Stress fractures of the foot - current evidence on management.

Stress fractures are a consequence of repeated submaximal loads with inadequate time for recovery and biologic repair or remodelling. The foot and ankle complex (FAC) represents a common site for development of stress fractures. Whilst the overall incidence of stress fractures is low, they are prevalent in athletes and military personnel causing significant time away from sports or work. Within these populations, certain stress fractures directly correlate to specific activities. Factors that commonly influence these fractures include an acute increase in new repetitive physical activity combined with muscle fatigue, training errors or improper athletic techniques, which challenge the regenerative and remodelling capacity of bone. Depending on the site that is subject to repetitive loading, various biomechanical factors can result in abnormal concentration of forces to specific areas of the FAC resulting in stress fracture. Decreased bone marrow density (BMD) is a major biologic cause for developing stress fractures. The female athlete triad comprising eating disorder, amenorrhea and osteoporosis in competitive athletes also predisposes to stress fractures. Vitamin D deficiency is also postulated to be the cause of these fractures and may contribute to poor healing. Clinical presentation is usually with vague pain of insidious onset which worsens with activity and improves with rest. Diffuse tenderness over the affected bone is common with only a minority having any visible swelling. Plain radiographs are the first line of investigation but rarely reveal an obvious fracture. MRI scans aid in diagnosis and CT scans help in treatment and characterisation of the fracture and monitor healing. Management relates to the site of injury, which stratifies them into high or low-risk. Stress fractures of the calcaneus, cuboid and cuneiforms are classed as low-risk fractures as they usually heal with simple activity modification or short duration of non-weight bearing. Stress fractures of the navicular, talus and hallucal sesamoids are classed as high-risk fractures due to higher rates of non-union and prolonged recovery time. Metatarsal fractures can be considered high or low-risk depending on location. These warrant aggressive management, often requiring surgical intervention. Adjuncts such as vitamin D supplements, external shockwave therapy, low-intensity pulsed ultrasound therapy have been used with varying success but there remains little supportive evidence of superiority in the available literature.

Identification of unique indolylcyanoethylenyl sulfonylanilines as novel structural scaffolds of potential antibacterial agents.

The increasing incidence of antibiotic resistance has forced the development of unique antimicrobials with novel multitargeting mechanisms to combat infectious diseases caused by multidrug-resistant pathogens. Structurally unique indolylcyanoethylenyl sulfonylanilines (ISs) were exploited as novel promising antibacterial agents to confront stubborn drug resistance. Some prepared ISs possessed favorable bacteriostatic action towards the tested bacteria. Especially, hydroxyethyl IS 14a exerted 8-fold more potent inhibitory efficacy against multidrug-resistant A. baumannii and E. coli 25922 with the low MIC of 0.5 µg/mL than norfloxacin, and showed low cell toxicity and rapid bactericidal property. Moreover, this compound also possessed obvious effect of eradicating bacterial biofilm, which could effectually relieve the development of drug resistance. A preliminary assessment of the antibacterial mechanism indicated that compound 14a could disintegrate membrane integrity leading to the leakage of intracellular protein, inactivation of lactate dehydrogenase and metabolism inhibition. Hydroxyethyl IS 14a mediated the accumulation of excess reactive oxygen species, which further contributed to reducing glutathione, resulting in oxidative damage to bacteria. Furthermore, IS 14a could intercalate into DNA to hinder the biological function of DNA. Quantum chemical study disclosed that IS 14a with the lowest energy gap was conducive to displaying high bioactivity. These findings demonstrated that hydroxyethyl IS 14a as a prospective antimicrobial candidate for combating A. baumannii and E. coli 25922 would be a promising starting point.

Effects of Food Source Availability, Host Egg:Parasitoid Ratios, and Host Exposure Times on the Developmental Biology of Megacopta cribraria Egg Parasitoids.

Parasitoids forage for hosts in dynamic ecosystems and generally have a short period of time to access hosts. The current study examined the optimal reproductive attributes of two egg parasitoids, Paratelenomus saccharalis Dodd (Hymenoptera: Platygastridae) and Ooencyrtus nezarae Ishii (Hymenoptera: Encyrtidae), of the kudzu bug, Megacopta cribraria Fabricius (Hemiptera: Plataspidae). The proportion of O. nezarae and P. saccharalis adult offspring that emerged from M. cribraria eggs and the sex ratio of the parasitoid offspring were compared among treatments for the effects of different adult parasitoid food sources, host egg-to-adult parasitoid ratios, and host exposure times. Our results suggest that honey solution as a food source, a 21:7 host-to-parasitoid ratio, and three-to-five days of exposure time optimized the production of female O. nezarae offspring. For P. saccharalis, honey solution as a food source, a 21:7 host-to-parasitoid ratio, and one day were optimal for maximizing female offspring production. These findings provide new information about the biology of these egg parasitoids.

