Numerical simulation of nanoneedle-cell membrane collision: minimum magnetic force and initial kinetic energy for penetration.

Aims and objectives: This research aims to develop a kinetic model that accurately captures the dynamics of nanoparticle impact and penetration into cell membranes, specifically in magnetically-driven drug delivery. The primary objective is to determine the minimum initial kinetic energy and constant external magnetic force necessary for successful penetration of the cell membrane.Model Development: Built upon our previous research on quasi-static nanoneedle penetration, the current model development is based on continuum mechanics. The modeling approach incorporates a finite element method and explicit dynamic solver to accurately represent the rapid dynamics involved in the phenomenon. Within the model, the cell is modeled as an isotropic elastic shell with a hemiellipsoidal geometry and a thickness of 200 nm, reflecting the properties of the lipid membrane and actin cortex. The surrounding cytoplasm is treated as a fluid-like Eulerian body.Scenarios and Results: This study explores three distinct scenarios to investigate the penetration of nanoneedles into cell membranes. Firstly, we examine two scenarios in which the particles are solely subjected to either a constant external force or an initial velocity. Secondly, we explore a scenario that considers the combined effects of both parameters simultaneously. In each scenario, we analyze the critical values required to induce membrane puncture and present comprehensive diagrams illustrating the results.Findings and significance: The findings of this research provide valuable insights into the mechanics of nanoneedle penetration into cell membranes and offer guidelines for optimizing magnetically-driven drug delivery systems, supporting the design of efficient and targeted drug delivery strategies.

Understanding the impact: an investigation into the National Brain Injury Awareness Week and public interest regarding concussion in Australia.

OBJECTIVES: The purpose of this study is to analyze the relationship between the occurrence of the National Brain Injury Awareness Week and public interest in the concussion topic in Australia through an analysis of Internet search activity data from Google Trends. STUDY DESIGN: Online retrospective observational study. METHODS: For the keyword "concussion", the search interest rate over a period of 10 years between August 2012 and August 2022 within Australia has been analyzed using the Google Trends tool. The rising related topics that contributed to the months with the highest search interest were extracted for each year and a trendline analysis was performed to capture temporal patterns. RESULTS: There was a significant difference in the average search interest between the month of August, when the Brain Injury Awareness Week is annually held, and the rest of the year (d = 0.09, p = 0.017). Also, May and August were the two months with the overall highest search interests (mean ± SD: 73.3 ± 5.16 and mean ± SD: 70.1 ± 5.49, respectively). Trendline analysis showed a positive slope of 0.3081 with R2 = 0.4462 for search interests of concussion over the 10-year period. CONCLUSIONS: The data suggest that there is a growing interest and potential awareness of concussion in Australia that seems highly limited to the context of sports such as football, rugby, and soccer. Major sports events, news coverage, and media exposure appear to be associated with this trend. The study highlights the importance of more investment in producing engaging media content to educate the public on concussion of different causes and improving strategies for National Brain Injury Awareness Week.

Numerical investigation of force and deflection of nanoneedle penetration into cell using finite element approach: Parameter study and experimental validation of results.

This paper aims to develop a numerical methodology to investigate the penetration process of nanoneedles into cells and the corresponding force and indentation length. The finite element approach via the explicit dynamic method handles convergence difficulties in the nonlinear phenomenon. The cell is modeled as an isotropic elastic hemiellipsoidal shell with a thickness of 200 nm, which represents the lipid membrane and actin cortex, encapsulating cytoplasm that is regarded as an Eulerian body because of its fluid-type behavior. Nanoneedles with diameters 400, 200, and 50 nm are considered for model development based on available experimental data. The Von Mises strain failure criterion is used for rupture detection. A parameter study using 1, 2.5, 5, 7.5, and 10 kPa shows that Young's modulus of the HeLa cell membrane is about 5 kPa. Moreover, a failure strain of 1.2 chosen among 0.2, 0.4, 0.6, 0.8, 1, and 1.2 matches best the experimental data. In addition, a diameter study shows that the relations between force-diameter and indentation length-diameter are linear and polynomial, respectively. Furthermore, regarding the experimental data and by using contour of minimum principal stress around needle and an analytical equation for calculation of buckling force of a woven fabric, we proposed that for a given cell, membrane structural stability-a function of the coupled effect of Young's modulus and actin meshwork size-contributes directly to needle insertion success rate for that type of cell.

