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Graphical abstract A century ago, the groundbreaking concept of the magic bullet was given by Paul Ehrlich. Since then, this concept has been extensively explored in various forms to date. The concept of multivalency is among such advancements of the magic bullet concept. Biologically, the concept of multivalency plays a critical role in significantly huge numbers of biochemical interactions. This concept is the sole reason behind the higher affinity of biological molecules like viruses to more selectively target the host cell surface receptors. Multivalent nanoconstructs are a promising approach for drug delivery by the active targeting principle. Designing and developing effective and target-specific multivalent drug delivery nanoconstructs, on the other hand, remain a challenge. The underlying reason for this is a lack of understanding of the crucial interactions between ligands and cell surface receptors, as well as the design of nanoconstructs. This review highlights the need for a better theoretical understanding of the multivalent effect of what happens to the receptor–ligand complex after it has been established. Furthermore, the critical parameters for designing and developing robust multivalent systems have been emphasized. We have also discussed current advances in the design and development of multivalent nanoconstructs for drug delivery. We believe that a thorough knowledge of theoretical concepts and experimental methodologies may transform a brilliant idea into clinical translation.

The objective of the present study was to evaluate the feasibility of pine needle biochar as a soil amendment to promote the growth of Bidens pilosa L. and enhance its ability to phytoextract the cadmium from soil. Pot experiments (50 d) were designed as control experiment (C); metal treatment (MT), 20 mg Cd kg-1; biochar treatment (BT100 or BT200), 100 or 200 mg kg-1; and metal-biochar treatment (MBT100 or MBT200), 20 mg Cd kg-1 and 100 or 200 mg biochar kg-1. The Cd (20 mg kg-1) or biochar treatment (100 mg kg-1) increased the dry weight and root length of B. pilosa. The biochar amendment enhanced the metal concentration in root and shoot of the plant. The plant could accumulate 39.47±5.44 mg Cd kg-1 in shoots (MT), which increased to 45.96±17.3 mg Cd kg-1 and 55.01±5.65 mg Cd kg-1 under biochar treatment sets MBT100 and MBT200, respectively. The Cd uptake by B. pilosa in MT, MBT100, and MBT200 treatments were 67.81 μg/plant, 78.58 μg/plant, and 76.13 μg/plant, respectively. The biochar amendments increased the proline concentrations while decreased the chlorophyll content in leaves indicating the stress on the plant. Overall, the result indicates that soil amended with pine needle biochar at 100 mg kg-1 increased the phytoremediation ability of B. pilosa.

Roux-en-Y gastric bypass (RYGB) has emerged as the most effective treatment in reversing insulin resistance in patients with type 2 diabetes mellitus (T2DM). A number of models and statistical tools have been proposed to predict patients likely to experience diabetes remission post-RYGB. The purpose of our study was to evaluate the preoperative accuracy of DiaRem score in predicting T2DM remission at 1 year of follow-up in a retrospective analysis of diabetic morbidly obese patients who underwent RYGB. One hundred and forty-three patients underwent RYGB between January 2018 and December 2018. We conducted a retrospective analysis in 55 patients (38.46%) with T2DM with 1 year of follow-up. DiaRem score was calculated, and patients were stratified in five groups. At a 1-year follow-up, we found a higher proportion of patients with T2DM remission in the lower score group compared to a lower proportion of patients with remission in the higher score group. We derived a DiaRem cut-off score of 6.5 that had high sensitivity and specificity to predict T2DM remission preoperatively. We found a significant decrease in BMI and HbA1C values post-operatively at 1 year following RYGB. DiaRem score is an easy to determine score based on basic clinical parameters that could identify patients with T2DM who would achieve maximal benefit in terms of remission after bariatric surgery. The development of a suitable scoring tool would be clinically useful as it would enable clinicians to better triage patients for RYGB.

