The Changing Face of Childhood Intussusception: A Refinement in the Technique of Saline Reduction and Outcome.

Aims: Intussusception is a common pediatric surgical emergency and an indicator for primary healthcare. We report our experience with childhood intussusception at a tertiary care hospital in the private sector in Central Kerala and add our refinement to the technique of hydrostatic saline reduction which had more desirable outcome. Settings and Design: Children presenting with the diagnosis of intussusception which were managed in our department of pediatric surgery at a private hospital in Kerala, India. Subjects and Methods: Eighty children, up to 15 years of age, (43 boys, 37 girls) confirmed to have intussusception on ultrasound and managed in our institution from October 2016 to July 2020 with hydrostatic saline reduction. Sixty-two (77%) of them were aged 3 months to 3 years (numbers <10 to be written in words); the age of idiopathic intussusception. Statistical Analysis Used: SPSS V25. Association between variables using Chi square test and independent t test. Results: A total of 80 children met the criteria out of that (n = 79) had successful nonoperative reduction. Hydrostatic saline enema 73, One Barium and five air enema. A child presented in shock was taken up for laparotomy and reduced operatively. Six recurred within 24 h (7% early recurrence) and a second attempt at nonoperative reduction succeeded in all six of them. (numbers <10 in words). Eleven children (14%) had a late recurrence, the attempt at saline hydrostatic reduction was successful in only 3 (27%) and 8 went on to have surgery. Six were successfully reduced operatively and 2 had resection anastomosis. Conclusions: After excluding those who need surgery on clinical grounds, we report a 98.7% success with nonoperative reduction for the first instance of intussusception, a 24 h recurrence of 7%, with successful repeat reductions in all. With the refinement in the technique, we could achieve a desirable outcome. At the first presentation, surgery was indicated in 1 of the 80 children. We report a late recurrence rate of 14%, with a 27% success rate for nonoperative reduction. No pathological lead points were identified even in this group. All the children had an uneventful and a faster recovery. In our series, we had 97.5% follow-up rate.

Treatment of Ischemic Stroke by Atorvastatin-Loaded PEGylated Liposome.

There is insufficient evidence on the effect of nanoparticles, particularly liposomes loaded with a statin, on acute ischemic stroke. We investigated the impact of atorvastatin-loaded PEG (polyethylene glycol) conjugated liposomes (LipoStatin) on the outcomes in rats with cerebral ischemia-reperfusion. PEGylated liposome loaded with atorvastatin was developed as a nanoparticle to specifically accumulate in an ischemic region and release the drug to ameliorate the harmful effects of the stroke. LipoStatin was administered to rats with transient middle cerebral artery occlusion through the tail vein immediately after reperfusion (LipoStatin group). LipoStatin efficiently accumulated at the cerebral ischemic injury site of the rat. The LipoStatin group showed a significantly reduced infarct volume (p < 0.01) in brain micro-MR imaging and improved neurological function recovery compared to the control group (p < 0.05). In addition, markedly improved brain metabolism using fluorine-18 fluorodeoxyglucose micro-PET/CT imaging was demonstrated in the LipoStatin group compared with the control group (p < 0.01). Mechanistically, as a result of evaluation through IL-1 beta, TNF-alpha, ICAM-1, and Iba-1 mRNA expression levels at 5 days after cerebral ischemia, LipoStatin showed significant anti-inflammatory effects. Protein expression of occludin, JAM-A, Caveolin-1, and eNOS by western blot at 3 days and fluorescent images at 7 days showed considerable recovery of blood-brain barrier breakdown and endothelial dysfunction. PEGylated LipoStatin can be more effectively delivered to the ischemic brain and may have significant neuroprotective effects. Thus, PEGylated LipoStatin can be further developed as a promising targeted therapy for ischemic stroke and other major vascular diseases.

In situ hypoxia modulating nano-catalase for amplifying DNA damage in radiation resistive colon tumors.

