the lack of objective, reliable predictors. We have previously provided proof of principle for the use of blood gene expression biomarkers to predict future hospitalizations due to suicidality, in male bipolar disorder participants. We now generalize the discovery, prioritization, validation, and testing of such markers across major psychiatric disorders (bipolar disorder, major depressive disorder, schizoaffective disorder, and schizophrenia) in male participants, to understand commonalities and differences. We used a powerful within-participant discovery approach to identify genes that change in expression between no suicidal ideation and high suicidal ideation states (n=37 participants out of a cohort of 217 psychiatric participants followed longitudinally). We then used a convergent functional genomics (CFG) approach with existing prior evidence in the field to prioritize the candidate biomarkers identified in the discovery step. Next, we validated the top biomarkers from the prioritization step for relevance to suicidal behavior, in a demographically matched cohort of suicide completers from the coroner's office (n=26). The biomarkers for suicidal ideation only are enriched for genes involved in neuronal connectivity and schizophrenia, the biomarkers also validated for suicidal behavior are enriched for genes involved in neuronal activity and mood. The 76 biomarkers that survived Bonferroni correction after validation for suicidal behavior map to biological pathways involved in immune and inflammatory response, mTOR signaling and growth factor regulation. mTOR signaling is necessary for the effects of the rapid-acting antidepressant agent ketamine, providing a novel biological rationale for its possible use in treating acute suicidality. Similarly, MAOB, a target of antidepressant inhibitors, was one of the increased biomarkers for suicidality. We also identified other potential therapeutic targets or biomarkers for drugs known to mitigate suicidality, such as omega-3 fatty acids, lithium and clozapine. Overall, 14% of the top candidate biomarkers also had evidence for involvement in psychological stress response, and 19% for involvement in programmed cell death/cellular suicide (apoptosis). It may be that in the face of adversity (stress), death mechanisms are turned on at a cellular (apoptosis) and organismal level. Finally, we tested the top increased and decreased biomarkers from the discovery for suicidal ideation (CADM1, CLIP4, DTNA, KIF2C), prioritization with CFG for prior evidence (SAT1, SKA2, SLC4A4), and validation for behavior in suicide completers (IL6, MBP, JUN, KLHDC3) steps in a completely independent test cohort of psychiatric participants for prediction of suicidal ideation (n=108), and in a future follow-up cohort of psychiatric participants (n=157) for prediction of psychiatric hospitalizations due to suicidality. The best individual biomarker across psychiatric diagnoses for predicting suicidal ideation was SLC4A4, with a receiver operating characteristic (ROC) area under the curve (AUC) of 72%. For bipolar disorder in particular, SLC4A4 predicted suicidal ideation with an AUC of 93%, and future hospitalizations with an AUC of 70%. SLC4A4 is involved in brain extracellular space pH regulation. Brain pH has been implicated in the pathophysiology of acute panic attacks. We also describe two new clinical information apps, one for affective state (simplified affective state scale, SASS) and one for suicide risk factors (Convergent Functional Information for Suicide, CFI-S), and how well they predict suicidal ideation across psychiatric diagnoses (AUC of 85% for SASS, AUC of 89% for CFI-S). We hypothesized a priori, based on our previous work, that the integration of the top biomarkers and the clinical information into a universal predictive measure (UP-Suicide) would show broad-spectrum predictive ability across psychiatric diagnoses. Indeed, the UP-Suicide was able to predict suicidal ideation across psychiatric diagnoses with an AUC of 92%. For bipolar disorder, it predicted suicidal ideation with an AUC of 98%, and future hospitalizations with an AUC of 94%. Of note, both types of tests we developed (blood biomarkers and clinical information apps) do not require asking the individual assessed if they have thoughts of suicide, as individuals who are truly suicidal often do not share that information with clinicians. We propose that the widespread use of such risk prediction tests as part of routine or targeted healthcare assessments will lead to early disease interception followed by preventive lifestyle modifications and proactive treatment.

