Healthcare online Keeping you up-to-date
VOL.  20     ISSUE:  7    July 2022 Medical Services Department

SQUARE Pharmaceuticals Ltd.





P G Dip. Business Management






Dear Doctor:

Welcome to our healthcare bulletin 'e-SQUARE' !

Our current issue focused on some interesting features like

"Sleep Mystery !", "Dementia Prediction !", "IVF Failure !", "Auditory Sensitivity !", "COVID-19 & Neurological Symptoms !", "Cancer Metastasis & Atherosclerosis !".

In our regular feature, we have some products information of SQUARE Pharmaceuticals Ltd. as well.

We always appratiate your feedback !

Click on to reply mode.

Yours sincerely,


Editorial Team

Reply Mode      : e-square@squaregroup.com

The views expressed in this publication do not necessarily reflect those of its editor or SQUARE PHARMACEUTICALS LTD.

 Sleep Mystery !

Sleep provides a major key to the mystery of consciousness

The researchers were surprised to discover that the brain's response to sound remains powerful during sleep in all parameters but one, the level of alpha-beta waves associated with attention to the auditory input and related expectations. This means that during sleep, the brain analyzes the auditory input but is unable to focus on the sound or identify it, and therefore no conscious awareness ensues. This study is unique in that it builds upon rare data from electrodes implanted deep inside the human brain, enabling high-resolution monitoring, down to the level of individual neurons, of the brain's electrical activity. For understandable reasons, electrodes cannot be implanted in the brain of living humans just for the sake of scientific research. But in this study, they were able to utilize a special medical procedure in which electrodes were implanted in the brains of epilepsy patients, monitoring activity in different parts of their brain for purposes of diagnosis and treatment. The researchers placed speakers emitting various sounds at the patient's bedside and compared data from the implanted electrodes neural activity and electrical waves in different areas of the brain during wakefulness vs. various stages of sleep. After sounds are received in the ear, the signals are relayed from one station to the next within the brain. Until recently it was believed that during sleep these signals decay rapidly once they reach the cerebral cortex. But looking at the data from the electrodes, scientists were surprised to discover that the brain's response during sleep was much stronger and richer than they had expected. Moreover, this powerful response spread to many regions of the cerebral cortex. The strength of brain response during sleep was similar to the response observed during wakefulness, in all but one specific feature, where a dramatic difference was recorded the level of activity of alpha-beta waves. The researchers explain that alpha-beta waves are linked to processes of attention and expectation that are controlled by feedback from higher regions in the brain. As signals travel 'bottom-up' from the sensory organs to higher regions, a 'top-down' motion also occurs. The higher regions, relying on prior information that had accumulated in the brain, act as a guide, sending down signals to instruct the sensory regions as to which input to focus on, which should be ignored. Thus, for example, when a certain sound is received in the ear, the higher regions can tell whether it is new or familiar, and whether it deserves attention or not. This kind of brain activity is manifested in the suppression of alpha-beta waves, and indeed, previous studies have shown a high level of these waves in states of rest and anesthesia. According to the current study, the strength of alpha-beta waves is the main difference between the brain's response to auditory inputs in states of wakefulness vs. sleep.

SOURCE: Science Daily News, July, 2022

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 Dementia Prediction !

Daily activity patterns may predict Alzheimer's and other cognitive decline in older adults