Radiation therapy (RT) is a mainstream clinical approach in cancer treatment. However, the therapeutic efficacy of RT is greatly hindered by the presence of excessive hydrogen peroxide (H2O2) in the hypoxic region of the solid tumor, thus leading to tumor recurrence and metastasis. Herein, a thioketal-linked amphiphilic nano-assembly (MTS) loaded with hydrophobic manganese oxide (HMO) nanoparticles (MTS@HMO) is examined as a promising multi-purpose reactive oxygen species (ROS)-catalytic nanozyme for transforming an RT-resistant hypoxic tumor microenvironment (TME) into an RT-susceptible one by scavenging ROS in the hypoxic core of the solid tumor. After intravenous injection, the MTS@HMO nano-assembly was able to sense and be degraded by the abundant ROS in the hypoxic TME, thereby releasing HMO particles for subsequent scavenging of H2O2. The oxygen generated during peroxide scavenging then relieved the hypoxic TME, thereby resulting in an increased sensitivity of the hypoxic tumor tissue towards RT. Moreover, the in situ hypoxic status was monitored via the T1-enhanced magnetic resonance (MR) imaging of the Mn2+ ions generated by the ROS-mediated degradation of HMO. The in vitro results demonstrated a significant H2O2 elimination and enhanced oxygen generation after the treatment of the MTS@HMO nano-assembly with tumor cells under hypoxic conditions, compared to the control MTS group. In addition, the combination of RT and pre-treatment with MTS@HMO nano-assembly significantly amplified the permanent DNA strand breaks in tumor cells compared to the control RT group. More importantly, the in vivo results proved that the systemic injection of the MTS@HMO nano-assembly prior to RT irradiation enhanced the RT-mediated tumor suppression and down-regulated the hypoxic marker of HIF-1α in the solid tumor compared to the control RT group. Overall, the present work demonstrates the great potential of the versatile ROS-catalytic hypoxia modulating strategy using the MTS@HMO nano-assembly to enhance the RT-induced antitumor efficacy in hypoxic solid tumors.

Human amniotic membrane vs collagen in the treatment of superficial second-degree burns in children.

OBJECTIVE: The authors compared a 1-time application of bovine collagen and human amniotic membrane (HAM) to treat children with superficial second-degree burns. MATERIALS AND METHODS: A prospective, blinded, internally randomized trial of 43 children was conducted. Fresh HAM (prepared in-house at the Christian Medical College, Vellore) and bovine collagen were applied to different halves of each wound and dried naturally to form a hard, shell-like, so-called exoskeleton. The shell was shed as epithelialization occurred beneath it. Clinical examination and serial photographs were used to track progress until the wound healed completely, as well as at 3 and 6 months after the burn injury. Two burns surgeons blinded to the material used evaluated the resulting scars using the Vancouver Scar Scale. RESULTS: The 43 children presented 3 hours after burn injury on average. A 1-time application was successful in 40 children (93%). After the dressing dried, all parents reported that their child was pain free and the exoskeleton could be handled over the burned area. A total of 16 children (37%) with a low-grade fever at the time of application were treated with simple antipyretic agents. Eight children reported itching at the dressing site. The dressing did not take or was removed in 3 children (7%). Minor serous collections occurred in 8 children who subsequently underwent aspiration. The median time to healing was 10 days in both study arms, with no significant difference in scarring between the 2 materials. Children with earlier shedding of the shell had significantly better scar quality (P <.001). CONCLUSIONS: Collagen and HAM are safe and provide a one-time ambulatory option for burn dressing with comparable time to healing and scarring. Earlier shedding of the dressing is predictive of better scar quality. Because HAM is inexpensive and simple to prepare and store, it is an excellent choice for use in economically disadvantaged areas where collagen may be unavailable.

Stimuli-Responsive Polymeric Nanomaterials for the Delivery of Immunotherapy Moieties: Antigens, Adjuvants and Agonists.

Immunotherapy has been investigated for decades, and it has provided promising results in preclinical studies. The most important issue that hinders researchers from advancing to clinical studies is the delivery system for immunotherapy agents, such as antigens, adjuvants and agonists, and the activation of these agents at the tumour site. Polymers are among the most versatile materials for a variety of treatments and diagnostics, and some polymers are reactive to either endogenous or exogenous stimuli. Utilizing this advantage, researchers have been developing novel and effective polymeric nanomaterials that can deliver immunotherapeutic moieties. In this review, we summarized recent works on stimuli-responsive polymeric nanomaterials that deliver antigens, adjuvants and agonists to tumours for immunotherapy purposes.

