Enhancing cell separation in a hybrid spiral dielectrophoretic microchannel: Numerical insights and optimal operating conditions.

Reliable separation of circulating tumor cells from blood cells is crucial for early cancer diagnosis and prognosis. Many conventional microfluidic platforms take advantage of the size difference between particles for their separation, which renders them impractical for sorting overlapping-sized cells. To address this concern, a hybrid inertial-dielectrophoretic microfluidic chip is proposed in this work for continuous and single-stage separation of lung cancer cell line A549 cells from white blood cells of overlapping size. The working mechanism of the proposed spiral microchannel embedded with planar interdigitated electrodes is validated against the experimental results. A numerical investigation is carried out over a range of flow conditions and electric field intensity to determine the separation efficiency and migration characteristics of the cell mixture. The results demonstrate the unique capability of the proposed microchannel to achieve high-throughput separation of cells at low applied voltages in both vertical and lateral directions. A significant lateral separation distance between the CTCs and the WBCs has been achieved, which allows for high-resolution and effective separation of cells. The separation resolution can be controlled by adjusting the strength of the applied electric field. Furthermore, the results demonstrate that the lateral separation distance is maximum at a voltage termed the critical voltage, which increases with the increase in the flow rate. The proposed microchannel and the developed technique can provide valuable insight into the development of a tunable and robust medical device for effective and high-throughput separation of cancer cells from the WBCs.

Separation of CTCs from WBCs using DEP-assisted inertial manipulation: A numerical study.

Isolation and detection of circulating tumor cells (CTCs) hold significant importance for the early diagnosis of cancer and the assessment of therapeutic strategies. However, the scarcity of CTCs among peripheral blood cells presents a major challenge to their detection. Additionally, a similar size range between CTCs and white blood cells (WBCs) makes conventional microfluidic platforms inadequate for the isolation of CTCs. To overcome these challenges, in this study, a novel inertial-dielectrophoretic microfluidic channel for size-independent, single-stage separation of CTCs from WBCs has been presented. The proposed device utilizes a spiral microchannel embedded with interdigitated electrodes. A numerical model is developed and validated to investigate the influence of various parameters related to the channel design, fluid flow, and electrode configuration. It was found that optimal separation of CTCs could be obtained at a relatively low voltage, termed the critical voltage. Furthermore, at the critical voltage of 7.5 V, the hybrid microchannel is demonstrated to be capable of separating CTCs from different WBC subtypes including granulocytes, monocytes, T-, and B-lymphocytes. The unique capabilities of the hybrid spiral microchannel allow for this size-independent isolation of CTCs from a mixture of WBCs. Overall, the proposed technique can be readily utilized for continuous and high-throughput separation of cancer cells.

Deterministic Lateral Displacement (DLD) Analysis Tool Utilizing Machine Learning towards High-Throughput Separation.

Deterministic lateral displacement (DLD) is a microfluidic method for the continuous separation of particles based on their size. There is growing interest in using DLD for harvesting circulating tumor cells from blood for further assays due to its low cost and robustness. While DLD is a powerful tool and development of high-throughput DLD separation devices holds great promise in cancer diagnostics and therapeutics, much of the experimental data analysis in DLD research still relies on error-prone and time-consuming manual processes. There is a strong need to automate data analysis in microfluidic devices to reduce human errors and the manual processing time. In this work, a reliable particle detection method is developed as the basis for the DLD separation analysis. Python and its available packages are used for machine vision techniques, along with existing identification methods and machine learning models. Three machine learning techniques are implemented and compared in the determination of the DLD separation mode. The program provides a significant reduction in video analysis time in DLD separation, achieving an overall particle detection accuracy of 97.86% with an average computation time of 25.274 s.

Current and Emerging Classes of Pharmacological Agents for the Management of Hypertension.

