Maternal and neonatal characteristics, operative details and outcomes in COVID-19 positive parturients undergoing cesarean sections: A retrospective observational study.

Background and Aims: There is a marked inclination towards cesarean sections as the preferred mode of delivery in parturients with COVID-19 disease. However, the challenges associated with planning and performing a surgery in the COVID-19 setup are considerable. These factors may lead to widespread changes in obstetric decision-making, operative planning, and perioperative outcomes. Thus, our study aimed to study the clinical and logistical factors involved in cesarean sections in COVID-19 parturients. Material and Methods: This was a retrospective observational study performed at a dedicated COVID-19 tertiary care center in India. All women undergoing cesarean section in the specially earmarked operating room between 1st May 2020 and 31st December 2020 were included in the study. The clinical characteristics, operative details, and neonatal details, along with maternal and fetal outcomes were noted and analyzed. Results: A total of 44 women underwent cesarean section during the study period, with elective and emergency surgeries numbering 22 each. No indication, apart from COVID-19 status, was listed in over one-fourth of the women (13/44). The most common preoperative comorbidity was hypothyroidism (12/44). Median surgical duration was 117.5 min (IQR 100-133), with a median of 7.5 (IQR 6-8.25) healthcare personnel in the OT. Over one-fourth (12/44) of the delivered babies had low birth weight, while 4.5% (2/44) tested positive for SARS-CoV-2. Conclusion: COVID-19 status alone continues to be a common indication for cesarean section. Operative time is increased, but the number of healthcare personnel involved can be trimmed with proper planning. Maternal and fetal outcomes are largely positive, with low transmission rates, but a considerable proportion of low-birth-weight neonates.

The effect of age and sex on esophageal hiatal surface area among normal North American adults using multidetector computed tomography.

The size of the esophageal hiatus is clinically important for preserving the integrity of the lower esophageal sphincter mechanism. The purpose of this study was to systematically establish the mean hiatal surface area (HSA) for normal North American adults under physiologic conditions and assess the relationship between sex and age on HSA. Multi-Detector Computer Tomogram (MDCT) images of the esophageal hiatus in 119 healthy adult subjects (61 males and 58 females with an age range of 24-88 years) were retrospectively analyzed using the multi-planar reconstruction (MPR) technique to directly measure their hiatal length (long axis), width (short axis) and surface area at end inspiration. The mean HSA for males was 2.88 cm2, with a standard deviation of 0.74 cm2. The mean HSA for females was 2.51 cm2, with a standard deviation of 0.68 cm2. There was a statistically significant difference in HSA between males and females (p = 0.0053); however, there was no statistically significant difference between the HSA among different age groups (p = 0.8439). Similarly, significant differences between males and females were demonstrated in both the length (p = 0.0263) and width (p = 0.0311) measurements, but there was no evidence of an association of these parameters with age. For the first time, the normal size of the hiatus at end inspiration has been established noninvasively for a population of healthy adults from MDCT images.

Potential of pigment epithelium-derived factor (PEDF) as a bone regenerative biopharmaceutical.

Bone is very much a dynamic tissue, capable of various functions not limited to protection of the marrow, serving as a reservoir for calcium, maintaining posture and facilitating mobility. It is also a tissue that is fully capable of regenerating itself at most stages of life, with a diminishing capacity with increasing age. Bone defects can arise from a variety of factors not limited to bone tumours and fractures. At present, clinically, most diseased bone is removed and the patient fitted with prosthetics, with use of certain factors such as bone morphogenetic proteins (BMPs) to aid healing. Recently, the protein pigment epithelium-derived factor (PEDF) has been found to have favourable effects on bone regeneration, which is reviewed here. Numerous studies have shown the potential of PEDF in vitro, with increasing reports of success in small animal models of bone trauma. This review puts forward the advantages, and some disadvantages, in the use of PEDF as a biopharmaceutical for bone regeneration.

Effect of preoperative flupirtine on postoperative morphine sparing in patients undergoing total abdominal hysterectomy.