Background Periodontitis is a microbial disease that leads to inflammation in the tooth-supporting tissues of the oral cavity that is common among the elderly. It is initiated by oral inflammation induced by bacterial dysbiosis. Choosing an appropriate antimicrobial agent with the right course of drug administration is the key to successful periodontal therapy. In recent times, with more biomarkers and the development of new technologies, several point-of-care testing (POCT) platforms have been developed for the diagnosis and monitoring of periodontitis. This review focuses on oral microbiology and the pathogenesis of periodontitis as well as recent insights into the in situ gel system for periodontitis. Design An exhaustive search was conducted in the following scientific databases Science Direct, Springer, Pub Med, and Google Scholar to review all relevant literatures. This is a comprehensive narrative review of the literature, summarizing the perspectives of the authors. Results Novel in situ forming gel is introduced at the site that shows a promising potential to overcome one of the main practical obstacles associated with the treatment of local periodontitis: partial adhesion to the surrounding tissue, causing in the accidental expulsion of at least parts of the implants from patient’s pockets. This results in a large residence time of the system at the site of action and uncertainty of the final exposure to the drug. Conclusion From the reviewed literature, it is concluded that experimental evidence suggests that the in situ gel-forming systems can be useful in treating several common diseases of the oral cavity. Future research should focus on clinical studies to be performed for the in situ gel to make a significant contribution to periodontitis. Graphical abstract

In the current scenario, the utility of peptide as the targeting ligand has been increased for the efficient diagnosis and treatment of tumor cells. Blood vessels of tumor cells show some molecular receptors on the endothelial cell surface which can differentiate these cells from the remaining vasculature of other normal cells and tissues. Thus, these molecular receptors functioned as the revolutionary and striking target for the effective cancer diagnosis and treatment. Integrin (αvβ3) receptors are highly overexpressed onto the tumor neovasculature and tumor cells. Arginine-Glycine-Aspartic (RGD) peptide may be attached to these overexpressed integrin receptors with high affinity. Therefore, RGD-based systems have been developed for the effective delivery of diagnostic agent and anticancer drug for the diagnosis and treatment of cancer cells, respectively. In this review, an overview of peptide based nanoparticle especially RGD based nanoparticle systems in the field of theranostic application is provided.

The aim of this work was to enhance the transportation of the galantamine to the brain via ascorbic acid grafted PLGA-b-PEG nanoparticles (NPs) using SVCT2 transporters of choroid plexus. PLGA-b-PEG copolymer was synthesized and characterized by 1H NMR, gel permeation chromatography, and differential scanning calorimetry. PLGA-b-PEG-NH2 and PLGA-b-mPEG NPs were prepared by nanoprecipitation method. PLGA-b-PEG NPs with desirable size, polydispersity, and drug loading were used for the conjugation with ascorbic acid (PLGA-b-PEG-Asc) to facilitate SVCT2 mediated transportation of the same into the brain. The surface functionalization of NPs with ascorbic acid significantly increased cellular uptake of NPs in SVCT2 expressing NIH/3T3 cells as compared to plain PLGA and PLGA-b-mPEG NPs. In vivo pharmacodynamic efficacy was evaluated using Morris Water Maze Test, Radial Arm Maze Test and AChE activity in scopolamine induced amnetic rats. In vivo pharmacodynamic studies demonstrated significantly higher therapeutic and sustained action by drug loaded PLGA-b-PEG-Asc NPs than free drugs and drug loaded plain PLGA as well as PLGA-b-mPEG NPs. Additionally, PLGA-b-PEG-Asc NPs resulted in significantly higher biodistribution of the drug to the brain than other formulations. Hence, the results suggested that targeting of bioactives to the brain by ascorbic acid grafted PLGA-b-PEG NPs is a promising approach.

Minimally invasive anal fistula treatment (MAFT) was introduced to minimize early postoperative morbidity, preserve sphincter continence, and reduce recurrence. We report our early experience with MAFT in 416 patients. Preoperative MRI was performed in 150 patients initially and subsequently thereafter. The technique involves fistuloscope-aided localization of internal fistula opening, examination and fulguration of all fistula tracks, and secure stapled closure of internal fistula opening within anal canal/rectum. MAFT was performed as day-care procedure in 391 patients (93.9 %). During surgery, internal fistula opening could not be located in 100 patients (24 %). Seven patients required readmission to hospital. Mean visual analog scale scores for pain on discharge and at 1 week were 3.1 (1–6) and 1.6 (0–3), respectively. Mean duration for return to normal activity was 3.2 days (2–11 days). Fistula recurrence was observed in 35/134 patients (26.1 %) at 1 year follow-up. MAFT may be performed as day-care procedure with benefits of less pain, absence of perianal wounds, faster recovery, and preservation of sphincter continence. However, long-term results from more centers are needed especially for recurrence.