Cardiovascular disease accounts for more than 17 million deaths globally every year, of which complications of hypertension account for 9.4 million deaths worldwide. Early detection and management of hypertension can prevent costly interventions, including dialysis and cardiac surgery. Non-pharmacological approaches for managing hypertension commonly involve lifestyle modification, including exercise and dietary regulations such as reducing salt and fluid intake; however, a majority of patients will eventually require antihypertensive medications. In 2020, the International Society of Hypertension published worldwide guidelines in its efforts to reduce the global prevalence of raised blood pressure (BP) in adults aged 18 years or over. Currently, several classes of medications are used to control hypertension, either as mono- or combination therapy depending on the disease severity. These drug classes include those that target the renin-angiotensin-aldosterone system (RAAS) and adrenergic receptors, calcium channel blockers, diuretics and vasodilators. While some of these classes of medications have shown significant benefits in controlling BP and reducing cardiovascular mortality, the prevalence of hypertension remains high. Significant efforts have been made in developing new classes of drugs that lower BP; these medications exert their therapeutic benefits through different pathways and mechanism of actions. With several of these emerging classes in phase III clinical trials, it is hoped that the discovery of these novel therapeutic avenues will aid in reducing the global burden of hypertension.

Energy, Exergy, Exergoeconomic, and environmental (4E) analyses of thermal power plants for municipal solid waste to energy application in Bangladesh.

With a population of 165 million, Bangladesh is undergoing rapid industrialization and urban development, and is well on track to move out from the group of least developed countries by 2024. This results in a significant increase in the urban energy needs and the amount of generated waste. Most of the municipal solid waste in Bangladesh is currently deposited in landfills, thereby contaminating nearby cultivable soils. It is desirable to have a system that recovers energy from the municipal solid waste in order to satisfy the increasing energy needs, while simultaneously addressing the land scarcity and pollution issues. This paper proposes using incineration to recover energy from municipal solid waste to produce electricity in the urban areas of Dhaka and Chattogram. A detailed technical analysis involving energy, exergy, exergoeconomic, and emission is presented. The power plants in these two cities show potential capacities of 169 MW and 83 MW respectively, with exergoeconomic factors of 61 %. The results indicate energy and exergy efficiencies of 32 % and 27 %, respectively, and a production cost in the range of 53.9-56.7 USD/MWh which is comparable to the production cost from the current power plants in Bangladesh. The proposed plants also result in a reduction in the greenhouse emissions and exhibit ecological efficiencies of over 87 %.

Consequences of maternal psychological stress during pregnancy for the risk of asthma in the offspring.

Asthma is a common lung condition that makes breathing difficult through the inflammation and constriction of the lung airways. Epidemiological evidence supports the presence of a positive association between prenatal maternal psychological stress (PMPS) and asthma in the offspring, suggesting the disease may have developmental origins. T-helper 2 (Th2) cells are a major subtype of T-helper cells, producing Th2 cytokines, which may be the main drivers of asthma symptoms. A Th2 dominant blood cytokine profile may therefore indicate an increased risk of asthma, as studies have shown a link between PMPS and a T-helper 2 (Th2) cytokine profile in offspring. The mechanism by which PMPS may cause Th2 cytokine dominance in the offspring is unclear. Epigenetic modifications in utero can lead to long-lasting effects that persist postnatally and have therefore been implicated in this relationship. Increased maternal blood cortisol levels due to PMPS may increase transfer of cortisol to the foetus, where the temporarily increased levels may induce changes in the epigenome. Evidence from animal studies suggests that genes controlling cytokine production in T cells can be epigenetically modified in a way that increases Th2 cytokine production. Other evidence suggests that methylation of the NR3C1 gene decreases hippocampal glucocorticoid receptor expression, leading to decreased negative regulation of the hypothalamus-pituitary-adrenal axis. This can increase cortisol production which has been shown to increase Th2 cytokine production. Therefore, the link between PMPS and a Th2 offspring cytokine profile, mediated through epigenetic changes, may explain the positive relationship between PMPS and asthma in the offspring.

Why Have Immunization Efforts in Pakistan Failed to Achieve Global Standards of Vaccination Uptake and Infectious Disease Control?

Immunization is one of the most successful public health initiatives in recent times. It is, therefore, worrying to learn the level of under-vaccination in Pakistan. Diseases that have been successfully eliminated through the aid of vaccination in other countries have not been eliminated in Pakistan. The reasons for this vary and show the uniqueness of the economic, healthcare and environmental landscape of Pakistan, through which public health programmes need to be implemented. The "Expanded Programme of Immunization" (EPI) is the main programme through which routine immunization is provided to the public. Within Pakistan, it has encountered many problems since its inception. This includes logistical obstacles, inefficient health worker attitudes, parental and female awareness, and education, the influence of religious community leaders and the complications that accompany conflict. When compared to globally standardised targets for immunization, Pakistan is trailing behind. Not achieving these targets is worrying from both a global perspective and within the national healthcare landscape of Pakistan. Research is necessary to bring together findings on the failings of routine immunization and polio campaigns; there are many intersecting factors that global health bodies and the Department of Health in Pakistan must address in order to relieve the burden of vaccine-preventable diseases (VPDs).