BACKGROUND: Flupirtine is a unique non-opioid, centrally acting analgesic with muscle relaxant properties. So far no study has evaluated, use of preoperative flupirtine on postoperative morphine sparing effect in patients undergoing total abdominal hysterectomy (TAH). MATERIALS AND METHODS: We performed a prospective, controlled, and randomized study in 50 female patients of American Society of Anesthesiologists physical status I-II, aged between 30 and 60 years scheduled for TAH under general anesthesia (GA). Patients were randomized to receive either single dose flupirtine 100 mg or placebo 1 h prior to surgery. A standard anesthetic and analgesic protocol was followed in both the groups. Postoperatively, a titrated loading dose of intravenous morphine 0.1 mg/kg was followed with patient-controlled analgesia with morphine (bolus of 0.01 mg/kg with a lockout time of 7 min). The primary outcome was cumulative morphine consumption at 48 h postoperatively. Secondary outcomes included hemodynamics, visual analog scale (VAS) at rest, VAS on cough, and any adverse effects. RESULTS: All enrolled 50 patients completed the follow-up. The cumulative mean morphine consumption (standard deviation [SD]) at 48 h (40.4 [6.0] vs. 47 [6.6] mg, P = 0.001) was reduced in-group flupirtine as compared with placebo. The cumulative mean VAS at rest (SD) (3 [0.7] vs. 3.7 [0.7], P = 0.001) and on cough (3 [0.9] vs. 3.8 [0.5], P = 0.002) were reduced in-group flupirtine as compared with placebo at 48 h postoperatively. CONCLUSION: Preoperative use of flupirtine exhibited morphine sparing effect in patients following TAH under GA at 48 h.

Treatment of bone disorders with parathyroid hormone: success and pitfalls.

Bone diseases such as osteoporosis, osteoarthritis, bone tumours and bone fractures are rather common and not just in the elderly. Parathyroid hormone (PTH) is responsible for maintaining calcium homeostasis, increasing bone mineral density (BMD), increasing cortical and trabecular bone thickness and thus increasing bone strength. Teriparatide (PTH 1-34) has the same effects as endogenous PTH and is pharmacologically used to treat bone diseases such as osteoporosis, osteoarthritis, bone fractures and bone tumours. This review discusses how PTH 1-34 plays a role in managing bone diseases. Clinical studies have shown that short or intermittent dosing of PTH 1-34 has minimal adverse effects, while long-term dosing (over two years) has been linked to de novo osteoarthritis and bone deformation. Currently PTH therapy is only approved in the treatment of post-menopausal osteoporosis, however it is also proven to have effects in treating osteoarthritis, bone tumours and bone fractures. If the patient undergoing therapy is closely monitored, the major pitfalls are very unlikely to take place, thus it is highly recommended that patients be closely monitored by a medical practitioner.

Reduction in tumour cell invasion by pigment epithelium-derived factor is mediated by membrane type-1 matrix metalloproteinase downregulation.

Prostate cancer and breast cancer are major killers among males and females respectively. In this study, pigment epithelium-derived factor (PEDF) was examined for its effect on commonly used human prostate cancer and human breast cancer cell lines. PEDF increased adhesion of cells to collagen-I, with decreased expression of phosphorylated focal adhesion kinase (p-Fak) consistent between the two cell types. Invasion of both tumour cell types through collagen-I was also reduced by PEDF, with decreased expression of membrane type-1 matrix metalloproteinase (MT1-MMP). These results were confirmed with specific antibodies to MT-MMP1. This study provides some vital clues as to which molecular players are perturbed by PEDF treatment of human prostate and breast cancer cells, raising hope that PEDF can in future be trialled against these major cancers in attempts to procure safer yet effective therapies for cancer.

Systemically administered PEDF against primary and secondary tumours in a clinically relevant osteosarcoma model.

BACKGROUND: Pigment epithelium-derived factor (PEDF) is an endogenous glycoprotein with a potential role as a therapeutic for osteosarcoma. Animal studies have demonstrated the biological effects of PEDF on osteosarcoma; however, these results are difficult to extrapolate for human use due to the chosen study design and drug delivery methods. METHODS: In this study we have attempted to replicate the human presentation and treatment of osteosarcoma using a murine orthotopic model of osteosarcoma. The effects of PEDF on osteosarcoma cell lines were evaluated in vitro prior to animal experimentation. Orthotopic tumours were induced by intra-tibial injection of SaOS-2 osteosarcoma cells. Treatment with PEDF was delayed until after the macroscopic appearance of primary tumours. Pigment epithelium-derived factor was administered systemically via an implanted intraperitoneal micro-osmotic pump. RESULTS: In vitro, PEDF inhibited proliferation, induced apoptosis and inhibited cell cycling of osteosarcoma cells. Pigment epithelium-derived factor promoted adhesion to Collagen I and inhibited invasion through Collagen I. In vivo, treatment with PEDF caused a reduction in both primary tumour volume and burden of pulmonary metastases. Systemic administration of PEDF did not cause toxic effects on normal tissues. CONCLUSION: Systemically delivered PEDF is effective in suppressing the size of primary and secondary tumours in an orthotopic murine model of osteosarcoma.