Iatrogenic enterotomy (IE) during laparoscopic ventral/incisional hernia repair (LIVHR) is reported to be associated with poorer surgical outcomes. We report our experience with diagnosis, management and complications in patients who had IE during LIVHR at our tertiary referral institute between 1994 and 2011. We retrospectively reviewed prospectively collected data of 2,346 patients who underwent LIVHR from 1994 to 2011. We identified 33 patients who had IE during LIVHR. All surgical procedures were performed by five consultants and fellows under supervision who followed a standardized operative protocol. Patients were followed up for 6 months to evaluate morbidity, mortality, additional surgical procedures, unplanned readmissions and hospital stay. Mortality occurred in 2 patients (6 %). Complications occurred in 16 patients (48.5 %). Median hospital stay was 3 days (2–36). Unplanned readmission was required in 6 patients (18 %). In 18 patients, (55 %) additional surgical procedures were required within 6 months of LIVHR. In 5 patients, the enterotomy was recognized postoperatively. These patients had worst outcomes [mortality 40 %, additional surgical procedures were required in all patients (100 %) and median hospital stay was 12 days (range 7–36)]. Iatrogenic enterotomy is a serious complication during LIVHR. IE is associated with mortality, morbidity, additional surgical procedures, unplanned readmissions and prolonged hospital stay. In patients where IE was recognized postoperatively, the prognosis was worst.

Suprapubic hernias are considered difficult to repair laparoscopically due to deficient posterior rectus sheath and proximity to important neurovascular structures and the urinary bladder. We retrospectively reviewed 72 patients (18 males, 54 females) who, between 1998 and 2008, had undergone laparoscopic repair for suprapubic hernial defects located less than 5 cm from the pubic arch. Five patients (6.9%) had recurrent hernias. A peritoneal flap was dissected distally to facilitate a mesh overlap of at least 5 cm from the hernial defect. The lower margin of the mesh was fixed under direct vision to Cooper’s ligaments bilaterally. The raised peritoneal flap was reattached to the anterior abdominal wall thereby partially extraperitonealizing the mesh. Mean diameter of the hernial defect was 5.2 cm (range = 3.1–7.3 cm) as measured intraperitoneally. Mean size of the mesh used was 328.8 cm2 (range = 225–506 cm2). Mean operating time was 116 min (range = 64–170 min). Overall complication rate was 27.8%. There were no conversions. No recurrences were observed at a mean follow-up of 4.8 years (range = 1.2–6.9 years) and a follow-up rate of 84.7% A mesh overlap of at least 5 cm and fixation of the lower margin of the mesh under direct vision to Cooper’s ligaments appears to confer increased strength and durability and contribute to low hernia recurrence rates in patients with suprapubic hernias.

A few patients who continue to suffer antecedent symptoms following laparoscopic cholecystectomy (LC) may harbor residual gallstones. The incidence of residual gallstones following cholecystectomy is2.5%. Many of these patients require a completion cholecystectomy to ameliorate their symptoms.We reviewed our experience of laparoscopic re-intervention for residual gallstones over a period of 10 years from January 1998 to December 2007. Twenty six patients underwent Laparoscopic completion cholecystectomy (LCC) for residual gallstone disease. Twelve patients had a previous LC (2 patients - subtotal cholecystectomy) and 9 patients had a previous open cholecystectomy (7 patients - subtotal cholecystectomy). Five patients had previously undergone a cholecystostomy. Diagnostic investigations included abdominal ultrasound, endoscopic ultrasound (EUS), magnetic resonance cholangio-pancreatography (MRCP) and endoscopic retrograde cholangio-pancreatography (ERCP).Findings included a remnant gallbladder in 3 patients, long cystic duct stump with impacted stone in 18 patients and a contracted gallbladder in 5 patients. All procedures were successfully completed laparoscopically. The mean operative time was 62 minutes and mean blood loss 50cc. Ten patient required abdominal drains postoperatively. Two patients had bilious drainage lasting 9 days and 11 days respectively. One patient died a week following surgery of acute myocardial infarction. Another patient died 6 months later of unrelated causes. The remaining patients have remained symptom free at a mean follow up of 3.2 years (range 7 months to 9 years).The possibility of residual gallstones increases with subtotal cholecystectomy and inadequate dissection of the Calot's triangle in the presence of acute inflammation. Laparoscopic re-intervention for treating residual gallstone disease is feasible and can be safely performed in centers of expertise.