Role of AYUSH Therapies in Modern Medicine: A Qualitative Study to Explore the Awareness and Attitudes of Doctors Towards the Utilization of Alternate System of Medicine for Diabetes Mellitus.

OBJECTIVE: To understand doctors' attitude to and awareness of AYUSH therapies for the treatment of diabetes mellitus (DM). METHODS: This qualitative study, using a usage-and-attitude survey, was conducted in secondary centers across Mumbai, India. The study surveyed 77 physicians, including those specializing in diabetes. RESULTS: The majority of doctors were aware of Ayurveda (69%) and Homeopathy (52%). Some doctors were aware of Unani (34%) and Siddha (32%). Most doctors (60%) thought that Ayurveda was effective in some way. Almost all doctors (97%) thought that allopathic medicine was effective for DM. The majority of doctors (68%) had not recommended AYUSH therapies as an adjunct to modern medicines. Approximately half of the doctors (52%) believed that AYUSH therapies posed a safety concern for patients and 46% thought that AYUSH therapies could not be used to manage any form of DM. A large group of doctors thought that the main barrier preventing AYUSH therapies from being integrated into current allopathic management of DM was the lack of strong scientific evidence and clinical trials. CONCLUSION: The majority of doctors are aware to some degree of Ayurveda and homeopathic forms of treatment. The majority believe that AYUSH therapies pose a safety concern for patients and have no role in treatment for any form of DM. The most common barrier preventing AYUSH therapies from becoming a mainstream treatment option for DM is the lack of scientific evidence. From this sample, it seems that greater efforts are required to conduct research into the efficacy and safety of AYUSH therapies to ensure that doctors are able to provide holistic care for patients with DM.

Evaluating the effectiveness of anti-Nogo treatment in spinal cord injuries.

As humans, we cannot regenerate axons within the central nervous system (CNS), therefore, making any damage to it permanent. This leads to the loss of sensory and motor function below the site of injury and can be crippling to a person's health. Spontaneous recovery can occur from plastic changes, but it is minimal. The absence of regeneration is due to the inhibitory environment of the CNS as well as the inherent inability of CNS axons to form growth cones. Amongst many factors, one of the major inhibitory signals of the CNS environment is the myelin-associated Nogo pathway. Nogo-A, Nogo-B and Nogo-C (Nogo), stimulate the Nogo receptor, inhibiting neurite outgrowth by causing growth cones to collapse through activation of Rho Kinase (ROCK). Antibodies can be used to target this signalling pathway by binding to Nogo and thus promote the outgrowth of neuronal axons in the CNS. This use of anti-Nogo antibodies has been shown to upregulate CNS regeneration as well as drastically improve sensory and motor function in both rats and primates when coupled with adequate training. Here, we evaluate whether the experimental success of anti-Nogo at improving CNS regeneration can be carried over into the clinical setting to treat spinal cord injuries (SCI) and their symptoms successfully. Furthermore, we also discuss potential methods to improve the current treatment and any developmental obstacles.

Voltage gated sodium channels as therapeutic targets for chronic pain.

Being maladaptive and frequently unresponsive to pharmacotherapy, chronic pain presents a major unmet clinical need. While an intact central nervous system is required for conscious pain perception, nociceptor hyperexcitability induced by nerve injury in the peripheral nervous system (PNS) is sufficient and necessary to initiate and maintain neuropathic pain. The genesis and propagation of action potentials is dependent on voltage-gated sodium channels, in particular, Nav1.7, Nav1.8 and Nav1.9. However, nerve injury triggers changes in their distribution, expression and/or biophysical properties, leading to aberrant excitability. Most existing treatment for pain relief acts through non-selective, state-dependent sodium channel blockage and have narrow therapeutic windows. Natural toxins and developing subtype-specific and molecular-specific sodium channel blockers show promise for treatment of neuropathic pain with minimal side effects. New approaches to analgesia include combination therapy and gene therapy. Here, we review how individual sodium channel subtypes contribute to pain, and the attempts made to develop more effective analgesics for the treatment of chronic pain.