Tibial Intramedullary Nailing by Suprapatellar Approach: Is It Quicker and Safer?

Background With the increasingly accepted method of suprapatellar tibial nailing for tibial shaft fractures, we aimed to compare intraoperative and postoperative outcomes of infrapatellar (IP) vs suprapatellar (SP) tibial nails. Methods This is a retrospective cohort analysis of 34 SP tibial nails over three years vs 24 IP tibial nails over a similar time frame. We compared total radiation dose (TRD), patient positioning time (PPT), fracture healing and follow up time. Knee pain in the SP group was evaluated utilising the Hospital for Special Surgery (HSS) Knee Injury and Osteoarthritis Outcome Score (KOOS). Results Fifty-eight patients with a mean age of 43 years were included. Mean intraoperative radiation dose for SP nails was 61.78 cGy (range: 11.60-156.01 cGy) vs 121.09 cGy (range: 58.01-18.03 cGy) for IP nails (p < 0.05). Mean PPT for SP nails was 10 minutes vs 18 minutes for IP nails (p < 0.05). All fractures united in the SP group vs one non-union in the IP group. Mean follow up was 5.5 months vs 11 months in the IP and SP groups, respectively. Mean KOOS was 7 (range: 0-22) at six months for the SP group. Conclusion The semi-extended position (SP group) leads to reduced TRD because of ease of imaging. Patients showed improved outcomes with shorter follow up and fracture union in all patients (SP group). The KOOS revealed that SP nail patients had minimal pain and good knee function. This study establishes a management and patient-reported outcome measures (PROMs) baseline for ongoing evaluation of SP nails.

Kudzu Bug (Megacopta cribraria) and Associated Egg Parasitoids Emergence Rates in Alabama are Predicted by Weather Indices.

The kudzu bug, Megacopta cribraria (Fabricius) (Hemiptera: Plataspidae), is a major economic pest of soybean in the southeastern United States. With climate warming, this pest is expected to move northward and cause additional crop damage. Parasitoid biocontrol is a potential method of integrated pest management for kudzu bug. Two species of egg parasitoid wasps have been observed emerging from kudzu bug egg masses in the southeastern United States: Paratelenomus saccharalis (Dodd) (Hymenoptera: Platygastridae) and Ooencyrtus nezarae (Ishii) (Hymenoptera: Encyrtidae). This paper used egg mass emergence data collected between 2018 and 2020 in Alabama soybean fields and compared the data to weather indices. Indices included the number of days with minimum temperatures below zero, accumulated rainfall (mm m-2), as well as species specific metrics of accumulated growing degree days, accumulated daily minimum temperature (°C), and accumulated daily maximum temperature (°C). Emergence of the generalist parasitoid, O. nezarae, was highly correlated with kudzu bug nymph abundance, accumulated degree day, accumulated daily temperatures, and precipitation. Ooencyrtus nezarae emergence was predicted in a stepwise regression equation by aggregated degree day and date of collection, which indicates that seasonality may be a predictor of its presence. In contrast, collections of the specialist parasitoid, P. saccharalis, were near-zero throughout the collection period, suggesting that this species may no longer be a usable biocontrol agent in the southeastern United States as a result of external limiting factors.

Aloe emodin-conjugated sulfonyl hydrazones as novel type of antibacterial modulators against S. aureus 25923 through multifaceted synergistic effects.

Aloe emodin-conjugated sulfonyl hydrazones were designed and synthesized as novel type of antibacterial modulators. Aloe emodin benzenesulfonyl hydrazone 5a (AEBH-5a) was preponderant for the treatment of S. aureus 25923 (MIC = 0.5 µg/mL) over norfloxacin and presented high selectivity between bacterial membranes and mammalian membranes. Especially, AEBH-5a could eliminate the formed biofilms and relieve the development of S. aureus 25923 resistance. The antibacterial mechanism of AEBH-5a from extracellularity to intracellularity illustrated that AEBH-5a could destroy bacterial membrane integrity, leading to the leakage of protein and nucleic acid. Besides, AEBH-5a could not only interact with DNA and induce oxidative stress but also inhibit lactate dehydrogenase (LDH) activity as well as render metabolic inactivation. In silico ADME studies prediction of AEBH-5a revealed a favorable bioavailability score and prominent drug-likeness profile. This research showed that the multifaceted synergistic effect initiated by aloe emodin-conjugated sulfonyl hydrazones is a reasonable and effective tactic to combat menacing bacterial infections.

