Karl Fischer titration

Karl Fischer titration is a classic titration method in chemical analysis that uses coulometric or volumetric titration to determine trace amounts of water in a sample. It was invented in 1935 by the German chemist Karl Fischer. Today, the titration is done with an automated Karl Fischer titrator.
Chemical principle.
The elementary reaction responsible for water quantification in the Karl Fischer titration is oxidation of sulfur dioxide with iodine:
This elementary reaction consumes exactly one molar equivalent of water vs. iodine. Iodine is added to the solution until it is present in excess, marking the end point of the titration, which can be detected by potentiometry. The reaction is run in an alcohol solution containing a base, which consume the sulfur trioxide and hydroiodic acid produced.
Coulometric titration.
The main compartment of the titration cell contains the anode solution plus the analyte. The anode solution consists of an alcohol (ROH), a base (B), SO2 and KI. Typical alcohols that may be used include ethanol, diethylene glycol monoethyl ether, or Methanol (absolute), sometimes referred to as Karl Fischer grade. A common base is imidazole.
The titration cell also consists of a smaller compartment with a cathode immersed in the anode solution of the main compartment. The two compartments are separated by an ion-permeable membrane.
The Pt anode generates I2 from the KI when current is provided through the electric circuit. The net reaction as shown below is oxidation of SO2 by I2. One mole of I2 is consumed for each mole of H2O. In other words, 2 moles of electrons are consumed per mole of water.
The end point is detected most commonly by a bipotentiometric titration method. A second pair of Pt electrodes is immersed in the anode solution. The detector circuit maintains a constant current between the two detector electrodes during titration. Prior to the equivalence point, the solution contains I− but little I2. At the equivalence point, excess I2 appears and an abrupt voltage drop marks the end point. The amount of charge needed to generate I2 and reach the end point can then be used to calculate the amount of water in the original sample.
Volumetric titration.
The volumetric titration is based on the same principles as the coulometric titration, except that the anode solution above now is used as the titrant solution. The titrant consists of an alcohol (ROH), base (B), SO2 and a known concentration of I2. Pyridine has been used as the base in this case.
One mole of I2 is consumed for each mole of H2O. The titration reaction proceeds as above, and the end point may be detected by a bipotentiometric method as described above.
Disadvantages and advantages.
The popularity of the Karl Fischer titration (henceforth referred to as KF) is due in large part to several practical advantages that it holds over other methods of moisture determination, such as accuracy, speed and selectivity.
KF is selective for water, because the titration reaction itself consumes water. In contrast, measurement of mass loss on drying will detect the loss of "any" volatile substance. However, the strong redox chemistry (SO2/I2) means that redox-active sample constituents may react with the reagents. For this reason, KF is unsuitable for solutions containing e.g. dimethyl sulfoxide.
KF has a high accuracy and precision, typically within 1% of available water, e.g. 3.00% appears as 2.97–3.03%. Although KF is a destructive analysis, the sample quantity is small and is typically limited by the accuracy of weighing. For example, in order to obtain an accuracy of 1% using a scale with the typical accuracy of 0.2 mg, the sample must contain 20 mg water, which is e.g. 200 mg for a sample with 10% water. For coulometers, the measuring range is from 1–5 ppm to about 5%. Volumetric KF readily measures samples up to 100%, but requires impractically large amounts of sample for analytes with less than 0.05% water. The KF response is linear. Therefore, single-point calibration using a calibrated 1% water standard is sufficient and no calibration curves are necessary.
Little sample preparation is needed: a liquid sample can usually be directly injected using a syringe. The analysis is typically complete within a minute. However, KF suffers from an error called "drift", which is an apparent water input that can confuse the measurement. The glass walls of the vessel adsorb water, and if any water leaks into the cell, the slow release of water into the titration solution can continue for a long time. Therefore, before measurement, it is necessary to carefully dry the vessel and run a 10–30-minute "dry run" in order to calculate the rate of drift. The drift is then subtracted from the result.
KF is suitable for measuring liquids and, with special equipment, gases. The major disadvantage with solids is that the water has to be accessible and easily brought into methanol solution. Many common substances, especially foods such as chocolate, release water slowly and with difficulty, requiring additional efforts to reliably bring the total water content into contact with the Karl Fischer reagents. For example, a high-shear mixer may be installed to the cell in order to break the sample. KF has problems with compounds with strong binding to water, as in water of hydration, for example with lithium chloride, so KF is unsuitable for the special solvent LiCl/DMAc.
KF is suitable for automation. Generally, KF is conducted using a separate KF titrator, or for volumetric titration, a KF titration cell installed into a general-purpose titrator. There are also oven attachments that can be used for materials that have problems being analyzed normally in the cell. The important aspect about the oven attachment is that the material doesn't decompose into water when heated to release the water. The oven attachment also supports automation of samples.
Using volumetric titration with visual detection of a titration endpoint is also possible with coloured samples by UV/VIS spectrophotometric detection.


