Linking: a dynamic electrophysiologic phenomenon in macroreentry circuits

The term "linking" has been used specifically to describe the mechanism for perpetuation of functional anterograde bundle branch block: namely, repetitive transseptal retrograde concealed penetration by impulses propagating along the contralateral bundle. We present selected examples that demonstrate tht linking-type phenomena actually have a wide spectrum of expression in human macroreentry circuits, particularly those incorporating either the bundle branches and His bundle or the normal pathway and Kent bundle. The examples presented are as follows: (1) persistent retrograde functional conduction delays in the His-Purkinje system during right ventricular pacing, (2) anterograde Kent bundle condution at rapid rates, dependent on prior block in the normal pathway, (3) persistent anterograde functional infra-His block of atrial impulses during rapid ventricular pacing in the presence of a retrogradely conducting accessory pathway, and (4) transient advancement of His activation with ventricular fusion complexes during overdrive ventricular pacing of bundle branch reentrant tachycardia. Based on these examples, we characterize linking as a generalized electrophysiologic phenomenon in which each successive impulse entering a macroreentry circuit propagates preferentially along one limb because of functional block in the contralateral limb resulting from the effects of the prior impulse. It is proposed that such functional block may be dynamically maintained either by repetitive impulse interference, which perpetuates local refractoriness (examples No. 1 to 3), or by repetitive impulse collision (example No. 4). The general conceptual scheme outlined can be applied to specific electrophysiologic phenomena associated with a wide variety of reentry circuits in man.     

Effects of Bovine Colostrum with or without Egg on In Vitro Bacterial-Induced Intestinal Damage with Relevance for SIBO and Infectious Diarrhea

Small intestinal bacterial overgrowth (SIBO) occurs commonly, is difficult to treat, and frequently recurs. Bovine colostrum (BC) and chicken eggs contain immunoglobulins and other components that possess antimicrobial, immunoregulatory, and growth factor activities; however, it is not known if they have the ability to reduce injury caused by the presence of bacteria associated with SIBO (Streptococcus, Escherichia coli, Staphylococcus, Bacteroides, Klebsiella, Enterococcus, and Proteus) and infectious diarrhea (enteropathogenic Escherichia coli, Salmonella). We examined the effects of BC, egg, or the combination, on bacterial growth and bacteria-induced changes in transepithelial electrical resistance (TEER) and bacterial translocation across confluent Caco-2 monolayers. BC, egg, or the combination did not affect bacterial growth. Adding bacteria to monolayers reduced TEER and (with minor variations among species) increased bacterial translocation, increased monolayer apoptosis (increased caspase-3 and Baxα, reduced Bcl2), increased intercellular adhesion molecule 1 (ICAM-1), and reduced cell adhesion molecules zonulin1 (ZO1) and claudin-1. BC, egg, or the combination reduced these effects (all p < 0.01) and caused additional increases in vascular endothelial growth factor (VEGF) and Heat Shock Protein 70 (Hsp70) expression. We conclude that BC ± egg strengthens mucosal integrity against a battery of bacteria relevant for SIBO and for infectious diarrhea. Oral BC ± egg may have clinical value for these conditions, especially SIBO where eradication of precipitating organisms may be difficult to achieve.     

Pakistan’s Response to COVID-19: Overcoming National and International Hypes to Fight the Pandemic

The COVID-19 outbreak started as pneumonia in December 2019 in Wuhan, China. The subsequent pandemic was declared as the sixth public health emergency of international concern on January 30, 2020, by the World Health Organization. Pakistan could be a potential hotspot for COVID-19 owing to its high population of 204.65 million and its struggling health care and economic systems. Pakistan was able to tackle the challenge with relatively mild repercussions. The present analysis has been conducted to highlight the situation of the disease in Pakistan in 2020 and the measures taken by various stakeholders coupled with support from the community to abate the risk of catastrophic spread of the virus.     

An Overview of the Treatment Options Used for the Management of COVID-19 in Pakistan: Retrospective Observational Study