Natural aloe emodin-hybridized sulfonamide aminophosphates as novel potential membrane-perturbing and DNA-intercalating agents against Enterococcus faecalis.

The dramatic rise in drug resistance accelerated the desire for new antibacterial agents to safeguard human health. This work constructed a novel type of aloe emodin-hybridized sulfonamide aminophosphates as unique potential antibacterial agents. The biological assay revealed that some target hybrids possessed potent inhibitory activity. Particularly, ethyl aminophosphate-hybridized sulfadiazine aloe emodin 7a (EASA-7a) not only displayed preponderant antibacterial efficiency against drug-resistant E. faecalis at low concentration as 0.25 µg/mL but also possessed strong bacteriostatic capacity and low propensity to develop resistance toward E. faecalis. The weak hemolysis toward human red blood cells and efficient biofilm-disruptive ability further implied the therapeutic potential of EASA-7a. Preliminary studies disclosed that the excellent antibacterial behavior of EASA-7a might be attributed to its capacity to permeate and depolarize the bacterial membrane, as well as promote ROS accumulation and intercalate with DNA. These findings manifested that EASA-7a was worthy of further development to combat life-threatening bacterial infections.

Characterization of Competitive Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.

Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is an enticing antimalarial drug target. Novel chemotypes are needed because existing inhibitors have safety issues that may prevent further development. This work demonstrates isoxazole-based compounds are potent ATP competitive inhibitors of PfPKG and discloses a new analogue in this series. Isoxazoles 3 and 5 had Ki values that are comparable to a known standard, 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H pyrrol-3-yl] pyridine. They also exhibited excellent selectivity for PfPKG over the human orthologue and the gatekeeper mutant T618Q PfPKG, which mimics the less accessible binding site of the human orthologue. The human orthologue's larger binding site volume is predicted to explain the selectivity of the inhibitors for the P. falciparum enzyme.

Direct and Indirect Competitive Interactions between Ooencyrtus nezarae and Paratelenomus saccharalis Parasitizing Megacopta cribraria Egg Patches.

The present study investigated egg parasitoid interspecific interactions between a generalist, Ooencyrtus nezarae Ishii (Hymenoptera: Encyrtidae) and a specialist, Paratelenomus saccharalis Dodd (Hymenoptera: Platygastridae) in a laboratory setting using kudzu bug (Megacopta cribraria Fabricius, (Hemiptera: Plataspidae)) eggs as their shared host. Three experiments were conducted to evaluate the emergence of wasps from parasitized hosts after the simultaneous and sequential release of wasps, monitor aggressive behavior of P. saccharalis, and quantify intraguild predation of O. nezarae larvae on heterospecific P. saccharalis larvae. Results showed that total host egg parasitism was higher when both wasps were released simultaneously than if wasps were released sequentially. Ooencyrtus nezarae produced more total offspring than P. saccharalis in all sequential/simultaneous treatments but produced male offspring in most cases. In the aggressive behavioral experiment, specialist, P. saccharalis used head butting to fight O. nezarae, but no other aggressions were observed. In an experiment examining intraguild predation, O. nezarae was able to develop in host eggs parasitized by P. saccharalis four days earlier, acting as a superior larval competitor. These findings shed light on the potential interspecific interactions between O. nezarae and P. saccharalis, which may determine their relative abundance and influence their compatibility in kudzu bug biological control programs.

Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.

The discovery of new targets for the treatment of malaria, in particular those aimed at the pre-erythrocytic stage in the life cycle, advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusiasm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, this paper presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity against multiple Plasmodium species that appears to be correlated with the in vitro potency.

A facile reaction to access novel structural sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents.