Comparative in vitro activity of carbapenems against clinical isolates of Acinetobacter baumannii.

AIMS: The aim of this multi-hospital study was to assess the in vitro activity of doripenem and its comparators, imipenem and meropenem, using the new CLSI breakpoints against a large population of a frequently isolated nosocomial pathogen, Acinetobacter baumannii. METHODS AND RESULTS: During a 2-year period, four referral or tertiary hospitals submitted 400 isolates of Ac. baumannii for susceptibility testing using imipenem, meropenem and doripenem via disc diffusion and E-test methods. A subset of 390 isolates was resistant to all three tested carbapenems. Doripenem and meropenem (MIC50 , 32 µg ml(-1) ) had comparable activity, albeit doripenem's activity was greater than imipenem (MIC50 , >32 µg ml(-1) ). A significantly higher proportion of the isolates were inhibited by doripenem than by imipenem at MIC values of 12, 16, 24 and 32 µg ml(-1) (P < 0·05). The cumulative percentage of imipenem MICs was lower compared to its comparators. The comparison of resistance rate to imipenem and meropenem based on old and new breakpoints showed <1% difference. The overall agreement between the two susceptibility testing methods was ≥95%. CONCLUSION: Doripenem has a slightly greater in vitro activity than imipenem in terms of zone breakpoints and MIC values, but its activity is comparable to meropenem. SIGNIFICANCE AND IMPACT OF THE STUDY: Doripenem should be considered as a therapeutic option for monotherapy or combination therapy, particularly when the therapeutic options are limited.

Tumour Necrosis Factor-alpha (TNF-α) and its soluble receptor type 1 (sTNFR I) in human active and healed leishmaniases.

The role of tumour necrosis factor-alpha (TNF-α) is not fully understood in human leishmaniasis. We analysed the alterations in the levels of TNF-α, soluble TNF receptor type 1 (sTNFR I), IL-17 and IL-22 productions in active and healed leishmaniases. Blood samples were collected from volunteers with active cutaneous leishmaniasis (ACL), the same subjects after lesion healing (healed CL = HCL), volunteers with active visceral leishmaniasis (AVL), healed VL (HVL) and healthy controls. Levels of cytokines were titrated on Leishmania Ag-stimulated PBMC culture. The mean level of TNF-α production from stimulated cells was significantly higher in ACL than controls (P < 0·001) and significantly reduced after treatment in HCL volunteers (P < 0·05). The mean level of sTNFR I production was significantly higher in ACL than controls (P < 0·001) and significantly reduced after treatment in HCL volunteers (P < 0·05). The mean level of IL-22 production in AVL was significantly higher than controls (P < 0·05) and was significantly lower in HVL compared with AVL (P < 0·001) and controls (P < 0·05). The levels of TNF-α (P = 0·0025) and sTNFR I (P < 0·01) productions from PBMCs showed significant decreasing trend after treatment in each CL volunteer. Reduction in TNF-α is associated with clinical response to treatment and healing of CL lesions due to L. major.

Plasma levels of tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor type 1 (sTNFR I) and IL-22 in human leishmaniasis.