The purported advantage of lightweight large-pore meshes is improved biocompatibility that translates into lesser postoperative pain and earlier rehabilitation. However, there are concerns of increased hernia recurrence rate. We undertook a prospective randomized clinical trial to compare early and late outcome measures with the use of a lightweight (Ultrapro) mesh and heavyweight (Prolene) mesh in endoscopic totally extraperitoneal (TEP) groin hernia repair. A prospective study was performed on 402 patients (191 in Ultrapro and 211 in Prolene group) with bilateral groin hernias who underwent endoscopic TEP groin hernia repair from March 2006 to June 2007. All operations were performed by five consultants following a standardized operative protocol. Chronic groin pain and hernia recurrence were evaluated as primary outcome measures. Secondary outcome measure were early postoperative pain, operative time, number of fixation devices required to fix the mesh, return to normal daily activities of work, seroma, and testicular pain. At 1-year follow-up, incidence in Ultrapro versus Prolene group for chronic groin pain was 1.6% vs. 4.7% (p = 0.178) and recurrence was 1.3% vs. 0.2% (p = 0.078). In Ultrapro versus Prolene group, mean visual analogue score for postoperative pain at day 7 was 1.07 vs. 1.31 (p = 0.00), mean return to normal activities was 1.82 vs. 2.09 days (p = 0.00), and mean number of fixation devices per patient required to fix the mesh was 4.22 vs. 4.08 (p = 0.043). Lightweight meshes appear to have advantages in terms of lesser pain and early return to normal activity. However, more patients had hernia recurrence with lightweight meshes, especially for larger hernias. We surmise that the lightweight meshes have greater tendency to get displaced from their intended position during desufflation at the conclusion of endoscopic TEP repair.

The role of laparoscopy in the management of incarcerated (irreducible) ventral hernia remains to be elucidated. We present our experience of the laparoscopic repair of incarcerated primary ventral and incisional hernias over an 8-year period. A retrospective review of the records of 112 patients undergoing laparoscopic repair for incarcerated primary ventral and incisional hernias from January 1998 to February 2006 was performed. The patient demographics, perioperative data, and postoperative complications were assessed. The procedure was completed entirely laparoscopically in 103 patients (91.9%) with the placement of intraperitoneal mesh. A sutured tissue repair (without mesh) was performed in seven patients and hernia repair was abandoned after laparoscopy in two patients. Five patients required limited conversion by a targeted skin incision for the resection of nonviable bowel (three patients) and to complete adhesiolysis within multiloculated hernial sacs (two patients). The contents of the hernial sacs were incarcerated omentum (42 patients), small bowel (28 patients), large bowel (six patients), and omentum and small bowel (34 patients). Of these, seven patients presented with signs of acute small-bowel obstruction. The mean size of the largest defect through which incarceration occurred was 3.5 ± 1.6 cm (range 1.5–7.5 cm) and the mean size of the mesh used was 379 ± 210 cm2 (range 225–780 cm2). The mean operative time was 96 ± 40.8 min (range 50–170 min). Inadvertent enterotomy occurred in four patients during bowel reduction and adhesiolysis. In two patients, the enterotomy was repaired by total laparoscopy followed by mesh placement, and two patients required conversion to formal laparotomy due to long-segment tears and peritoneal contamination. The average postoperative hospital stay was 2.8 ± 1.5 days (range 1–6.5 days). Postoperative complications occurred in 20.5% patients. There was no mortality. Hernia recurred in three patients at a mean follow-up of 48 ± 28.3 months (range 1–84 months). Laparoscopic ventral abdominal wall hernia repair can be safely performed with a low complication rate, even in incarcerated hernias. Careful bowel reduction with adhesiolysis and mesh repair in an uncontaminated abdomen with a 5-cm mesh overlap remain key factors for a successful outcome.