Leukoencephalopathy with neuroaxonal spheroids

Leukoencephalopathy with neuroaxonal spheroids (LENAS) is an extremely rare kind of leukoencephalopathy and is classified as a neurodegenerative disease. LENAS is a cause of severe and subacute dementia that results from damage to certain areas of the brain. This damage is to a type of brain tissue called white matter and axon damage due to swellings which are termed spheroids.
The rarity and unknown prevalence of this disease may be due to most symptoms being similar to other common disorders, leading to misdiagnosis. LENAS normally has an adult onset (but also can be present in childhood), which can present on MRIs that mimics progressive multiple sclerosis and is thus misdiagnosed for this instead.
The genetic etiology of LENAS is known to follow an autosomal dominant pattern through a mutation in the CSF1R gene.
Signs and Symptoms.
The signs and symptoms that are present vary with each individual as some may have all symptoms while some may only have some listed below. However, the progression of this disease is different with each individual which reflects how the symptoms change over time. Further, the damage that we see to the myelin and axons is thought to contribute to many of the neurological signs and symptoms that are shown in this condition. The most frequent symptoms are categorized into psychiatric, psychotic and neurologic.
General Symptoms.
While these vary among individuals as mentioned, over time, almost all patients with this condition will be unable to walk, speak and care for themselves.
Causes.
Leukoencephalopathy with neuroaxonal spheroids (LENAS) is believed to occur when presence of white matter degeneration and axonal spheroids are seen with a brain biopsy or an MRI.
White matter consists of nerve fibers (axons) covered by a substance called myelin that insulates and protects them. The axons extend from nerve cells (neurons) and transmit nerve impulses throughout the body.
The result of spheroids in the brain leads to this significant decline of functioning that progressively worsens the brain function and leads to varied symptoms. However, why this occurs is still not entirely understood, thus more research is continuously being done to this day.
There have been identifiable genetic differences that are better understood. This disease is inherited while following an autosomal dominant pattern.
Genetic Etiology.
There are identifiable genetic causes that are better understood with this disease. LENAS is caused by a mutation in a gene, specifically the CSF1R gene. This mutation changes protein receptors on the gene which normally plays a role in important cell signaling pathways; however, this altercation inhibits the regular function.
Normal Function of CSF1R Gene
The colony stimulating factor 1 receptor (CSFR1) gene regularly functions by giving instructions for making a protein termed the colony stimulating factor 1 receptor (CSF-1 receptor). Proteins in general attach (bind) to their specific receptor which "turns on" (activates) to stimulate a cascade of cellular signaling pathways crucial for cell function to occur. These events occur with the specific CSF-1 protein. As it binds and is activated, it allows for important cellular processes to occur which include cell growth, division, and maturation of cells to in turn take on specific functions.
Glial cells, located in the brain, are responsible for protection and maintenance of neurons. In a healthy brain, the membrane of glial cells are abundant with the CSF-1 receptor gene and is also thought to be an important player in the proliferation and differentiation of these cells.
"Mutated CSF1R Gene".
There are several types of mutations that occur in genes. The majority of CSF1R genetic mutations in LENAS occur due to a type of mutation which is called a missense mutation. Missense mutations occur when there is a change in a single amino acid of a protein. This single change can result in problems with functions of the protein, like the CSF-1 receptor. The kinase domain, which is the region of CSF-1 receptor where the mutation occurs, is altered and thus the normal function that activates other proteins is compromised and cannot stimulate cell signaling pathways properly.