Could the link between drug addiction in adulthood and substance use in adolescence result from a blurring of the boundaries between incentive and hedonic processes?

There is a broad consensus that the development of drug addiction in adulthood is closely linked to the onset of drug use in adolescence. However, the relationship between drug exposure during adolescence and subsequent vulnerability to addiction is yet to be fully understood. This review will first use evidence from adult studies on reward and addiction to give an up-to-date reference point of normal reward-circuitry and the maladaptive changes that later occur in addiction. This will then be compared with current evidence from adolescent studies on reward-circuitry. Similarities between the reward processes governing characteristic behavioral traits in adolescence and the reward profile in adult addiction could help to explain why the risk of later developing addiction is increased when substance use is initiated in adolescence. We argue that the age of onset is a major risk factor in the development of substance use disorder due to a blurring of the boundaries between incentive and hedonic processes, which occurs during adolescence. A deeper understanding of the processes that mediate this blurring could open new avenues for the prevention and treatment of adult drug addiction.

What are the links between hypoxia and Alzheimer's disease?

Alzheimer's disease (AD) is the most common neurodegenerative disease. Histological characterization of amyloid plaques and neurofibrillary tangles in the brains of AD patients, alongside genetic studies in individuals suffering the familial form of the disease, has fueled the accumulation of the amyloid-ß protein as the initial pathological trigger of disease. Association studies have recently showed that cerebral hypoxia, via both genetic and epigenetic mechanisms, increase amyloid-ß deposition by altering expression levels of enzymes involved in the production/degradation of the protein. Furthermore, hypoxia has also been linked to neuronal and glial-cell calcium dysregulation through formation of calcium-permeable pores, dysregulated glutamate signaling, and intracellular calcium-store dysfunction. Hypoxia has also been strongly linked to neuroinflammation; however, this relationship to AD has not been thoroughly discussed in the literature. Here, we highlight and organize critical research evidence showing that in both hypoxic and AD brains, there are similarities in terms of 1) the substances mediating/modulating the neuroinflammatory environment and 2) the immune cells that drive the formation of these substances.

Current perspective on the role of insulin and glucagon in the pathogenesis and treatment of type 2 diabetes mellitus.

According to the World Health Organization, 422 million adults worldwide live with diabetes mellitus (DM), a significant portion of whom have type 2 diabetes. The discovery of insulin as a key regulator of glucose metabolism has revolutionized our understanding of DM and provided several therapeutic avenues. Most studies have so far predominantly focused on the role of insulin in type 2 diabetes. However, the balance between insulin and glucagon is essential in ensuring glucose homeostasis. In this review, we begin by evaluating the principal differences between insulin and glucagon with regard to their mechanism and control of their secretion. Next, we discuss their mode of action and effects on metabolism. We further explore how the two hormones impact the natural history of type 2 diabetes. Finally, we outline how current and emerging pharmacological agents attempt to exploit the properties of insulin and glucagon to benefit patients with type 2 diabetes.

The unique invasiveness of glioblastoma and possible drug targets on extracellular matrix.

Glioblastoma, or glioblastoma multiforme (GBM), is described as one of the most invasive cancer types. Although GBM is a rare disease, with a global incidence of <10 per 100,000 people, its prognosis is extremely poor. Patient survival without treatment is ~6 months, which can be extended to around 15 months with the standard treatment protocol. Given the propensity of GBM cells to show widespread local invasion, beyond the margins seen through the best current imaging techniques, tumor margins cannot be clearly defined. Recurrence is inevitable, as the highly invasive nature of GBM means complete surgical resection of the tumor is near impossible without extensive damage to healthy surrounding brain tissue. Here, we outline GBM cell invasion in the unique environment of the brain extracellular matrix (ECM), as well as a deeper exploration of the specific mechanisms upregulated in GBMs to promote the characteristic highly invasive phenotype. Among these is the secretion of proteolytic enzymes for the destruction of the ECM, as well as discussion of a novel theory of amoeboid invasion, termed the "hydrodynamic mode of invasion". The vast heterogeneity of GBM means that there are significant redundancies in invasive pathways, which pose challenges to the development of new treatments. In the past few decades, only one major advancement has been made in GBM treatment, namely the discovery of temozolomide. Future research should look to elucidate novel strategies for the specific targeting of the invasive cells of the tumor, to reduce recurrence rates and improve patient overall survival.