Wearable movement tracking devices may someday be useful in providing early warnings of cognitive decline among older adults. The researchers analyzed data from ActiGraph activity monitors, which use an activity tracking sensor similar to those found in smart watches. They found significant differences in movement patterns between participants with normal cognition and those with mild cognitive impairment or Alzheimer's disease. These differences included less activity during waking hours and more fragmented activity during afternoons among the mild cognitive impairment participants. The recent introduction of wearable activity tracking devices, which are now used by tens of millions of people around the world, has presented an important opportunity for health researchers to measure and track changes in physical movement. The devices can provide automatic, objective measures of daytime physical activity, sleep patterns, heart rate, and blood oxygen levels and they are typically Internet connected, allowing their manufacturers to build datasets covering millions of users. Researchers previously did not have such an easy way to access such health relevant data at such a large scale. The aim of the new study was to determine if activity tracker patterns recorded from a cohort of older adults differ meaningfully between the cognitively normal and the cognitively impaired. Alzheimer's disease, the most common form of dementia, is known to be a decades long process, and researchers generally expect that future disease modifying interventions will be more effective when started earlier in the disease course. If scientists could identify a distinctive change in activity that predicts the slide into mild cognitive impairment and, eventually, Alzheimer's and other forms of dementia, then in principle older individuals who show this change in activity could be given further cognitive testing and, when available, earlier treatment. These included 36 participants with either mild cognitive impairment or Alzheimer's diagnoses. Adjusting for differences based on age, sex, and race, the researchers found that overall differences in all day activity measures were not strongly different between the mild cognitive impairment and normal cognition groups. However, when the researchers focused on activity patterns during certain times of the day, some differences were revealed. In the mornings and even more so in the afternoons, the mild cognitive impairment group had significantly lower measures of activity compared to the normal group. The most striking finding was that activity "fragmentation" a breaking up of activity into smaller time periods was 3.4 percent higher for the mild cognitive impairment/Alzheimer's participants during the afternoon period. Seeing this difference in the afternoons was interesting one of the main symptoms of Alzheimer's dementia is the 'sundowning' phenomenon involving increased confusion and mood changes that start in the afternoon, and it might be that these activity markers are capturing some movement related to these symptoms.

SOURCE: Science Daily News, July 2022

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 IVF Failure !

 Many IVF embryos fail to develop

In humans, a fertilized egg is no guarantee of reproductive success. Most embryos stop developing and perish within days of fertilization, usually because they have an abnormal number of chromosomes. Now, researchers at Columbia University Vagelos College of Physicians and Surgeons have found that most of these mistakes are due to spontaneous errors in DNA replication in the earliest phase of cell division. The findings provide new insights into the basic biology of human reproduction and in the long term could lead to improvements in the success rate of in vitro fertilization (IVF). Approximately 24 hours after a human egg is fertilized, the process of cell division begins. During cell division, the entire genome containing more than 3 billion base pairs of DNA must be faithfully duplicated. The duplicate sets of chromosomes must then be separated so that each daughter cell receives a complete set. In many human embryos created for IVF, something goes wrong and some cells within the embryo have too few or too many chromosomes. Researchers have theorized that errors occur during the final phase of cell division, when the duplicate sets of chromosomes separate into two identical daughter cells. Most of these failures were attributed to issues with the microtubule spindle, the apparatus that pulls the two sets of chromosomes apart. But studies found that chromosomal abnormalities stem from errors that occur much earlier in the process of cell division when the genome's DNA is duplicated. If the DNA is not copied precisely, the spindle malfunctions and places the wrong number of chromosomes into each daughter cell. When DNA duplication is abnormal, the spindle does not function normally. Though the studies were conducted with embryos created in a petri dish including from individuals undergoing IVF and egg donors who were not seeking fertility treatment the same problems may contribute to the failure of embryos created in natural human reproduction. The source of DNA copying errors in embryos appears to spring from obstacles within the DNA's double helix. Though the precise reason for these obstacles is not yet known, they cause duplication of the DNA to pause, or even stop, which results in DNA breakage and an abnormal number of chromosomes. Spontaneous DNA errors can occur as early as the first cycle of cell division in human embryos, the researchers found, as well as in subsequent cell divisions. If too many cells in the early embryo are affected by chromosomal abnormalities, the embryo cannot develop further. Most human embryos created for IVF stop developing within days after fertilization. This inefficiency of human development is an obstacle to successful fertility treatments. Many women undergoing fertility treatment require multiple IVF cycles in order to get pregnant, and some never get pregnant at all. Not only is this enormously expensive, it's emotionally taxing. The researchers are planning additional studies looking at DNA damage during replication in the hope of understanding normal and disease causing variations in the human germ line. In the long term, these studies may lead to methods to reduce the risk of genetic abnormalities and embryo attrition for patients undergoing IVF.