Development and Characterization of the Paclitaxel loaded Riboflavin and Thiamine Conjugated Carbon Nanotubes for Cancer Treatment.

PURPOSE: In the present investigation, we prepared and evaluated the paclitaxel loaded riboflavin and thiamine conjugated multi walled carbon nanotubes (PTX-Rf-MWCNTs and PTX-Tm-MWCNTs) for targeted delivery to cancer employing MCF-7 cancer cell lines. METHODS: The developed conjugates were characterized using FTIR, NMR spectroscopy, electron microscopy drug loading, release, stability, hemolytic, ex vivo and in vivo studies etc. RESULTS: The percent entrapment efficiency was found to be 87.92 ± 0.48 and 82.75 ± 0.47% of PTX-Tm-MWCNTs, PTX-Rf-MWCNTs, respectively. The percent hemolysis of purified MWCNTs, PTX-MWCNTs, PTX-Tm-MWCNTs and PTX-Rf-MWCNTs was found to be 20.49 ± 0.97, 37.39 ± 0.78, 14.61 ± 0.84 and 11.17 ± 0.77% respectively. The PTX-Tm-MWCNTs and PTX-Rf-MWCNTs showed more cytotoxic effect as compared to PTX and PTX-MWCNTs with PTX-Rf-MWCNTs exhibiting the maximum cytotoxic potential. CONCLUSION: Thus in final outcome, we concluded that the riboflavin and thiamine conjugated MWCNTs shown great promising potential in the treatment of cancer, but more exhaustive data is needed in future.

Kommerell's diverticulum: A rare aortic arch anomaly.

Anomalies of the aortic arch associated with diverticulum are rare. We present a case of incidentally detected right-sided aortic arch with Kommerell's diverticulum and aberrant left subclavian artery.

One platform comparison of estrone and folic acid anchored surface engineered MWCNTs for doxorubicin delivery.

Our main aim in the present investigation was to assess and compare the in vitro and in vivo cancer targeting propensity of doxorubicin (DOX) loaded folic acid (FA) and estrone (ES) anchored PEGylated multiwalled carbon nanotubes (MWCNTs) employing tumor bearing Balb/c mice. The DOX was loaded into the developed functionalized MWCNTs after proper characterization using dialysis diffusion method. The in vitro, ex vivo, and in vivo studies were performed on the MCF-7 cell line for assessment of the cancer targeting propensity. Both qualitative and quantitative cell uptake studies indicated the preferential higher uptake of estrone anchored nanotube formulation compared to other formulations and free DOX owing to the overexpression of estrogen receptors (ERs) on human breast MCF-7 cells. Similarly, the pharmacokinetic and increased antitumor activities also confirmed the elevated cancer targeting propensity of the estrone and folic acid anchored MWCNT formulations. The DOX/ES-PEG-MWCNTs has also shown significantly longer survival span (43 days) than free DOX (18 days) and control group (12 days). Present outcomes from the ex vivo and in vivo studies are deemed to be of great scientific value and shall assist targeted drug delivery formulation scientists for selection of the targeting moieties in the treatment of human breast cancer.

Effects of advanced maternal age and race/ethnicity on placental weight and placental weight/birthweight ratio in very low birthweight infants.

To study the association of advanced maternal age (AMA) and race/ethnicity on placental pathology in very low birthweight (VLBW) infants. Retrospective analysis of placental pathology of inborn singleton VLBW infants from a regional level 3 NICU between July, 2002 and June, 2009. Subjects were stratified by age and race/ethnicity. Statistical analysis included One-way ANOVA, Chi Square and multivariable analyses. A total of 739 mother/infant dyads were included. AMA was associated with a decrease in placental weight and placental weight/birthweight ratio. Black/Non-Hispanic mothers ≥35 had a lower placental weight (p = 0.01) and lower placental weight/birth weight ratio (z-score, -0.45 ± 0.71 vs -0.04 ± 1.1, p = 0.01) compared to Black/Non-Hispanic mothers <35 years of age. After controlling for gestational age, race/ethnicity, maternal diabetes, maternal smoking, maternal hypertension and clinical chorioamnionitis, AMA, but not race/ethnicity, remained independently associated with placental weight/birthweight ratio z score (full model r(2) = 0.22, p < 0.01). In our study sample of VLBW infants, placental weight and placental weight/birthweight ratio were lower in mothers of advanced maternal age compared to mothers <35 years of age. Our data suggest that maternal age affects placentation in VLBW infants, which could influence maternal and neonatal outcomes.