A novel type of sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents was constructed via the unique ring-opened reaction of oxiranes by imidazoles for the first time. Some developed target hybrids showed potential antimicrobial potency against the tested microbes. Especially, imidazole derivative 5f could strongly suppressed the growth of MRSA (MIC = 4 µg/mL), which was 2-fold and 16-fold more potent than the positive control sulfathiazole and norfloxacin. This compound exhibited quite low propensity to induce bacterial resistance. Antibacterial mechanism exploration indicated that compound 5f could embed in MRSA DNA to form steady 5f-DNA complex, which possibly hinder DNA replication to exert antimicrobial behavior. Molecular docking showed that molecule 5f could bind with dihydrofolate synthetase through hydrogen bonds. These results implied that imidazole derivative 5f could be served as a promising molecule for the exploration of novel antibacterial candidates.

Potential antibacterial ethanol-bridged purine azole hybrids as dual-targeting inhibitors of MRSA.

A new class of antibacterial ethanol-bridged purine azole hybrids as potential dual-targeting inhibitors was developed. Bioactivity evaluation showed that some of the target compounds had prominent antibacterial activity against the tested bacteria, notably, metronidazole hybrid 3a displayed significant inhibitory activity against MRSA (MIC = 6 µM), and had no obvious toxicity on normal mammalian cells (RAW 264.7). In addition, compound 3a also did not induce drug resistance of MRSA obviously, even after fifteen passages. Molecular modeling studies showed that the highly active molecule 3a could insert into the base pairs of topoisomerase IA-DNA as well as topoisomerase IV-DNA through hydrogen bonding. Furthermore, a preliminary study on the antibacterial mechanism revealed that the active molecule 3a could rupture the bacterial membrane of MRSA and insert into MRSA DNA to block its replication, thus possibly exhibiting strong antibacterial activity. These results strongly indicated that the highly active hybrid 3a could be used as a potential dual-targeting inhibitor of MRSA for further development of valuable antimicrobials.

Novel chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids as potential antibacterial repressors against methicillin-resistant Staphylococcus aureus.

The increasing resistance of methicillin-resistant Staphylococcus aureus (MRSA) to antibiotics has led to a growing effort to design and synthesize novel structural candidates of chalcone-conjugated, multi-flexible end-group coumarin thiazole hybrids with outstanding bacteriostatic potential. Bioactivity screening showed that hybrid 5i, which was modified with methoxybenzene, exerted a significant inhibitory activity against MRSA (MIC = 0.004 mM), which was 6 times better than the anti-MRSA activity of the reference drug norfloxacin (MIC = 0.025 mM). Compound 5i neither conferred apparent resistance onto MRSA strains even after multiple passages nor triggered evident toxicity to human hepatocyte LO2 cells and normal mammalian cells (RAW 264.7). Molecular docking showed that highly active molecule 5i might bind to DNA gyrase by forming stable hydrogen bonds. In addition, molecular electrostatic potential surfaces were developed to explain the high antibacterial activity of the target compounds. Furthermore, preliminary mechanism studies suggested that hybrid 5i could disrupt the bacterial membrane of MRSA and insert itself into MRSA DNA to impede its replication, thus possibly becoming a potential antibacterial repressor against MRSA.

Identification of aplysinopsin as a blood-brain barrier permeable scaffold for anti-cholinesterase and anti-BACE-1 activity.

Aplysinopsins are a group of marine-derived indole alkaloids that display diverse array of pharmacological effects. However, their effect on anti-Alzheimer targets has not been reported. Herein, we report the synthesis of aplysinopsin (1) and its effect on cholinesterases and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1). It inhibits electric eel acetylcholinesterase (AChE), equine serum butyrylcholinesterase (BChE), and human BACE-1 with IC50 values of 33.9, 30.3, and 33.7 µM, respectively, and excellent BBB permeability (Pe 8.92 × 10-6 cm/s). To optimize its sub-micromolar activity, the first-generation analogs were prepared and screened. Two most active analogs 5b and (Z)-8g were found to effectively permeate the BBB (Pe > 5 × 10-6 cm/s). The N-sulphonamide derivative 5b display better cholinesterase inhibition, whereas the other analog (Z)-8g strongly inhibits BACE-1 (IC50 0.78 µM) activity. The analog 5b interacts primarily with PAS of AChE, and thus exhibit a mixed-type of inhibition. In addition, aplysinopsin along with new analogs inhibited the self-induced Aß1-42 aggregation. The data presented herein indicate that the aplysinopsin-scaffold holds a potential for further investigation as a multi-targeted anti-Alzheimer agent.

Novel Schiff base-bridged multi-component sulfonamide imidazole hybrids as potentially highly selective DNA-targeting membrane active repressors against methicillin-resistant Staphylococcus aureus.