The pathophysiological role of PEDF in bone diseases.

First discovered in 1991 as a factor secreted by retinal pigment epithelial cells, the potency of pigment epithelium derived factor (PEDF) as an anti-angiogenic has led to examination of its role in active bone growth, repair and remodelling. In the musculoskeletal system, PEDF expression occurs particularly at sites of active bone formation. Expression has been noted in osteoblasts and to a lesser degree osteoclasts, the major classes of bone cells. In fact, PEDF is capable of inducing differentiation of precursor cells into mature osteoblasts. Expression and localisation are closely linked with that of vascular endothelial growth factor (VEGF). Studies at the epiphyseal plate have revealed that PEDF expression plays a key role in endochondral ossification, and beyond this may account for the epiphyseal plate's innate ability to resist neoplastic cell invasion. Collagen-1, the major protein in bone, is avidly bound by PEDF, implicating an important role played by this protein on PEDF function, possibly through MMP-2 and -9 activity. Surprisingly, the role of PEDF has not been evaluated more widely in bone disorders, so the challenge ahead lies in a more diverse evaluation of PEDF in various osteologic pathologies including osteoarthritis and fracture healing.

Delivery of nanoparticulate drug delivery systems via the intravenous route for cancer gene therapy.

While the systemic route of administration enables therapeutic genes to spread through the bloodstream and access target cells, it is a challenge to achieve this. Several studies demonstrate that systemic administration of therapeutic genes or other nucleic acid-based constructs such as siRNA to solid tumors as well as cancer metastases are better with nanoparticulate systems compared to administration of free (uncomplexed) nucleic acids. Nanoparticle-based nucleic acid delivery systems might be more pertinent, due to the several privileges in terms of enhanced tissue penetrability, improved cellular uptake and to a lesser extent, targeted gene delivery to the cells of interest provided targeting ligands are used. Systemic delivery of nanoplexes has already been reported with different nanoparticles containing DNA via various routes of administration. The goal of the present article is to review the current state of intravenous delivery of nanoparticles for gene therapy of cancer.

Recent developments in liposomes, microparticles and nanoparticles for protein and peptide drug delivery.

Proteins and peptides are increasingly recognized as potential leads for the development of new therapeutics for a variety of human ailments. Due to their relatively specific mode of action, proteins and peptides can be administered at relatively low doses for therapeutic effects. As natural biological products, these low doses reduce the risk otherwise caused by other small molecular drugs or larger charged molecules. Unfortunately, their therapeutic potential and clinical application is frequently hampered by various obstacles to their successful delivery. This review discusses the recent developments in the fields of liposome, microparticle and nanoparticle pertinent to protein and peptide delivery covering those systems tested and/or validated in vivo.

Development of chondrosarcoma animal models for assessment of adjuvant therapy.

Chondrosarcoma is a primary cancer of bone causing significant morbidity due to local recurrence and limited treatment options. Relatively few chondrosarcoma animal models have been developed, and the only orthotopic model is technically demanding and has limited clinical relevance. The aim of this review is to assess the features of current animal chondrosarcoma models for the purpose of developing new models in which to test adjuvant chondrosarcoma therapy. The available literature on this topic was identified using the PubMed database, and then analysed for relevance to the human chondrosarcoma disease and feasibility in testing new therapeutic agents. Animal-derived chondrosarcoma models comprise predominantly allograft tumour transplanted into the rat (Swarm rat chondrosarcoma) or the hamster. These types of models are less relevant to the human disease and have been more useful for evaluation of chondrosarcoma growth and histology than in developing novel therapeutic agents. The athymic nude mouse has enabled reliable human xenograft transplantation. A number of human chondrosarcoma cell lines have been successfully used to generate tumours in this species, including OUMS-27 and HCS-2/A. Although effective in demonstrating anti-tumour effects of a number of agents, the lack of a representative orthotopic model diminishes overall clinical relevance. More clinically relevant models of human chondrosarcoma progression are required either through transgenic mice or orthotopic human xenograft models.