Although this is the primary type of mutation in LENAS, other types may occur as well but it is not as well understood for this disease.
This genetic mutation is related to LENAS and said to be the main cause but how these lead to damage in the white matter and associated symptoms (cognitive and movement impairment symptoms) is still not fully clear.
Inheritance.
LENAS is inherited in an autosomal dominant pattern. This means that one copy of the mutated gene in each cell is sufficient to cause the disorder.
If one parent who is unaffected and one parent who is affected with LENAS give birth to four children, at least two of the four will become affected and have the disorder because the affected parent would pass on the one copy of the gene. In most cases, an affected person does inherit the mutation from one affected parent but not all cases.
There have been very few reports of cases that result from new mutations have been seen as well as cases in which there has been no history of LENAS. These few reports are not as concrete or well understood yet and further studies should be conducted.
Pathophysiology.
Neuropathology.
LENAS is seen with damage to the white matter and axons within the brain. The external human LENAS brain shows findings in several major structures. There is mild atrophy of the frontoparietal regions of the brain and a mild reduction of the thalamus and rostral (front) part of the caudate nucleus (which is located in an area of the brain called the basal ganglia). Abnormalities in the frontal, frontoparietal, and temporal lobes are most severe and predominant with LENAS and asymmetry of the cerebral hemispheres has sometimes been found. LENAS also may show moderately enlarged lateral ventricles and atrophy in corticospinal tracts as well as in the pons.
The area where it is seen to be the most pronounced abnormalities appear in the white matter below the pre- and postcentral gyri that extend through the posterior limb of the internal capsule into pyramidal tracts of the brain stem.
Specific Immunostains are used as the easiest identification of neuroaxonal spheroids in LENAS which appear as round to oval shaped swellings and are seen in affected white matter. If there appears to be a large amount of loss in myelin sheaths on axons and these spheroids, LENAS progressed to become widespread.
Electron Microscopy has also been used to identify spheroids. In LENAS, evidence of the spheroids may show neurofilaments that are scattered amount electron-dense material and mitochondria.
Subcortical U-fibers in the brain appear to be relatively "spared", meaning they seem to not be involved in most cases but this does not mean they are not always/eventually involved. U-fibers represent connections which are between adjacent areas of the brain located within the cortex or deep in the white matter that are one of the last parts of the brain to be myelinated. In LENAS, it has been found that because these U-fibers are last to myelinate normally, they are also last to be affected as the disease progresses.
Biochemistry.
The primary biochemical defect in LENAS disrupts normal states and may involve oxidative stress. Ceroids, which are essentially products of unsaturated fatty acids that build up, are found in macrophages and other glia is thought to be an end-product of oxidative damage, indicative of membrane damage from abnormal accumulation.
The high levels of Iron is also present in LENAS which can be associated to cause an increased level of toxic free radicals and causing oxidative damage to the body, causing failure in our cellular energy systems.
Disease Mechanism.
The mechanism of LENAS still seems to remain unclear and it varies as more research on this is being done. Some mechanisms that can be of clinical importance of why individuals show certain symptoms and which area of the brain has been shown to be consistent.