The role of pro-inammatory cytokine tumor necrosis factor-alpha (TNF-α) in human leishmaniasis is not fully understood. We analyzed the alterations in the plasma levels of TNF- α, soluble TNF receptor type 1 (sTNFR I), IL-17 and IL-22 in the volunteers with leishmaniasis. Blood samples were collected from patients with active cutaneous leishmaniasis (CL), the same CL patients after standard antimonial therapy as healed CL, active visceral leishmaniasis (VL) and healed VL volunteers. Levels of the cytokines were titrated on plasma samples by sandwich ELISA method. The mean level of TNF-α was significantly higher in active CL patients than healthy controls (P<0.001) and significantly reduced after treatment in the same volunteers (P<0.001). The mean level of sTNFR I was significantly higher in active CL patients than healthy controls (P<0.05). The mean level of IL-22 in plasma of the AVL patients was significantly higher than that of healthy control group (P<0.05). There is a negative correlation between the levels of TNF-α and sTNFR I and healing of CL. Measurement of cytokines in plasma samples is more feasible than cell culture in evaluation of immune response in human leishmaniasis.

Effects of Rotational Motion in Robotic Needle Insertion.

BACKGROUND: Robotic needle insertion in biological tissues has been known as one the most applicable procedures in sampling, robotic injection and different medical therapies and operations. OBJECTIVE: In this paper, we would like to investigate the effects of angular velocity in soft tissue insertion procedure by considering force-displacement diagram. Non-homogenous camel liver can be exploited as a tissue sample under standard compression test with Zwick/Roell device employing 1-D axial load-cell. METHODS: Effects of rotational motion were studied by running needle insertion experiments in 5, 50 and 200 mm/min in two types of with or without rotational velocity of 50, 150 and 300 rpm. On further steps with deeper penetrations, friction force of the insertion procedure in needle shaft was acquired by a definite thickness of the tissue. RESULTS: Designed mechanism of fixture for providing different frequencies of rotational motion is available in this work. Results for comparison of different force graphs were also provided. CONCLUSION: Derived force-displacement graphs showed a significant difference between two procedures; however, tissue bleeding and disorganized micro-structure would be among unavoidable results.

Plasma levels of tumor necrosis factor-alpha (TNF-α), TNF-α soluble receptor type 1 (sTNFR I) and IL-22 in human leishmaniasis

The role of pro-inammatory cytokine tumor necrosis factor-alpha (TNF-α) in human leishmaniasis is not fully understood. We analyzed the alterations in the plasma levels of TNF- α, soluble TNF receptor type 1 (sTNFR I), IL-17 and IL-22 in the volunteers with leishmaniasis. Blood samples were collected from patients with active cutaneous leishmaniasis (CL), the same CL patients after standard antimonial therapy as healed CL, active visceral leishmaniasis (VL) and healed VL volunteers. Levels of the cytokines were titrated on plasma samples by sandwich ELISA method. The mean level of TNF-α was significantly higher in active CL patients than healthy controls (P<0.001) and significantly reduced after treatment in the same volunteers (P<0.001). The mean level of sTNFR I was significantly higher in active CL patients than healthy controls (P<0.05). The mean level of IL-22 in plasma of the AVL patients was significantly higher than that of healthy control group (P<0.05). There is a negative correlation between the levels of TNF-α and sTNFR I and healing of CL. Measurement of cytokines in plasma samples is more feasible than cell culture in evaluation of immune response in human leishmaniasis.

Isospora belli associated recurrent diarrhea in a child with AIDS.

Persistent diarrhea is a major manifestation of Acquired Immunodeficiency Syndrome (AIDS) which might be more complicated in Human Immunodeficiency Virus (HIV) infected children especially those from developing countries. There are numerous reports showing the emergence of intestinal opportunistic coccidian parasites, mostly Cryptosporidium parvum and Isospora belli in HIV-infected individuals. The prevalence of isosporiasis is probably underestimated in developing countries because routinely not all HIV-infected patients are examined for the presence of this protozoan infection. Here we report a case of HIV-infected isosporiasis presenting with failure to thrive and persistent diarrhea. Since I. belli infection in children responds well to therapy with trimethoprim-sulfamethoxazole, isosporiasis should be considered as a treatable infection in AIDS, if it is detected at proper time.