Current and future treatments of bone metastases.

Bone metastases contribute to a significant degree of morbidity in patients with common cancers through the development of skeletal related events (SRE) such as bone pain and pathological fracture. Traditional therapy has relied on surgical removal of lesions and, with the advent of adjuvant therapies, has been combined with radiotherapy, chemotherapy, and more recently osteoclast inhibiting agents like bisphosphonates. Although these therapeutic combinations can achieve a degree of local control, and rarely cure, across the vast majority of metastatic cancers they provide only palliation. Newer molecular agents currently under investigation, combined with innovations in surgery and radiation therapy offer a more targeted approach to bone metastasis. These utilise our understanding of key steps in the metastatic cascade including chemotactic attraction to bone, secretion of proteases, the cancer supporting microenvironment of bone matrix and the RANK-RANKL interaction for osteoclast activation. Direct inhibition of metastasis progression and osteolysis with less reliance on cytotoxic agents and invasive therapy should result in improved metastatic control, longer survival and less overall morbidity.

C-jun: pharmaceutical target for DNAzyme therapy of multiple pathologies.

Recent studies have demonstrated the potential of DNAzymes for therapy of various diseases via mRNA target-specific cleavage. One such target, the basic region-leucine zipper protein c-Jun, has been targeted and efficacy seen in such pathologies as cancer, ocular neovascularisation, arterial thickening, acute inflammation, and rheumatoid arthritis. This review discusses these cases in turn, and presents some new data on the applicability of a c-jun DNAzyme against a panel of cancer cells. Importantly, downregulation of c-jun is noted to cause apoptotic death of cancer cells. These studies collectively demonstrate the potential of this DNAzyme as a lead candidate for DNAzyme therapeutics.

Pigment epithelium-derived factor (PEDF): drug developmental challenges ahead for a budding anti-angiogenic.

One of the most potent anti-angiogenic biological discovered to date, pigment epithelium-derived factor (PEDF) is fast becoming an exciting and promising lead candidate. Recent studies have shown that even shortened versions of the protein can serve as therapeutic agents with similar activity as the parent molecule. The next obvious challenge is to find ways to deliver this molecule in vivo with enhanced pharmacodynamics and reduced toxicity. Several methods to achieve this are proposed.

Angiogenesis inhibitors and the need for anti-angiogenic therapeutics.

Angiogenesis is the formation of new blood vessels from pre-existing vessels to form capillary networks, which, among other diseases, such as diabetic retinopathy and macular degeneration, is particularly important for tumor growth and metastasis. Thus, depriving a tumor of its vascular supply by means of anti-angiogenic agents has been of great interest since its proposal in the 1970s. This review looks at the common angiogenic inhibitors (angiostatin, endostatin, maspin, pigment epithelium-derived factor, bevacizumab and other monoclonal antibodies, and zoledronic acid) and their current status in clinical trials.

Pigment epithelium-derived factor overexpression inhibits orthotopic osteosarcoma growth, angiogenesis and metastasis.

Despite significant improvements, the current management of primary osteosarcoma is still limited by the development of metastatic disease, which occurs in approximately 30% of patients despite aggressive multiagent chemotherapy and tumor-ablative surgery. Therefore, there is a need for the development of novel agents to improve the outcome of these patients. Pigment epithelium-derived factor (PEDF) has been shown to be one of the most potent inhibitors of angiogenesis, and more recently has demonstrated a functional role in tumor growth, invasion and metastasis. In this study we report, for the first time, the multitargeted role of PEDF in the inhibition of growth, angiogenesis and metastasis of two orthotopic models of osteosarcoma (rat UMR 106-01 and human SaOS-2). Through stable plasmid-mediated gene transfer of full-length human PEDF, we show that PEDF overexpression significantly reduced tumor cell proliferation (P<0.05) and Matrigel invasion (UMR(PEDF), P<0.001; SaOS(PEDF), P<0.05) and increased adhesion to collagen type-1 (P<0.01), in vitro. In vivo, PEDF overexpression dramatically suppressed orthotopic osteosarcoma growth (P<0.05) and the development of spontaneous pulmonary metastases (UMR(PEDF), P<0.05; SaOS(PEDF), P<0.001). Furthermore, PEDF-overexpressing tumors exhibited reduced intratumoral angiogenesis, evidenced by a significant decrease in microvessel density (P<0.05). Therefore, together these results suggest that PEDF may be a new and promising approach for the treatment of osteosarcoma.