Normally, the frontal lobe in our brain are important for our higher level executive functions. Predominance of white matter damage in this lobe has been found to be consistent with both the psychiatric and behavioral signs and symptoms pertaining to LENAS. The underlying symptoms seen of frontotemporal dementia seen commonly in LENAS is associated with the temporal lobe damage. There is a large disconnect in the brain between the lobes that reflect the neuropsychiatric symptoms that are common with the disease.
Ataxia, which is related to our daily voluntary movements of muscles, are often present even in patients without cerebellar involvement which could reflect either minimal damage to the cerebellum or diffuse cerebral white matter lesions.
Diagnosis.
The diagnosis of LENAS is usually based on medical and family history, genetic testing, extensive imaging and other supplemental testing. As this disease is extremely rare, diagnosis is still very complex as many of these diagnostic criteria for LENAS can be mistaken for similar neurodegenerative disorders. The differential diagnosis of leukoencephalopathy in general is very extensive and specialized investigations are required to make an accurate diagnosis.
Diagnostic Criteria.
"Note: This criteria was established by a group consisting of board-certified neurologists from the Mayo Clinic, Niigata University, Shinshu University School of Medicine, Kyoto Prefectural University of Medicine, and Tokushima University Graduate School."
Genetic Testing.
Single-Gene testing is first performed for sequence analysis of the CSF1R gene.
A multi-gene panel that includes CSF1R gene and other genes of interest may be considered for differential diagnoses.
If necessary, more comprehensive genomic testing (not always available though) can be performed.
Prevention.
There currently is not any suggestive findings of preventative measures that should be taken for LENAS before diagnosis. However, prevention of secondary complications can be taken once diagnosis is confirmed.
Prevention of Secondary Complications.
Social problems such as unemployment, divorce, financial troubles, and alcoholism as well as suicidal tendencies are often associated as this disease worsens over time. Some of these social consequences may be avoided if family members are informed early about the nature of this disorder as well as if it is diagnosed early enough.
As depression is a major symptom associated, suicidal tendencies may occur. Antidepressant medications can be prescribed for this depression for the attempt to help with depression but they have not shown long-term benefit to date.
Agents and Circumstances to Avoid.
The following should be avoided not to prevent the disease, but rather to prevent this disease from progressing faster and causing symptoms to worsen:
Treatment.
No specific therapy for LENAS is currently known or proven to cure this disease, but management of it should be immediately initiated following diagnosis. While more research should be taken, some suggest that hematopoietic stem cell transplantation may show a therapeutic role for this disease.
Management.
Management is important in support of this disease and includes attention to general care and nutrition requirements and other possible drug therapies that may help or slow the progression of the disease.
L-dopa or other dopaminergic therapies have not yet been beneficial in individuals with this disease but was noted that it may be worth trying as it does not show negative effects.
Antipsychotics are in general not recommended due to extrapyramidal side effects. However, they may be used in aggressive individuals.
Anti-seizure medications should be initiated in individuals who are having seizure activity along with having this disease as it is reported to be beneficial.
Surveillance.
Periodic clinical evaluation and surveillance to monitor the progression of the disease is appropriate to determine if changes need to be made:
Prognosis.