Corrigendum: Tumor Microenvironment-Stimuli Responsive Nanoparticles for Anticancer Therapy.

[This corrects the article DOI: 10.3389/fmolb.2020.610533.].

Hyponatremia among Postoperative Children Administered with Hypotonic Fluids in a Tertiary Care Hospital: A Descriptive Cross-sectional Study.

INTRODUCTION: Hypotonic solutions in postoperative children may cause hyponatremia. Considering humidity and temperatures in India, this study was conducted to find out the prevalence of hyponatremia among postoperative children who were administered with hypotonic solutions in a tertiary care hospital. METHODS: A descriptive cross-sectional study was conducted at a tertiary care hospital. Ethical approval was taken from the institutional review board of Christian Medical College, Vellore, India (Reference number: 9177). Children aged less than 15 years undergoing elective surgery, requiring fasting for more than 12 hours post-operatively with normal preoperative electrolytes and renal functions were included. Hypotonic fluids were administered following existent protocol. Electrolytes were repeated immediate postoperatively and at 12-24 hours. Data was entered into and analyzed using the Statistical Package for the Social Sciences version 18.0. Point estimate at 90% Confidence Interval was calculated along with frequency and proportion for binary data. RESULTS: Among 109 participants, hyponatremia in the postoperative period was seen in 53 (48.6%) (40.7-56.5 at 90% Confidence Interval) children. Hyponatremia was found in the immediate postoperative period in 10 (9.2%) children. All received Ringer Lactate as maintenance intra-operatively and none were severe enough to need correction. In the 12-24-hour sample, 43 (39.41%) had hyponatremia and none in severe category. CONCLUSIONS: Asymptomatic hyponatremia was noted in normal children planned for elective surgery. Among children managed with the existing institutional perioperative (hypotonic) fluid management protocol, subclinical postoperative hyponatremia within 12-24 hours of surgery was noted in a significant proportion, which was more in the hot and warm months in tropics. There are grounds for switching to isotonic fluids for perioperative management.

Intravitreal Injection of Liposomes Loaded with a Histone Deacetylase Inhibitor Promotes Retinal Ganglion Cell Survival in a Mouse Model of Optic Nerve Crush.

Various neuroprotective agents have been studied for the treatment of retinal ganglion cell (RGC) diseases, but issues concerning the side effects of systemically administered drugs and the short retention time of intravitreally injected drugs limit their clinical applications. The current study aimed to evaluate the neuroprotective effects of intravitreally injected trichostatin A (TSA)-loaded liposomes in a mouse model of optic nerve crush (ONC) and determine whether TSA-loaded liposomes have therapeutic potential in RGC diseases. The histone deacetylase inhibitor, TSA, was incorporated into polyethylene glycolylated liposomes. C57BL/6J mice were treated with an intravitreal injection of TSA-loaded liposomes and liposomes loaded with a lipophilic fluorescent dye for tracking, immediately after ONC injury. The expression of macroglial and microglial cell markers (glial fibrillary acidic protein and ionized calcium binding adaptor molecule-1), RGC survival, and apoptosis were assessed. We found that the liposomes reached the inner retina. Their fluorescence was detected for up to 10 days after the intravitreal injection, with peak intensity at 3 days postinjection. Intravitreally administered TSA-loaded liposomes significantly decreased reactive gliosis and RGC apoptosis and increased RGC survival in a mouse model of ONC. Our results suggest that TSA-loaded liposomes may help in the treatment of various RGC diseases.

A bilirubin-conjugated chitosan nanotheranostics system as a platform for reactive oxygen species stimuli-responsive hepatic fibrosis therapy.