How the discovery of rituximab impacted the treatment of B-cell non-Hodgkin's lymphomas.

Non-Hodgkin's lymphoma (NHL) is the sixth-most common cancer in the UK, accounting for around 13,700 new cases every year. Until the late 1990s, treatment relied on intensive chemotherapy, such as CHOP (cyclophosphamide-doxorubicin HCl-vincristine [Oncovin]-prednisone). The use of standard CHOP therapy and its variations had resulted in poor five-year survival rates (as low as 26%), particularly in patients with aggressive NHL. Rituximab (Rituxan) was the first chimeric (mouse/human) monoclonal antibody approved for the treatment of NHL. It was approved by the US Food and Drug Administration in 1997 for indolent forms of NHL. It subsequently received EU approval in June 1998, and was licensed under the trade name Mabthera (Roche, Basel, Switzerland). It then went on to be approved for the first-line treatment of aggressive forms of NHL, such as diffuse large B-cell lymphoma (to be used in combination with CHOP or other anthracycline-based chemotherapy) in 2006. It is directed against the CD20 protein, an antigen found on the surface of B-cell lymphomas. With minimal toxicity, activity as a single-agent (for indolent forms of NHL) and safety when combined with chemotherapy (for aggressive forms), it represents great progress in this field. Here, we analyze how this antibody therapeutic was developed from basic molecular and cellular considerations through to preclinical and clinical evaluations and how it came to be a first-line treatment for NHL, and we discuss the impacts the advent of rituximab had on treatment outcomes for patients with DLBCL compared with the pre-rituximab era.

The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson's disease.

Despite decades of research, the mechanism of Parkinson's disease pathogenesis remains unclear. Studies have focused heavily on the protein α-synuclein, which is the primary component of Lewy bodies, the pathologic inclusions that are the hallmark of Parkinson's on the cellular level. While the roles of α-synuclein in causing mitochondrial dysfunction and disruptions to the proteasomal system have been well documented, recently, its role in effecting microtubule dynamics has been investigated as a potential source of pathogenicity. Here, we evaluate the evidence for and against the role of α-synuclein in destabilizing microtubules, causing axonal transport deficits and eventually neurodegeneration. We present evidence for a model where α-synuclein has both a direct and indirect effect on microtubule stability. Directly, it may act as a microtubule-associated protein, binding to microtubules and directly effecting their dynamics. Indirectly, it may promote the hyperphosphorylation of the microtubule stabilizing protein, tau, leading to tau aggregation with other microtubule stabilizing proteins, hence indirectly causing microtubule destabilization. This model provides insights into the function of α-synuclein and tau in Parkinson's disease pathogenesis and raises the possibility that this role that may also be conserved in Alzheimer's disease.

Evaluating the use of corticosteroids in preventing and treating bronchopulmonary dysplasia in preterm neonates.

Approximately 15 million babies worldwide are born premature, and complications of prematurity are one of the leading causes of death in neonates. Neonatal respiratory distress syndrome (NRDS) and bronchopulmonary dysplasia (BPD) are two of the most common and serious consequences of prematurity. Synthetic corticosteroids, including dexamethasone, have been central in efforts to treat and prevent BPD. There is strong evidence to show that prenatal corticosteroids reduce infant mortality and the incidence of NRDS, leading to their widespread use in obstetric units. However, data suggest that they are not as effective in reducing the incidence of BPD as NRDS, which may be due to the multifactorial pathogenesis of BPD. On the other hand, the use of postnatal corticosteroids in preterm infants is much more controversial. They have been shown to improve lung function and help in reducing the need for mechanical ventilation. These benefits, however, are associated with a range of adverse short- and long-term effects. This review will discuss the benefits and consequences of corticosteroids in treating BPD and will examine alternative treatments and future research that may improve the understanding of BPD and inform clinical practice.