Because of how rare this genetic condition is an exact prognosis is still not known and varies. Some data has suggested that the median age of onset is 45 years old, but patients with onset as young as 18 years old has also been described. Further, it is believed that the median life expectancy is 6 years but is also extremely variable as it has also been reported that some patients survived up to 29 years after the onset of symptoms.
While gaining a definitive prognosis for this disease studies suggest a few different techniques that may or may not benefit in getting a better prognosis for the individual patient:
Epidemiology.
Epidemiological studies for rare diseases are difficult to have exact and known values that are still difficult to find. However, most studies show the mean age of onset was 43 years old (range 18–78 years old), with a mean death at 53 years (range 23–84 years) and the mean disease duration was found to be 6.8 years (range 1–29 years).
History.
LENAS was first reported in multiple members of a large Swedish pedigree in 1984. In this family, 17 out of 71 subjects from 4 generations were affected with this disease. It was found that the age onset of this family varied from 8 to 60 years of age. The age of death in this family was 39 to 89 years with a time between onset and death varied from 3 months to over 30 years. Some patients in this family rapidly developed severe dementia and died a few months after this onset whereas others had a more prolonged progression of the disease. This family was also to have reported sporadic patients as well.
Prevalence.
To date, the prevalence of this disease is unclear. Literature has few publications to date of this due to the rarity of the disease. However, a study done in 2011 found information dating back to 1970 that identified 51 individual cases fulfilling criteria to be identified. Today, there could be more confirmed cases but these data have not increased significantly.
Research.
The need for future research in this disease is necessary for varied reasons. First, this disease is still so rare and it is to this date very difficult to diagnose. Further, the signs and symptoms of this disease are often confused with other diseases that are more well known and misdiagnosis often occurs. This disease can commonly be mistaken for Multiple Sclerosis (MS) or another form of a more common leukoencephalopathy or neurodegenerative diseases as well. However, some current research has been done primarily on case studies in which scientists are attempting to find new mutations or new ways to diagnose. There are a few studies however that pose to lean in the direction of therapeutical's using hematopoietic stem cell transplantation therapy.
Hematopoietic Stem Cell Therapy.
Bone marrow is the soft spongy area in some larger bones of the body that produces many cells which make up red blood cells, white blood cells and platelets. These cells are developed from a type of cell found in bone marrow, termed hematopoietic stem cells. The body is able to direct these stem cells to develop in the blood at any given moment and this is a rapid process. Most of the stem cells remain in the marrow until they are mature which then they are released for specific functions in the body such as carrying oxygen, providing infection protection, and helping blood clotting. Stem cells found in circulating blood are able to be extracted for stem cell therapy use and research.
A study done using hematopoietic stem cell therapy (HSCT) showed clinical benefit but suggested further exploration must be done. Findings using HSCT was beneficial in recessive disorders and saw that it may similarly enhance CSF1R signaling after partial loss seen in LENAS. In the subjects who had LENAS were introduced to HSCT and the finding of further progressed cells was minimal 15 years after the therapy was finished. The most important finding in the subject was that they retained a high level of communication and survived beyond 15 years after onset of symptoms. This is very rare for LENAS as it has been reported to be averaged at 6.8 years for surviving after the onset. This finding provides hope for future research direction and suggests that there may be great benefit to slow the progression of LENAS using HSCT.