The development of nanoparticles that can be used as stimuli-responsive drug carriers for the treatment of different diseases has been an emerging area of research. In this study, we designed a chitosan-bilirubin micelle (ChiBil) carrying losartan, which is responsive to intrinsic reactive oxygen species (ROS), for the treatment of hepatic fibrosis. Because bilirubin is hydrophobic in nature, its carboxyl group was conjugated to an amine group from chitosan using EDC-NHS chemistry to form an amphiphilic conjugate, ChiBil. Losartan is an angiotensin receptor blocker that reduces hepatic fibrosis, and it was used as the therapeutic payload in this study to form ChiBil-losartan micelles. The release characteristics of ChiBil-losartan were tested by ROS generation to confirm losartan release. Human hepatic stellate cell line LX2 was found to be the best in vitro model for the study. The reduction of hepatic stellate cell activation after treatment with ChiBil-losartan was analyzed based on the expression of alpha-smooth muscle actin (α-SMA) in both in vitro and in vivo studies. Advanced liver fibrosis was induced in C3H/HeN mice using a thioacetamide (TAA) via intraperitoneal injection and 10% ethanol (EtOH) in their drinking water. In addition, the hydroxyproline levels, histopathological evaluation, and mRNA quantification in the liver showed a decreased collagen content in the treated groups compared to that in the untreated control group. Macrophage infiltration studies and qPCR studies of inflammatory markers also proved the reduction of hepatic fibrosis in the treatment group. The intravenous administration of ChiBil-losartan resulted in decreased fibrosis in a TAA/EtOH-induced liver fibrosis mouse model. The in vitro and in vivo results suggest that the ROS stimuli-responsive ChiBil nanoparticles carrying losartan may be a potent therapeutic option for the treatment of hepatic fibrosis. The combined effect of losartan and bilirubin exhibited a decreased hepatic fibrosis both in vitro and in vivo.

Author Correction: Remote targeted implantation of sound-sensitive biodegradable multi-cavity microparticles with focused ultrasound.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Effect of hepato-toxins in the acceleration of hepatic fibrosis in hepatitis B mice.

Chronic liver diseases such as hepatitis B viral (HBV) infection and liver fibrosis have been a major health problem worldwide. However, less research has been conducted owing to the lack of animal models. The key purpose of this study was to determine the effects of different hepatotoxins in HBV-affected liver. In this study, we successfully generated a combined liver fibrosis model by administering HBV 1.2 plasmid and thioacetamide/ethanol (TAA/EtOH). To our knowledge, this is the first study in which an increase in the liver fibrosis level is observed by the intraperitoneal administration of TAA and EtOH in drinking water after the hydrodynamic transfection of the HBV 1.2 plasmid in C3H/HeN mice. The HBV+TAA/EtOH group exhibited higher level of hepatic fibrosis than that of the control groups. The hepatic stellate cell activation in the TAA- and EtOH-administered groups was demonstrated by the elevation in the level of fibrotic markers. In addition, high levels of collagen content and histopathological results were also used to confirm the prominent fibrotic levels. We established a novel HBV mice model by hydrodynamic injection-based HBV transfection in C3H/HeN mice. C3H/HeN mice were reported to have a higher HBV persistence level than that of the C57BL/6 mouse model. All the results showed an increased fibrosis level in the HBV mice treated with TAA and EtOH; hence, this model would be useful to understand the effect of hepatotoxins on the high risk of fibrosis after HBV infection. The acceleration of liver fibrosis can occur with prolonged administration as well as the high dosage of hepatotoxins in mice.

Tumor Microenvironment-Stimuli Responsive Nanoparticles for Anticancer Therapy.

Cancer is a disease that affects a large number of people all over the world. For treating cancer, nano-drug delivery system has been introduced recently with objective of increasing therapeutic efficiency of chemotherapeutic drug. The main characteristics of this system are the encapsulation of the insoluble chemotherapeutic cargo, increasing the period of circulation in the body, as well as the delivery of the drug at that specific site. Currently, the nano-drug delivery system based on the stimuli response is becoming more popular because of the extra features for controlling the drug release based on the internal atmosphere of cancer. This review provides a summary of different types of internal (pH, redox, enzyme, ROS, hypoxia) stimuli-responsive nanoparticle drug delivery systems as well as perspective for upcoming times.