BackgroundSince the first reports of COVID-19 infection, the foremost requirement has been to identify a treatment regimen that not only fights the causative agent but also controls the associated complications of the infection. Due to the time-consuming process of drug discovery, physicians have used readily available drugs and therapies for treatment of infections to minimize the death toll.ObjectiveThe aim of this study is to provide a snapshot analysis of the major drugs used in a cohort of 1562 Pakistani patients during the period from May to July 2020, when the first wave of COVID-19 peaked in Pakistan.MethodsA retrospective observational study was performed to provide an overview of the major drugs used in a cohort of 1562 patients with COVID-19 admitted to the four major tertiary-care hospitals in the Rawalpindi-Islamabad region of Pakistan during the peak of the first wave of COVID-19 in the country (May-July 2020).ResultsAntibiotics were the most common choice out of all the therapies employed, and they were used as first line of treatment for COVID-19. Azithromycin was the most prescribed drug for treatment. No monthly trend was observed in the choice of antibiotics, and these drugs appeared to be a random but favored choice throughout the months of the study. It was also noted that even antibiotics used for multidrug resistant infections were prescribed irrespective of the severity or progression of the infection. The results of the analysis are alarming, as this approach may lead to antibiotic resistance and complications in immunocompromised patients with COVID-19. A total of 1562 patients (1064 male, 68.1%, and 498 female, 31.9%) with a mean age of 47.35 years (SD 17.03) were included in the study. The highest frequency of patient hospitalizations occurred in June (846/1562, 54.2%).ConclusionsGuidelines for a targeted treatment regime are needed to control related complications and to limit the misuse of antibiotics in the management of COVID-19.     

Acute hyperthermia following stereotactic radiosurgery for pituitary adenoma

A 71-year-old male presented with a large pituitary adenoma with superior extension into the optic chiasm and suprasellar cistern. He was treated with stereotactic radiosurgery to a dose of 16 Gy. Approximately 1 h after radiosurgery he developed fever; his temperature peaked at 105.1 degrees F and normalized about 20 h later. This case demonstrates that acute hyperthermia is a potential complication following high dose stereotactic radiosurgery for large pituitary tumours.     

Volume fast spin-echo imaging of the cervical spine

RATIONALE AND OBJECTIVES: The authors prospectively evaluated a T2-weighted, three-dimensional (3D) volume, fast spin-echo (SE) pulse sequence in assessment of the cervical spine and compared it with standard imaging protocol. MATERIALS AND METHODS: Eighteen patients with neck pain underwent magnetic resonance (MR) imaging at 1.5 T with two-dimensional (2D) fast SE and axial 3D gradient-echo (GRE) protocols and with an additional sagittal T2-weighted volume fast SE protocol. The spinal cord and canal, neural foramina, and intervertebral disks were assessed by two neuroradiologists, and the results were compared with reports from the standard protocol. The quality of the partition (direct sagittal) and reconstructed images were evaluated. RESULTS: No differences existed in the assessment of spinal cord disease or disk herniation with 2D fast SE and volume fast SE imaging. Some mild variation occurred in assessment of the neural foramina. Partition images demonstrated a high level of resolution and contrast, while reconstructed images had consistently lower quality. However, this did not impede detection and grading of disk or spinal abnormalities, which were adequately shown on volume fast SE sagittal images. Neural foramina were well demonstrated on axial reconstructions from volume fast SE imaging. CONCLUSION: Volume fast SE imaging provides information about the spinal cord, canal, disks, and neural foramina that is comparable to the information provided by routine imaging. Its thinner sections and multiplanar reconstruction capability are advantages over 2D imaging. Its greater tissue contrast with better visualization of the cervical cord, greater signal-to-noise ratio, and less susceptibility artifact are advantages over 3D GRE imaging.     

Interactions of Phosphodiester and Phosphorothioate Oligonucleotides with Intestinal Epithelial Caco-2 Cells

Purpose. Oral bioavailability for antisense oligonucleotides has recently been reported but the mechanistic details are not known. The proposed oral delivery of nucleic acids will, therefore, require an understanding of the membrane binding interactions, cell uptake and transport of oligonucleotides across the human gastro-intestinal epithelium. In this initial study, we report on the cell-surface interactions of oligonucleotides with human intestinal cells. Methods. We have used the Caco-2 cell line as an in vitro model of the human intestinal epithelium to investigate the membrane binding interactions of 20-mer phosphodiester (PO) and phosphorothioate (PS) oligonucleotides. Results. The cellular association of both an internally [³H]-labelled and a 5end [³²P]-labelled PS oligonucleotide (3.0% at 0.4 µM extracellular concentration) was similar and was an order of magnitude greater than that of the 5end [³²P]-labelled PO oligonucleotide (0.2%) after 15 minutes incubation in these intestinal cells. The cellular association of PS was highly saturable with association being reduced to 0.9% at 5 µM whereas that of PO was less susceptible to competition (0.2% at 5 µM, 0.1% at 200 µM). Differential temperature-dependence was demonstrated; PS interactions were temperature-independent whereas the cellular association of PO decreased by 75% from 37°C to 17°C. Cell association of oligonucleotides was length and pH-dependent. A decrease in pH from 7.2 to 5.0 resulted in a 2- to 3-fold increase in cell-association for both backbone types. This enhanced association was not due to changes in lipophilicity as the octanol:aqueous buffer distribution coefficients remained constant over this pH range. The ability of NaCl washes to remove surface-bound PS oligonucleotides in a concentration-dependent manner suggests their binding may involve ionic interactions at the cell surface. Cell-surface washing with the proteolytic enzyme, Pronase^®, removed approximately 50% of the cell-associated oligonucleotide for both backbone types. Conclusions. Binding to surface proteins seems a major pathway for binding and internalization for both oligonucleotide chemistries and appear consistent with receptor (binding protein)-mediated endocytosis. Whether this binding protein-mediated entry of oligonucleotides can result in efficient transepithelial transport, however, requires further study.     