Synthesis and characterization of folate-targeted dextran/retinoic acid micelles for doxorubicin delivery in acute leukemia.

Folate and retinoic acid grafted/dextran (FA-RA/DEX) copolymers with different molecular weight of DEX were synthesized using carbonyldiimidazole and dimethylaminopyridine for targeted delivery of doxorubicin (DOX) in acute myelogenous leukemia (AML). The copolymers structure was confirmed by (1)H NMR and FTIR. Critical micelle concentration (CMC) of each copolymer was determined using pyrene as a fluorescent probe. DOX was loaded in micelles by the direct dissolution method. Physical properties of micelles, including particle size, zeta potential, drug loading efficiency, and drug release profiles, were examined. The orientation of the folate ligand on the surface of the micelles was studied by X-ray photoelectron spectroscopy (XPS) technique. The cytotoxicity of micelles loaded with DOX at different concentrations was studied in KG1 cells using MTT assay and their cellular uptake by flow cytometry technique. FTIR and (1)H NMR spectra confirmed successful production of the targeted micelles and XPS spectra showed the surface orientation of folate. R15D10F7 copolymer produced micelles with particle size of 82.86 nm, polydispersity index of 0.3, zeta potential of -4.68 mV, drug loading efficiency of 96%, and release efficiency of 63%. DOX loaded in folate-targeted micelles of RA/DEX was more toxic than that in nontargeted micelles and free drug and seems promising in reducing drug resistance in AML.

Hyperoside and anthocyanin content of ten different pomegranate cultivars.

Pomegranate (Punica granatum L.) is native to the Mediterranean region and has been used extensively as a medicine in many counties. Hyperoside is known as an important flavonoid with antioxidant activity and anti hypertension effect. Anthocyanins are the active component in several herbal medicines, thus accurate measurement of hyperoside and anthocyanins, along with their degradation indices, is very useful to food technologists and horticulturists. The aim of the current study was to determine the antioxidant capacity as hyperoside and anthocyanin content of ten different Iranian pomegranate cultivars. Spectroscopic analyses of the pomegranate showed Black peel cultivar had the highest hyperoside content (25.93 +/- 2.87, 620.41 +/- 30.32 mg/100 g) in its pulp and peel, respectively. Based on this study, the amounts of anthocyanin in pulp ranged between 1.56 +/- 0.05 and 3.89 +/- 0.07 mg g(-1) which related to Sweet white peel and Sweet alac cultivars, respectively. More over the highest and also the lowest peel anthocyanin contents related to these cultivars. The results revealed that the hyperoside and also anthocyanin peel content of each variety is higher than its pulp content. In addition the potency of black peel (Medicinal pomegranate) and Sweet alac cultivars for prevention of coronary heart disease and hypertension were presented.

Synthesis and antioxidant evaluation of 4-(furan-2-yl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate esters.

Biginelli-type pyrimidines contain an interesting moiety which has attracted considerable attention of medicinal chemists in the last few decades. Despite the very diverse pharmacologic effects ascribed to this kind of pyrimidines, there are few reports on the antioxidant evaluation of Biginelli pyrimidines. In this study synthesis of some novel Biginelli-type pyrimidines is reported. The prepared compounds are ester derivatives of 6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate with a simple hetaryl group, furan, at C-4 position of the pyrimidine ring. These compounds were evaluated for free radical and H(2)O(2) scavenging activities. The reducing power of these compounds was also determined. Compound 3c was the most potent one in diphenyl picrylhydrazine scavenging activity assay with the IC(50) of 0.6 mg/ml. The results of reducing power assays proved that 3d and 3e are moderate reducing agents. All of the studied compounds were very weak in scavenging hydrogen peroxide compared with gallic acid.

Synthesis and antioxidant evaluation of some novel ortho-hydroxypyridine-4-one iron chelators.