During laparoscopic ventral/incisional hernia repair (LVIHR), conversion to conventional (open) technique is required when safe adhesiolysis is not possible, incarcerated bowel in hernial sac cannot be reduced or for repair of iatrogenic enterotomies. A formal laparotomy in these circumstances entails significant morbidity due to factors such as wound infection, prolonged immobility, and longer hospital stay. During a period between 1994 and 2007, 1,503 LVIHRs were performed at our centre following a standardized protocol by five consultants and fellows. Out of these, 6 patients had a formal laparotomy in the initial part of our experience and 26 patients had a limited conversion to facilitate completion of LVIHR. We have devised the term “limited conversion” for the procedure wherein bowel reduction/adhesiolysis/enterotomy repair was performed through a small targeted skin incision. This was followed by laparoscopic placement of intraperitoneal mesh. Conversion to an open procedure was required in 32 (2.1%) out of 1,503 LVIHR procedures. Twenty-six patients underwent a limited conversion and completion of the repair by laparoscopy. All but one of these patients had intraperitoneal placement of mesh by laparoscopic route. The wound complication rate was 3.8% (one patient), the mean hospital stay was 2.1 days, and mean operative time was 124 min. Limited conversion offers a safe alternative to a formal laparotomy in patients with bowel incarcerated in hernial sacs or in patients requiring extensive bowel adhesiolysis. Patient morbidity is reduced due to the targeted skin incision whilst retaining several advantages of a minimal access approach viz. laparoscopic evaluation of the entire abdominal wall and placement of a large intraperitoneal prosthesis.

Background The blood-brain barrier (BBB) is an obstacle for pharmacologists wishing to find treatments for patients with brain disorders. The BBB restricts the uptake of many valuable hydrophilic drugs and limits their efficacy because of the presence of tight junctions, a high metabolic capacity, low pinocytic vesicular traffic, and efficient efflux mechanisms.

The aim of the present study was to design a depot delivery system of acyclovir sodium using multivesicular liposomes (MVLs) to overcome the limitations of conventional therapies and to investigate its in vivo effectiveness for sustained delivery. MVLs of acyclovir were prepared by the reverse phase evaporation method. The loading efficiency of the MVLs (45%-82%) was found to be 3 to 6 times higher than conventional multilamellar vesicles (MLVs). The in vitro release of acyclovir from MVL formulations was found to be in a sustained manner and only 70% of drug was released in 96 hours, whereas conventional MLVs released 80% of drug in 16 hours. Following intradermal administration to Wistar rats, the MVL formulations showed effective plasma concentration for 48 hours compared with MLVs and free drug solution (12-16 hours). C(max) values of MVL formulations were significantly less (8.6-11.4 microg/mL) than MLV and free drug solution (12.5 microg/mL). The AUC(0-48) of the MVL formulations was 1.5- and 3-fold higher compared with conventional liposomes and free drug solution, respectively. Overall, formulations containing phosphatidyl glycerol as negatively charged lipid showed better results. The MVL delivery system as an intradermal depot offers the advantage of a very high loading and controlled release of acyclovir for an extended period of time. The increase in AUC and decrease in C(max) reflects that the MVL formulations could reduce the toxic complications and limitations of conventional iv and oral therapies.