Fabrication and Characterization of Au-Decorated MCM-41 Mesoporous Spheres Using Laser-Ablation Technique

This study reports the synthesis of Au-decorated MCM-41 mesoporous nanoparticles using a laser-ablation technique. It was observed that the number of Au attached to MCM-41 nanostructures was dependent on the amount of encapsulated Cationic surfactant (cetyl ammonium bromide (CTAB) volume. The chemical group of the prepared nanoparticles was analyzed by FT-IR spectroscopy, where different absorption peaks corresponding to Au and MCM-41 were observed. The observed band region was ∼1090, 966, 801, 2918, and 1847 cm⁻¹ for different samples, clearly confirming the successful preparation of MCM-41 with CTAB and Au-decorated MCM-41 nanoparticles using environmentally friendly laser-ablation approach. The surface morphology of the prepared nanoparticles were performed using TEM techniques. The TEM analysis of the MCM-41 specimen showed silica spheres with an average size of around 200 nm. Furthermore, Raman spectroscopy was done to evaluate the chemical structure of the prepared nanoparticles. It was seen that the prepared Au NPs decorated the MCM-41 system facilitated strong Raman peaks of CTAB. In addition, eight distinct Raman peaks were observed in the presence of Au NPs. This new functionalized method using the laser-ablation approach for mesoporous nanoparticles will participate effectively in multiple applications, especially the encapsulated molecule sensing and detection.     

Eye bank versus surgeon prepared Descemet stripping automated endothelial keratoplasty tissues: Influence on adhesion force in a pilot study

Purpose:To evaluate and compare the biomechanical properties of the eye bank-prepared and surgeon prepared Descemet stripping automated endothelial keratoplasty (DSAEK) tissues.Methods:In this laboratory study, corneal tissues for research were randomly allocated in the following groups: a) surgeon-cut DSAEK and b) eye bank-prepared (pre-cut and pre-loaded) DSAEK. Endothelial cell loss (ECL), immunostaining for tight junction protein ZO-1, elastic modulus, and adhesion force were investigated.Results:ECL was not found to be significantly different between surgeon-cut DSAEK (7.8% ±6.5%), pre-cut DSAEK (8.6% ±2.3%), and pre-loaded DSAEK (11.1% ±4.8%) (P = 0.5910). ZO-1 was expressed equally across all groups. Surgeon-cut DSAEK grafts showed a significantly higher elastic modulus compared to pre-cut and pre-loaded DSAEK groups (P = 0.0047 and P < 0.0001, respectively). Adhesion force was significantly greater in the surgeon-cut DSAEK compared to pre-cut (P < 0.0001) or pre-loaded DSAEK groups (P = 0.0101).Conclusion:The laboratory data on the biomechanics of DSAEK grafts suggests that surgeon-cut DSAEK grafts present higher elastic modulus and adhesion force compared to eye bank-prepared DSAEK grafts.     

Exploring the anticancer activities of novel bioactive compounds derived from endophytic fungi: mechanisms of action,current challenges and future perspectives

Cancer is the second leading cause of death all around the world. The natural compounds derived from the endophytic flora of fungi are possible solutions to cancer treatment because they are safe for health, cost-effective, biocompatible and have fewer toxicity issues. The active ingredients in endophytic fungi that are responsible for anti-cancer activities are alkaloids, terpenoids, glycosides, saponin, peptides, steroids, phenols, quinones, and flavonoids. This review highlights the anti-cancer activities of entophytic fungus against human papillary thyroid carcinoma (IHH4), human pancreatic (PANC-1), ovarian (OVCAR-3), hepatic (HepG2), lung (A-549), human lymphoma (U937), human skin carcinoma (A431), breast (MCF-7), and Kaposi’s sarcoma. The emerging evidence suggested that bioactive compounds isolated from endophytic fungi showed their anti-cancer activities by revealing the disturbance of the microtubule network caused by increased levels of Bax and Bcl-2 proteins that triggers cell cycle arrest at the G2-M phase, by inhibiting the DNA replication via binding with topoisomerase II, by regulating the activity of extracellular signal-regulated kinase and NF-kB, by evaluating the levels of p21, p27, and cyclins B/D1/E that led to cell death by apoptosis and cell cycle arrest. This review will assist readers in better comprehending bioactive chemicals and the beneficial interaction between the fungal endophytes and medicinal plants.