Enhanced in vivo tumour response from combination of carboplatin and low-dose c-myc antisense oligonucleotides.

BACKGROUND: Phosphorothioate oligonucleotides ([S]ODNs) contain a modified phosphate backbone. Antisense [S]ODNs targeted to specific oncogenes have been used to varying success in vivo. Carboplatin is a commonly used chemotherapeutic and is associated with chemoresistance in some human tumours. The potential for combined antisense [S]ODNs and carboplatin chemotherapy has only recently been explored in vivo. MATERIALS AND METHODS: This study examines the effect of c-myc antisense oligomers delivered in isolation as naked DNA and in combination with carboplatin upon the growth kinetics of an in vivo transplantable adenocarcinoma using rodents. RESULTS: Tumours treated with a combination of 600 microg of 15-mer c-myc phosphorothioate antisense oligodeoxyribonucleotide and an intravenous administration of carboplatin (3 mg/kg), demonstrated a significant (p<0.05) retardation in tumour growth kinetics relative to a control. Two mismatch antisense controls did not significantly inhibit tumour growth. C-myc protein studies in tumour sections failed to show significant differences in c-myc expression in any of the treated tumours. CONCLUSION: This study demonstrates that carboplatin affects the relative abundance of c-myc and that combination treatment of carboplatin and c-myc phosphorothioate antisense oligonucleotides in vivo results in synergistic tumour retardation.

Immunostimulatory activity of cationic-lipid-nucleic-acid complexes against cancer.

Recent studies have highlighted the immunostimulatory nature of nucleic acids and the enhancement of such immunostimulation when nucleic acids are complexed to cationic liposomes to form cationic-lipid-nucleic-acid-complexes or lipoplexes. While such immunostimulation may have deleterious consequences for nucleic acid delivery, especially in the field of gene therapy, it may be harnessed for efficacious usage against the various forms of cancer.

Conformational changes in beta-endorphin as studied by electrospray ionization mass spectrometry.

Because of a wide range of physiological functions, the structure of beta-endorphin (BE) is of great interest. In this study, conformational changes in BE induced by methanol are explored with electrospray ionization-mass spectrometry (ESI-MS). Differences in the charge-state distribution (CSD) and the extent of hydrogen/deuterium (H/D) exchange were used to monitor the conformational changes. The latter experiments were conducted via time-resolved ESI-MS in a continuous-flow apparatus. Both these techniques demonstrate that BE exists in a random coil open structure in aqueous media, but it acquires a more compact conformation with increased concentration of methanol. The H/D exchange experiments reveal that BE forms 61% alpha-helix in mixed solvents.

Particle-mediated intravascular delivery of oligonucleotides to tumors: associated biology and lessons from genotherapy.

For a solid tumor to become life-threatening, an adequate blood supply has to be established. Although neovascularization has dire consequences for the host, it furnishes a common route through which tumors may be accessed and eradicated by drugs. The fact that a tumor's vasculature is relatively more permeable than that of healthy host tissue means selective delivery of drugs may be achieved. The role played by the cells making up the tumor vascular bed, vascular endothelial cells (VECs), has to be evaluated closely in attempts to design ways for enhancing drug delivery to solid tumors via the vasculature. The two major roles of VECs in the body, as barrier and as transport, are both highly pertinent to drug delivery. Our review examines how VECs may be manipulated in vivo to improve the selective delivery of carriers for oligonucleotide constructs to solid tumors. It also discusses how oligonucleotide drugs may be targeted against tumor VECs on the premise that by killing these cells, the tumor itself will perish. Cationic liposomes and microspheres are the major delivery vehicles discussed, with added analyses of such other nucleic acid carriers as nanospheres, dendrimers, and polyethyleneimine.