SOURCE: Science Daily News, July, 2022

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Auditory Sensitivity !

A new mechanism identified responsible for controlling auditory sensitivity

A new study published in PNAS highlights a newly identified mechanism of how auditory sensitivity is regulated that could temporarily reduce sensitivity of the auditory system to protect itself from loud sounds that can cause irreversible damage. The researchers tested a decades old hypothesis which proposed that the gating spring, a tiny, nanometer scale protein structure which mechanically opens and closes an ion channel in sensory hair cell. These cells in response to sound vibrations, can act directly as a controller of the channel's activity. Previous work in the auditory field has focused mostly on understanding mechanisms which target the ion channel. This study provides the first evidence that the gating spring itself has the capacity to modulate the sensitivity of the channel. This study documents the first time to understand a mechanism that regulates auditory sensitivity on both the molecular and mechanical levels. Researchers also uncovered a new mechanism of modulating sensitivity, which opens the door to discovering more about how the auditory system functions generally and uses this to both maximize the range of sounds that we can detect and protect the vital sensory cells from potential damage. The mechanism discussed in the study works by modifying a physical property of the gating spring, its stiffness, which is responsible for controlling how much the channel opens and closes in response to sound vibrations that enter the inner ear. The researchers studied the properties of the gating spring and the resulting activity of the channel in single sensory hair cells, and found that cyclic adenosine monophosphate (cAMP), a specific type of signaling molecule, reduced the stiffness of the gating spring and decreased the channel's sensitivity which is the first time a physiological mechanism for controlling gating spring stiffness has been identified. Identifying the underlying mechanism of this process physiologically and mechanically, provides an avenue for future research and provides an opportunity for the field to develop a new type of drug that can be used to prevent a type of hearing loss that occurs from exposure to very loud sound.

SOURCE: Science Daily News, July 2022

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 COVID-19 & Neurological Symptoms !

SARS-CoV-2 hijacks nanotubes between neurons to infect them

COVID-19 often leads to neurological symptoms, such as a loss of taste or smell, or cognitive impairments, both during the acute phase of the disease and over the long term with "long COVID" syndrome. But the way in which the infection reaches the brain was previously unknown. Scientists from Institute Pasteur and CNRS laboratories have used state-of-the-art electron microscopy approaches to demonstrate that SARS-CoV-2 hijacks nanotubes, tiny bridges that link infected cells with neurons. The virus is therefore able to penetrate neurons despite the fact that they are lacking the ACE2 receptor that the virus usually binds to when infecting cells. A study published recently in Science Advances shows that the virus uses nanotubes that form between infected cells and neurons to gain access to neurons. These transient dynamic structures are a result of membrane fusion in distant cells. They enable the exchange of cellular material without the need for membrane receptors, the normal means of entering and exiting the cytoplasm. The Membrane Traffic and Pathogenesis Unit has already found that nanotubes play a role in degenerative diseases such as Alzheimer's and Parkinson's by facilitating the transport of proteins responsible for these diseases. Although the human cell receptor ACE2 serves as a gateway for SARS-CoV-2 to enter lung cells the main target of the virus and cells in the olfactory epithelium, it is not expressed by neurons. But viral genetic material has been found in the brains of some patients, which explains the neurological symptoms that characterize acute or long COVID. The olfactory mucosa has previously been suggested as a route to the central nervous system, but that does not explain how the virus is able to enter neuronal cells themselves. According to this new study, SARS-CoV-2 is also thought to be capable of inducing the formation of nanotubes between infected cells and neurons, as well as among neurons, which would explain how the brain is infected from the epithelium. The research team revealed multiple viral particles located both inside and on the surface of nanotubes. Since the virus spreads more rapidly and directly from within nanotubes than by exiting one cell to move to the next via a receptor, this mode of transmission therefore contributes to the infectious capacity of SARS-CoV-2 and its spread to neuronal cells. But the virus also moves on the external surface of nanotubes, where it can be guided more quickly to cells that express compatible receptors. This publication combines research on in vitro cultures, showing that healthy neuronal cells are infected if they come into contact with infected cells, with the use of state-of-the-art microscopy tools. This study is an example of how basic interdisciplinary research, involving cellular biologists, virologists and state-of-the-art imaging techniques, can lead to new discoveries. It paves the way for further research on the role of cell-to-cell communication in the spread of SARS-CoV-2.