A series of ortho-hydroxypyridine-4-ones were prepared in high yields and evaluated for antioxidant and iron chelating activities. N(1)-H hydroxypyridinones Va, Vb, and Ve were the best radical scavengers in DPPH free radical scavenging assay. Compound Vb was proved to be the most potent compound in hydrogen peroxide scavenging assay. All of the synthesized compounds had very close chelating ability, compounds containing N(1)-CH3 hydroxypyridinone ring were stronger chelating agents.

Immune response of BALB/c mice against an experimental vaccine of Alum precipitated autoclaved Leishmania major (Alum-ALM) mixed with BCG or Mycobacterium vaccae.

Immune response in BALB/c mice immunized 3 times with different doses (50 µg or 200 µg of protein) of Alum precipitated autoclaved Leishmania major (Alum-ALM) mixed with either BCG (1x10(7); CFU) or different doses of killed Mycobacterium vaccae (1x10(6), 1x10(7)) was assessed. Mice immunized with low dose of Alum-ALM mixed with either BCG or low M. vaccae showed a significantly higher IFN-gamma production and a lower IL-4 level and a significantly lower parasite burden compared to the control PBS injected group. It seems that immunization with a low dose of Alum-ALM mixed with an adjuvant induces a Th1 type of immune response in susceptible BALB/c mice.

Differential in vitro CD4+/CD8+ T-cell response to live vs. killed Leishmania major.

Clinical trials of killed Leishmania vaccines showed a limited efficacy compared with leishmanization (LZ). The reason for this difference in protection against cutaneous leishmaniasis (CL) is not known and in vivo studies on T-cell function may provide valuable information. Nevertheless, there are limited studies on the nature of the stimulatory effects of live vs. killed parasites on human T cells in vitro. A total of nine Leishmanin Skin Test+ volunteers with a history of self-healing CL (HCL) and seven healthy volunteers were included in this study. 5,6-carboxyfluroescein diacetate succinimidyl ester-labelled CD4(+)/CD8(+) lymphocytes were cultured with killed Leishmania Lysate (Killed LL) or live Leishmania major (Live LM) and analysed for proliferation using flow cytometry. Culture supernatants were used for cytokine titration. In HCL volunteers, upon stimulation with killed LL, the number of proliferated CD4(+)/CD8(+) cells was significantly more than that of unstimulated (P < 0.001) or live LM stimulated (P < 0.05) cells, or cells from controls (CD4(+)/CD8(+): P < 0.05/P < 0.001). Stimulation of CD4(+) cells with Live LM (P < 0.001) or Killed LL (P < 0.05) induced a significantly higher IFN-gamma production compared with that of controls, but Live LM induced significantly (P < 0.05) more IFN-gamma than Killed LL. A significantly (P < 0.05) higher IFN-gamma production was observed when CD8(+) cells were stimulated with Live LM. Cells from HCL volunteers showed significantly more IL-10 production to Live LM stimulation compared with that of controls (CD4(+): P < 0.05 /CD8(+): P < 0.001) or cells stimulated with Killed LL (CD4(+)/CD8(+): P < 0.001/P < 0.0005). Whereas Killed LL induced more proliferation response in purified T cells, Live LM induced cytokine production without significant induction of proliferation. The results from healed CL volunteers in this study could be implicated in further studies on T-cell response in vaccinated individuals.

Modelling the interaction of ankle-foot orthosis and foot by finite element methods to design an optimized sole in steppage gait.

In this study, based on kinematics data in steppage gait, a finite element model of human gait with ankle-foot orthosis (AFO) has been proposed to optimize the role of AFO through minimizing stress in the patients' sole. The required kinetics data for the model were captured through a force plate and then analysed by 3D-DOCTOR and ANSYS software. In the proposed three-dimensional finite element model the transmitted tension in soft tissue and bones during gait was calculated. By changing the thickness and materials of different layers of sole in AFO the tension variations have been assessed. Unlike previous studies, the effect of orthosis on tension generated in bones and muscles has been dynamically and continuously modelled and the contact between AFO and sole has been considered in this model. By using the optimized sole the stress distribution has been changed by +50.38% in the forefoot, +15% in the midfoot and -37.79% in the hindfoot. The tension reduction in the sole can improve the effect of AFO during abnormal gait. It is possible to design each orthosis sole based on the kinetics data of each patient.