Retraction: Radio frequency triggered curcumin delivery from thermo and pH responsive nanoparticles containing gold nanoparticles and its in vivo localization studies in an orthotopic breast tumor model.

[This retracts the article DOI: 10.1039/C4RA05727A.].

Testicular Volume in a Cohort of Prepubertal Indian Children.

CONTEXT: There are orchidometer-based testicular volume nomograms for Indian children; however, accurate and reliable values measured by ultrasound are lacking. AIMS: The aim of this study was to (1) measure the testicular volumes of boys from birth to 8 years and generate reference values and (2) to identify factors if any that may influence variation in testicular volumes. SETTINGS AND DESIGN: This was a prospective observational study conducted on 320 children in the Department of Pediatric Surgery, Christian Medical College, Vellore, India. SUBJECTS AND METHODS: A total of 320 boys without any genital abnormalities were studied. The testes were scanned using a linear transducer, and the length, width, and depth of each testis were recorded. Testicular volume was calculated using Lambert's equation - length × width × depth × 0.71. STATISTICAL ANALYSIS USED: Mean testicular volumes and standard deviation for every year of age were calculated. The centile values for testicular volume were computed using R software. RESULTS: Age-specific nomogram of each testis was created separately. Interobserver variability of the measurement was shown to be up to 0.3 ml. No difference was demonstrated in the testicular volumes between the right and left testis. No correlation was found between body weight and body mass index with testicular volume. From the data on differences in size between the two sides, a volume differential index of 27% corresponds to the 95th centile. CONCLUSIONS: Reference values have been created for testicular volumes in prepubertal Indian children that could be used to assess the effects of disease and surgical interventions in this age group.

Remote targeted implantation of sound-sensitive biodegradable multi-cavity microparticles with focused ultrasound.

Ultrasound-enhanced drug delivery has shown great promise in providing targeted burst release of drug at the site of the disease. Yet current solid ultrasound-responsive particles are non-degradable with limited potential for drug-loading. Here, we report on an ultrasound-responsive multi-cavity poly(lactic-co-glycolic acid) microparticle (mcPLGA MP) loaded with rhodamine B (RhB) with or without 4',6-diamidino-2-phenylindole (DAPI) to represent small molecule therapeutics. After exposure to high intensity focused ultrasound (HIFU), these delivery vehicles were remotely implanted into gel and porcine tissue models, where the particles rapidly released their payload within the first day and sustained release for at least seven days. RhB-mcPLGA MPs were implanted with HIFU into and beyond the sub-endothelial space of porcine arteries without observable damage to the artery. HIFU also guided the location of implantation; RhB-mcPLGA MPs were only observed at the focus of the HIFU away from the direction of ultrasound. Once implanted, DAPI co-loaded RhB-mcPLGA MPs released DAPI into the arterial wall, staining the nucleus of the cells. Our work shows the potential for HIFU-guided implantation of drug-loaded particles as a strategy to improve the local and sustained delivery of a therapeutic for up to two weeks.

Biomedical Applications for Gas-Stabilizing Solid Cavitation Agents.

For over a decade, advancements in ultrasound-enhanced drug delivery strategies have demonstrated remarkable success in providing targeted drug delivery for a broad range of diseases. In order to achieve enhanced drug delivery, these strategies harness the mechanical effects from bubble oscillations (i.e., cavitation) of a variety of exogenous cavitation agents. Recently, solid cavitation agents have emerged due to their capacity for drug-loading and sustained cavitation duration. Unlike other cavitation agents, solid cavitation agents stabilize gaseous bubbles on hydrophobic surface cavities. Thus, the design of these particles is crucial. In this Review, we provide an overview of the different designs for solid cavitation agents such as nanocups, nanocones, and porous structures, as well as the current status of their development. Considering the numerous advantages of solid cavitation agents, we anticipate further innovations for this new type of cavitation agent across a broad range of biomedical applications.

Hyaluronan-Stabilized Redox-Sensitive Nanoassembly for Chemo-Gene Therapy and Dual T1/T2 MR Imaging in Drug-Resistant Breast Cancer Cells.