Nanostructured lipid carriers based nanogel for meloxicam delivery: mechanistic, in-vivo and stability evaluation.

AIM: Our investigation was aimed to investigate the potential suitability of meloxicam-loaded nanostructured lipid carriers (MLX-NLC) gel for topical application. MAIN METHODS: MLX-NLC gel was prepared and in vivo skin penetration ability of the NLC gel was evaluated using confocal laser scanning microscopy. We studied the effect of MLX-NLC gel on the changes in lipid profile of skin to get an insight into its skin penetration enhancement mechanism. Acetic acid induced writhing test was performed to evaluate the analgesic effect. Drug concentration-time profile of MLX in rat plasma and skin after topical and oral treatment with MLX-NLC gel and oral MLX-solution, respectively, was observed. MLX-NLC gel was subjected to primary skin irritation test, sub-acute dermal toxicity study. Storage stability of MLX-NLC gel was also assessed for 90 days. KEY FINDINGS: NLC gel was effective in permeating Rhodamine 123 to deeper layers of rat skin. Changes in skin lipid prolife were observed in the rat skin on treatment with MLX-NLC gel and the results supported skin lipid extraction as a possible penetration enhancement mechanism. MLX-NLC gel demonstrated sustained pain inhibitory effect. Pharmacokinetics study established that topical application of MLX-NLC gel had the potential to avoid systemic uptake and hence the risk of systemic adverse effects. MLX-NLC gel demonstrated good skin tolerability and biosafety. Excellent physical stability of nanogel was observed at 4 ± 2 °C. SIGNIFICANCE: The study revealed that NLC gel is a promising carrier system for the topical application of MLX without side effects.

Development and characterization of folate anchored Saquinavir entrapped PLGA nanoparticles for anti-tumor activity.

OBJECTIVE: Saquinavir (SQV) is a US-FDA approved HIV protease inhibitor (HPI) for HIV cure. The purpose of the present investigation was to develop and characterize the anticancer potential of the SQV-loaded folic acid (FA) conjugated PEGylated and non-PEGylated poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) (SQV-Fol-PEG-PLGA and SQV-Fol-PLGA) employing PC-3 (human prostate) and MCF-7 (human breast) cancer cell lines. MATERIALS AND METHODS: Developed NPs were characterized by IR, NMR, DSC, XRD, size, charge and further tested for drug loading and cellular uptake properties. RESULT: The entrapment efficiency was found to be 56 ± 0.60 and 58 ± 0.80 w/v for SQV-Fol-PEG-PLGA and SQV-PLGA NPs, respectively. The obtained results of SQV-Fol-PEG-PLGA showed enhanced cytotoxicity and cellular uptake and were most preferentially taken up by the cancerous cells via folate receptor-mediated endocytosis (RME) mechanism. At 260 µM concentration, SQV-PLGA NPs and SQV-Fol-PEG-PLGA NPs showed 20%, 20% and 23% cell growth inhibition in PC-3 cells, respectively whereas in MCF-7 cells it was 12%, 15% and 14% cell growth inhibition, respectively. CONCLUSIONS: Developed targeted SQV-Fol-PEG-PLGA NPs were superior anticancer potential as compared to non-targeted SQV-PLGA NPs. Thus, these targeted NPs provide another option for anticancer drug delivery scientists.