A new type of Schiff base-bridged multi-component sulfonamide imidazole hybrids with antimicrobial potential was developed. Some target compounds showed significant antibacterial potency. Observably, butylene hybrids 4h exhibited remarkable inhibitory efficacy against clinical MRSA (MIC = 1 µg/mL), but had no significant toxic effect on normal mammalian cells (RAW 264.7). The highly active molecule 4h was revealed by molecular modeling study that it could insert into the base-pairs of DNA hexamer duplex and bind with the ASN-62 residue of human carbonic anhydrase isozyme II through hydrogen bonding. Furthermore, further preliminary antibacterial mechanism experiments confirmed that compound 4h could effectively interfere with MRSA membrane and insert into bacterial DNA isolated from clinical MRSA strains through non-covalent bonding to produce a supramolecular complex, thus exerting its strong antibacterial efficacy by impeding DNA replication. These findings strongly implied that the highly active hybrid 4h could be used as a potential DNA-targeting template for the development of valuable antimicrobial agent.

An unexpected discovery toward novel membrane active sulfonyl thiazoles as potential MRSA DNA intercalators.

Aim: With the increasing emergence of drug-resistant bacteria, the need for new antimicrobial agents has become extremely urgent. This work was to develop sulfonyl thiazoles as potential antibacterial agents. Results & methodology: Novel hybrids of sulfonyl thiazoles were developed from commercial acetanilide and acetylthiazole. Hybrids 6e and 6f displayed excellent inhibitory efficacy against clinical methicillin-resistant Staphylococcus aureus (MRSA) (minimum inhibitory concentration = 1 µg/ml) without obvious toxicity toward normal mammalian cells (RAW 264.7). The combination uses were found to improve the antimicrobial ability. Further preliminary antibacterial mechanism experiments showed that the active molecule 6f could effectively interfere with MRSA membrane and insert into MRSA DNA. Conclusion: Compounds 6e and 6f could serve as potential DNA-targeting templates toward the development of promising antimicrobial agents.

Design and biological evaluation of a novel type of potential multi-targeting antimicrobial sulfanilamide hybrids in combination of pyrimidine and azoles.

This work explored a novel type of potential multi-targeting antimicrobial three-component sulfanilamide hybrids in combination of pyrimidine and azoles. The hybridized target molecules were characterized by 1H NMR, 13C NMR and HRMS spectra. Some of the developed target compounds exerted promising antimicrobial activity in comparison with the reference drugs norfloxacin and fluconazole. Noticeably, sulfanilamide hybrid 5c with pyrimidine and indole could effectively inhibit the growth of E. faecalis with MIC value of 1 µg/mL. The active molecule 5c showed low cell toxicity and did not obviously trigger the development of resistance towards the tested bacteria strains. Mechanism exploration indicated that compound 5c could not only exert efficient membrane permeability, but also intercalate into DNA of resistant E. faecalis to form 5c-DNA supramolecular complex, which might be responsible for its antimicrobial action. The further investigation showed that this molecule could be effectively transported by human serum albumins through hydrogen bonds and van der Waals force.

Isoform-Selective PI3K Inhibitors for Various Diseases.

Phosphoinositide 3-kinases (PI3Ks) are a family of ubiquitously distributed lipid kinases that control a wide variety of intracellular signaling pathways. Over the years, PI3K has emerged as an attractive target for the development of novel pharmaceuticals to treat cancer and various other diseases. In the last five years, four of the PI3K inhibitors viz. Idelalisib, Copanlisib, Duvelisib, and Alpelisib were approved by the FDA for the treatment of different types of cancer and several other PI3K inhibitors are currently under active clinical development. So far clinical candidates are non-selective kinase inhibitors with various off-target liabilities due to cross-reactivities. Hence, there is a need for the discovery of isoform-selective inhibitors with improved efficacy and fewer side-effects. The development of isoform-selective inhibitors is essential to reveal the unique functions of each isoform and its corresponding therapeutic potential. Although the clinical effect and relative benefit of pan and isoformselective inhibition will ultimately be determined, with the development of drug resistance and the demand for next-generation inhibitors, it will continue to be of great significance to understand the potential mechanism of isoform-selectivity. Because of the important role of type I PI3K family members in various pathophysiological processes, isoform-selective PI3K inhibitors may ultimately have considerable efficacy in a wide range of human diseases. This review summarizes the progress of isoformselective PI3K inhibitors in preclinical and early clinical studies for anticancer and other various diseases.