Immune response of BALB/c mice against an experimental vaccine of Alum precipitated autoclaved Leishmania major (Alum-ALM) mixed with BCG or Mycobacterium vaccae

Immune response in BALB/c mice immunized 3 times with different doses (50 mug or 200 mug of protein) of Alum precipitated autoclaved Leishmania major (Alum-ALM) mixed with either BCG (1 x10(7); CFU) or different doses of killed Mycobacterium vaccae (1 x10(6), 1 x10(7)) was assessed. Mice immunized with low dose of Alum-ALM mixed with either BCG or low M. vaccae showed a significantly higher IFN-gamma production and a lower IL-4 level and a significantly lower parasite burden compared to the control PBS injected group. It seems that immunization with a low dose of Alum-ALM mixed with an adjuvant induces a Th1 type of immune response in susceptible BALB/c mice.

Modelling of human walking to optimise the function of ankle-foot orthosis in Guillan-Barré patients with drop foot.

INTRODUCTION: This paper deals with the dynamic modelling of human walking. The main focus of this research was to optimise the function of the orthosis in patients with neuropathic feet, based on the kinematics data from different categories of neuropathic patients. METHODS: The patient's body on the sagittal plane was modelled for calculating the torques generated in joints. The kinematics data required for mathematical modelling of the patients were obtained from the films of patients captured by high speed camera, and then the films were analysed through a motion analysis software. An inverse dynamic model was used for estimating the spring coefficient. RESULTS: In our dynamic model, the role of muscles was substituted by adding a spring-damper between the shank and ankle that could compensate for their weakness by designing ankle-foot orthoses based on the kinematics data obtained from the patients. The torque generated in the ankle was varied by changing the spring constant. Therefore, it was possible to decrease the torque generated in muscles which could lead to the design of more comfortable and efficient orthoses. CONCLUSION: In this research, unlike previous research activities, instead of studying the abnormal gait or modelling the ankle-foot orthosis separately, the function of the ankle-foot orthosis on the abnormal gait has been quantitatively improved through a correction of the torque.

Safety assessments of agricultural machinery in Iran.

Serious agriculture-related accidents are increasing in Iran, and this has come to the attention of authorities and planners. Due to the lack of data for this region of the world, research was conducted in different states of Iran to assess the most common causes of agriculture-related injuries. The relevant factors were divided into the three groups: personal, mechanical, and environmental. The major personal factors were education level, age, experience, injured limb, hospitalization period, gender, injury level, training, working hours, and insurance. The mechanical factors were machine type, machine part, mechanism of injury, machine's effective life, work activity at the time of injury, safety equipment, and insurance. The environmental factors were time of incident, geographical conditions of the accident location, and the time lapse between the accident and arrival at the hospital. The interactions between the various factors were also analyzed. All data were collected directly from farmers or their relatives. Data collection efforts were led by an official from the nearest health center or the local government agricultural office. The results indicated that 53% of injuries were related to personal factors, and 40% were related to the combination of personal and mechanical factors. The results confirmed that tractors and rotating parts were associated with the highest percentage of injuries in machine-related accidents. Lack of safety equipment and working beyond effective machine life was also observed in most cases. Personal factors need to be carefully considered in this region; insufficient levels of education and training were the main personal factors related to agricultural accidents. The results suggest that experience without training does not prevent injury, as more than 80% of injuries occurred to individuals with no training. Statistical analysis confirmed a significant effect of safety equipment and training on injuries. This study showed that agricultural injuries were severe in 60% of cases.