Allothalamus

The Allothalamus is a division used by some researchers in describing the thalamus.
Paramedian formation.
This or periventricular formation lies along the wall of the third ventricle. In man where there is no or almost no adhaesio interthalamica this is reduced to a thin layer medial to the medial nucleus. This lamina has no clear subdivisions and the formation may be seen as one entity. Contrarily to the isothalamus it stains for numerous mediators. Its connections are not really known, participating in periventricular systems.
Intralaminar-limitans formation Il-Li.
This does not include the central region (centre-median, see below). Along with the paramedian formation, it makes a kind of capsule around the medial nucleus ("circular nucleus"). Together they are deeply regressive structures in evolution. Only its anterior part is clearly present in humans. Caudally, dorsal to the central region it breaks into small islands. Some of them are just posterior to the central complex. In the part dorsal to the complex, the aspect is deeply different from what is seen in macaques where "intralaminar" elements receive particular afferents such as cerebellar and tectal. The tectal afferents observed in macaques for instance have probably moved to the lateral region in humans, in VImM and VA. In any case the connections demonstrated in macaques cannot be assessed simply. The regression of intralaminar elements is to be contrasted with the huge increase of the cerebral cortex in man to ponderate the role of the intralaminar formation into the unspecific activation of the cortex. The nucleus limitans appears with primates. Its lower border clearly indicate that of the pulvinar. Along with intralaminar islands, it receives spinothalamic afferences. Having the same properties, it is linked to them in the intralaminar-limitans formation. The posterior part receives axons from the spinothalamic fascicle and from the tectum. It sends its axons to the striatum constituting in man only a weak part of the thalamo-striatal connection.
Central region C.
This corresponds to the "centre médian -parafascicular complex". Considering its ontogenesis, position, structure and connections, it does not belong, as usually said, to the intralaminar group. It is almost everywhere surrounded by a capsule. Dorsally this is made by a ventral extension of the lamina medialis but laterally, this is made by the lamina centralis separating it from the lateral region. In upper primates, the region or complex is not constituted by two but by three nuclei with their own neuronal species (Fenelon "et al."1994). From there, two opposed interpretations were proposed concerning the belonging of the intermediate part: either to the centre médian (Vogt & Vogt, 1941) or to the parafascicular nucleus (Niimi et al., 1960). This is undecidable. It has thus been proposed to group the three elements together in the regio Centralis (since it is a classical nucleus). From medially to laterally, one describes the pars parafascicularis, the pars media and the pars paralateralis. The first two strongly stain for acetylcholinesterase. They have strong connections with elements of the basal ganglia system. The pars parafascicularis is linked bilaterally to the substantia nigra. It receives in addition axons from the superior colliculus. Its sends axons to the associative striatum. The pars media receives a major connection from the medial pallidum. It also receives axons from the motor and premotor cortex. Its major efference is to the striatum (sensorimotor territory) (Fenelon "et al." 1991). It is one element of the Nauta-Mehler's circuit (striatum-pallidum-pars media-striatum). The two medial elements are the main contributors to the thalamo-striatal connection. Their mediator is glutamate. The third, most lateral part (paralateral) receives from and sends axons to the central cortex, motor and premotor. The central region thus appears not as a nonspecific part of the thalamus but as one element of the basal ganglia system: one of its regulators. see Primate basal ganglia system.


Vestibular nuclei

The vestibular nuclei (VN) are the cranial nuclei for the vestibular nerve located in the brainstem.
In Terminologia Anatomica they are grouped in both the pons and the medulla in the brainstem.
Structure.
Path.
The fibers of the vestibular nerve enter the medulla oblongata on the medial side of those of the cochlear, and pass between the inferior peduncle and the spinal tract of the trigeminal nerve.
They then divide into ascending and descending fibers. The latter end by arborizing around the cells of the medial nucleus, which is situated in the area acustica of the rhomboid fossa. The ascending fibers either end in the same manner or in the lateral nucleus, which is situated lateral to the area acustica and farther from the ventricular floor.
Some of the axons of the cells of the lateral nucleus, and possibly also of the medial nucleus, are continued upward through the inferior peduncle to the roof nuclei of the opposite side of the cerebellum, to which also other fibers of the vestibular root are prolonged without interruption in the nuclei of the medulla oblongata.
A second set of fibers from the medial and lateral nuclei end partly in the tegmentum, while the remainder ascend in the medial longitudinal fasciculus to arborize around the cells of the nuclei of the oculomotor nerve.
Fibers from the lateral vestibular nucleus also pass via the vestibulospinal tract, to anterior horn cells at many levels in the spinal cord, in order to co-ordinate head and trunk movements.
Subnuclei.
There are 4 subnuclei; they are situated at the floor of the fourth ventricle.