Targeted drug delivery has gained recognition in modern therapeutics and attempts are being made to explore the potential of cell biology-related bioevents in the development of specific and target-oriented systems. In connection to modern therapeutic systems, most of the emphasis has been laid upon the bioconjugated drug delivery systems. Bioconjugates involve the linking of two or more molecules to form a novel complex having the combined properties of its individual components. The nature of the linking agent between the pharmacologic agent and the delivery-augmenting moiety dictates the degree of successful delivery and its outcome. The component for the bioconjugated drug delivery includes receptors and ligands, where the receptors act as molecular targets or portals whereas ligands with receptors provide selective and specific trafficking towards the targeting site. Recently, a number of bioconjugated systems have been discovered for the site-specific presentation and delivery of various bioactive substances using biorelevant ligands, including antibodies, glycoprotein, viral proteins, and molecules of endogenous origin. In this review, the potential of transferrin (Tf) and Tf conjugates of liposomes in site-specific drug delivery systems are discussed. Tf is an abundant component of serum with the capacity to bind and transport iron, while Tf receptor (TfR), a dimeric transmembrane glycoprotein, is present on the surface of the most proliferating, higher eukaryotic cells. Tf expression is also found in nonproliferating tissues, such as hepatocytes, tissue macrophages, pituitary cells, pancreatic islet cells, and the endothelium of brain capillaries. Tumor cells frequently carry elevated numbers of TfRs compared with corresponding normal cells, and reduced serum levels of Tf are often observed in patients with tumors. In the past, various strategies have been developed, which include coupling of the liposomal surface with Tf by using various linking agents. Low-molecular weight drugs and proteins as well as liposomes can be linked with Tf. The Tf-coupled vesicular system is physicochemically stable in the bioenvironment and is site-specific. The aim of coupling liposomes with Tf is to improve the physical and biochemical stability of liposomes and make them appropriate for targeting specific organs and cells. Tf may be widely applied either as a carrier or targeting ligand in the active targeting of anticancer agents, proteins, and genes to primarily proliferating malignant cells that overexpress TfRs. Tf has been used as a molecular conjugate to deliver DNA to erythroleukemic, lung, and liver cell lines. Tf can also be modified with the positive charge N-acylurea groups to make them suitable for electrostatic binding of DNA, in order to achieve a well defined DNA-binding ligand for receptor-mediated gene transfer. Association of Tf with lipoplexes, in particular the negatively charged ternary complexes, significantly overcomes the inhibitory effect of serum and facilitates efficient transfection in many cell lines, including HeLa, K-562 cells, and lung carcinoma cells Calu-3 and H-292 cells. Tf-lipoplex has demonstrated high efficiency in tumor-targeted gene delivery and long-term therapeutic accuracy in systemic p53 gene therapy for both human head and neck cancer and prostate cancer. Tf and Tf-coupled liposomal drug delivery systems may prove particularly valuable to enable the use of a drug that seems to be ineffective or toxic if delivered systematically. The delivery of drugs to the brain has been particularly challenging because of the presence of the blood-brain barrier, which restricts the passage of most therapeutic agents into the brain. Therefore, active targeting of the brain is crucial for effective treatment of brain diseases. The anti-TfR antibody, such as OX26, when coupled with therapeutic agents, has shown potential in drug and gene delivery to the brain.

Hepaticojejunostomy is performed to reestablish bilioenteric continuity. During a 5-year period between July 1998 and July 2003, the authors attempted hepaticojejunostomy by a total laparoscopic approach in 10 patients with benign stricture disorders of the extrahepatic biliary tree. Six of these patients had type 1 (extrahepatic, fusiform) choledochal cyst and presented with pain, fever, and jaundice. Four of the patients had iatrogenic biliary strictures after cholecystectomy (2 patients after laparoscopic cholecystectomy and 2 patients after open cholecystectomy). These patients had a variable presentation 1 to 3 weeks after the primary procedure, with peritonitis and/or cholangitis or only progressive jaundice. For nine of the patients (90%), the procedure was completed entirely laparoscopically. The mean operative time was 326.6 min for the patients with choledochal cysts and 268 min for the patients with iatrogenic strictures. One patient with stricture after open cholecystectomy underwent conversion to an open repair because of severe anatomic distortion and fibrosis. Four patients drained bile postoperatively for 5 to 7 days. One patient with iatrogenic biliary stricture after open cholecystectomy required open revision of the anastomosis 18 months after laparoscopic hepaticojejunostomy because of recurrent cholangitis. The remaining eight patients (80%) were doing well a mean follow-up period of 3.1 years (range, 3 months to 5 years). Total laparoscopic hepaticojejunostomy is feasible for a select group of patients, but requires advanced laparoscopic skills, including intracorporeal suturing. It must be attempted only in centers well versed in advanced laparoscopic surgery.