SOURCE: Science Daily News, July 2022

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Cancer Metastasis & Atherosclerosis !

A common mechanism for cancer metastasis and atherosclerosis

A key molecule for cancer metastasis has been identified as a molecule already known for its involvement in cardiovascular disease, suggesting a possible treatment approach for both diseases simultaneously. Cancer is the uncontrolled growth of body cells leading to the formation of tumors, triggered by the accumulation of mutations in a cell's genome. In order to become malignant, metastasizing cancer, tumor cells go through a series of transformations involving interactions between the body's immune system and the tumor. However, many mechanistic details in this process are still unclear, making the prevention and treatment of cancer notoriously difficult. However, there is growing evidence that in tumor progression to metastasis, inflammation of endothelial cells is a key process. Concerned with the molecular mechanism behind this process in cancer malignancy, a team of researchers have discovered that, in malignant tumors, endothelial cells accumulate low-density lipoprotein  (LDL) and attract neutrophils. Neutrophils are immune suppressor cells which are known to contribute to tumor progression. Previous work by the team had revealed that blood vessels in malignant tumors expressed a high level of proteoglycans, and it is known that cancerous tissue is inflamed. These features are similar to what is seen in atherosclerosis, and the team wished to investigate if the similarities went deeper. The research team showed that metastasizing tumors, in contrast to non-metastasizing ones, accumulate proteoglycan molecules. These, in turn, attach to and accumulate LDL to the walls of blood vessels. The bound LDL becomes oxidized. There are also high levels of its receptor, called "LOX-1," in the blood vessel lining endothelial cells of metastasizing tumors. This, they found, causes these cells to produce inflammation signals that attract neutrophils. They then proved that in mice, the suppression of LOX-1 can significantly reduce tumor malignancy, and also that LOX-1 overexpression caused an increase in signaling molecules attracting neutrophils. As the team hypothesized, this sequence of interactions observed in malignant tumors occurs in atherosclerosis. Even though some questions remain open, especially on the mechanism of how neutrophils contribute to cancer malignancy, this study is the first to explicitly prove the mechanistic commonalities between cardiovascular disease and cancer progression and trace the mechanism involving LDL accumulation and LOX-1 expression in in vivo tumor tissue. Their present study focused on the importance of LOX-1 in endothelial cells as a common factor between cancer and atherosclerosis. The study also points to a promising approach for treating and preventing malignant cancer and cardiovascular disease by targeting neutrophil recruitment to endothelial cells. The number of patients with cancer who die not of cancer, but of cardiovascular events, is increasing. Targeting the LOX-1/oxidized LDL axis might be a promising strategy for the treatment of the two diseases concomitantly.

SOURCE: Science Daily News, July 2022

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Products of SQUARE Pharmaceuticals Ltd.

  Product Glympa TM
  Generic Name Empagliflozin & Linagliptin
  Strength 10/ 5 mg & 25/5 mg
  Dosage form Tablet
  Therapeutic Category Oral Antidiabetic Preparation
  Product Mirader TM  
Generic Name Mirabegron
Strength 25 mg
Dosage form Extended Release Tablet
Therapeutic Category Urological Preparation
  Product Sopilax TM
  Generic Name Sodium Picosulfate
Strength 10 mg
  Dosage form Tablet & Oral Solution
  Therapeutic Category Laxative

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