Tailoring combinatorial therapies along with real-time monitoring strategies has been the major focus of overcoming multidrug resistance in cancer. However, attempting to develop a multifunctional nanoplatform in a single construct leads to compromising therapeutic outcomes. Herein, we developed a simple, theranostic nanoassembly containing a hyaluronic acid-stabilized redox-sensitive (HART) polyethylenimine polyplex composed of a doxorubicin (DOX) intercalated Bcl-2 shRNA encoded plasmid along with a green-synthesized hausmannite (Mn3O4) and hematite (Fe3O4) nanoparticle (GMF). The highly stable HART nanoassembly has enhanced CD44-mediated intracellular uptake along with hyaluronidase (hylase) and redox-responsive drug-gene release. With Bcl-2 gene silencing induced by the successful delivery of HART in multidrug-resistant MCF7 breast cancer cells, the synergistic cytotoxic effect of Bcl-2 silencing and DOX was achieved. In addition, the HART nanoassembly containing GMF exhibited excellent dual MRI contrast (T1/T2) by reducing artifact signals. Overall, the HART nanoassembly with its enhanced theranostic properties has the potential to improve the therapeutic efficacy in future preclinical and clinical trials.

Stricture Urethra in Children: An Indian Perspective.

BACKGROUND: Pediatric urethral stricture and its treatment have functional implications in the growing child. SUBJECTS AND METHODS: A retrospective study of records on urethral strictures encountered in our institution between January 2005 and May 2016 yielded 23 boys against a backdrop of 19,250 admissions during the same period; stenosis and strictures after hypospadias repair were not included in this study. Demographic data were collected from the charts, and the success of repair was assessed clinically by success of repair was assessed clinically by observing for presence or absence of symptoms such as dribbling, straining at voiding, adequacy of urinary stream and radiologicaly by assessing the micturition phase of voiding cystourethrogram. Success was defined as successful initiation, flow, and completion of voiding with radiological evidence of reestablishment of urethral continuity. RESULTS: The most common cause of urethral stricture was perineal or pelvic trauma (56.5%). Three after surgery for anorectal malformation (13.04%) and 2 (8.6%) followed otherwise unspecified urethritis. Transperineal and transpubic anastomotic routes were used for surgery. Redo surgery was required in 47.8%. The overall success rate was 82%. A self-catheterizable mitrofanoff channel was created as part of the primary procedure in 63.6% (7/11) or after the failure of the first procedure in 36.3% (4/11). CONCLUSION: The majority of urethral strictures are long-segment strictures or those with complete disruption not amenable to endoscopic techniques. The aim of the surgery is to obtain end-to-end opposition of healthy proximal and distal urethra. The route - transperineal or transpubic - which will give the best access to the ends of the urethra is determined by the location and extent of the stricture and the alteration in anatomy as a consequence of the pelvic fracture. Even after the introduction of laser and endoscopic techniques, surgical repair is required to tackle the majority of urethral strictures in children.

Hexa-functional tumour-seeking nano voyagers and annihilators for synergistic cancer theranostic applications.

In order to meet the unmet medical needs for effective cancer treatment, multifunctional nanocarriers based on iron oxide nanoparticles hold tremendous promise. Here we report a superparamagnetic iron oxide nanoparticles based hexa-functional nanosystem for synergistic cancer theranostic applications by offering active tumour targeting, accumulation and complementary imaging capability by combining magnetic resonance imaging as well as near-infrared fluorescence, magnetophotothermia and chemotherapy. The uniquely designed nanosystem exhibited a paramount increase in the antitumour efficacy through the simultaneous application of multiple thermal effects called magnetophotothermia, which outweighed the therapeutic efficacy of the current thermo-chemo therapies or stand-alone therapies. The active tumour-seeking property with prolonged tumour accumulation and complementary imaging capability with improved sensitivity and resolution also augments the therapeutic efficacy of the proposed nanosystem. Additionally, the work proposes a deep-learning-based tumour cell nuclei detection technique from H&E stained images in anticipation of providing much inspiration for the future of precision histology.