5-HT receptor

5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission. The serotonin receptors are activated by the neurotransmitter serotonin, which acts as their natural ligand.
The serotonin receptors modulate the release of many neurotransmitters, including glutamate, GABA, dopamine, epinephrine / norepinephrine, and acetylcholine, as well as many hormones, including oxytocin, prolactin, vasopressin, cortisol, corticotropin, and substance P, among others. Serotonin receptors influence various biological and neurological processes such as aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. They are the target of a variety of pharmaceutical and recreational drugs, including many antidepressants, antipsychotics, anorectics, antiemetics, gastroprokinetic agents, antimigraine agents, hallucinogens, and entactogens.
Serotonin receptors are found in almost all animals and are even known to regulate longevity and behavioral aging in the primitive nematode, "Caenorhabditis elegans".
Classification.
5-hydroxytryptamine receptors or 5-HT receptors, or serotonin receptors are found in the central and peripheral nervous systems.
They can be divided into 7 families of G protein-coupled receptors except for the 5-HT3 receptor, a ligand-gated ion channel, which activates an intracellular second messenger cascade to produce an excitatory or inhibitory response.
In 2014, a novel 5-HT receptor was isolated from the small white butterfly, Pieris rapae, and named pr5-HT8. It does not occur in mammals and shares relatively low similarity to the known 5-HT receptor classes.
Subtypes.
The 7 general serotonin receptor classes include a total of 14 known serotonin receptors. The specific types have been characterized as follows:
Note that there is no 5-HT1C receptor since, after the receptor was cloned and further characterized, it was found to have more in common with the 5-HT2 family of receptors and was redesignated as the 5-HT2C receptor.
Very nonselective agonists of 5-HT receptor subtypes include ergotamine (an antimigraine), which activates 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. LSD (a psychedelic) is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist.
Expression patterns.
The genes coding for serotonin receptors are expressed across the mammalian brain. Genes coding for different receptors types follow different developmental curves. Specifically, there is a developmental increase of HTR5A expression in several subregions of the human cortex, paralleled by a decreased expression of HTR1A from the embryonic period to the post-natal one.
5-HT-like.
A number of receptors were classed as "5-HT-like" - by 1998 it was being argued that, since these receptors were "a heterogeneous population of 5-HT1B, 5-HT1D and 5-HT7" receptors the classification was redundant.


Krasnohrad

Krasnohrad or Krasnograd () is a city in Kharkiv Oblast (province) of Ukraine. From 1784 to 1922, it was known as Kostyantynohrad or Konstantingrad. It serves as the administrative center of Krasnohrad Raion. In 2020, the population was estimated to be
The city of Krasnohrad was founded as a Bilevska fortress in 1731–1733, as part of the Ukrainian line defence fortifications, which ran from the Dnieper to the Donets. The fortress was named after the Russian military garrison that was formed in a town of Belyov (near Tula). In 1784, the fortress was renamed Kostyantynohrad, and in 1797, it received city status. In 1922, it was renamed Krasnohrad.
It is located on the Berestova River to the south of the city of Kharkiv.


Journal of Neuroscience Methods

The Journal of Neuroscience Methods is a peer-reviewed scientific journal covering scientific techniques and protocols used in any branch of neuroscience research. It was established in 1979. The editor-in-chief is Giuseppe Di Giovanni, Professor of Neuroscience at the University of Malta and Honorary Professor at Cardiff University, UK. Journal Neuroscience Methods is published 18 times a year by Elsevier.
Associate Editors: Vince Calhoun (The Mind Research Network, Albuquerque, New Mexico, USA), David Carter (Cardiff University, Cardiff, UK), Philippe De Deurwaerdère (Université de Bordeaux, Bordeaux Cedex, France), Robert Hampson (Wake Forest University Health Sciences, Winston-Salem, North Carolina, USA), Liset Menendez de la Prida (Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain), Gernot Riedel (University of Aberdeen, Foresterhill, Scotland, UK), Floris Wouterlood (Vrije Universiteit Amsterdam, Amsterdam, Netherlands).
Previous editors in Chief: Vincenzo Crunelli (Cardiff University, Cardiff, UK), Greg Gerhardt (University of Kentucky, Chandler Medical Centre, Lexington, Kentucky, USA), J.S. Kelly (Department of Pharmacology, University of Edinburgh, Edinburgh, UK) and N. Bowery (University of Birmingham, Birmingham, UK).
Abstracting and indexing.
The journal is abstracted and indexed in:
According to the "Journal Citation Reports (JCR)", the journal has a 2018 impact factor of 2.785, ranking it 31st out of 79 journals in the category "Biochemical Research Methods" and 135th out of 267 journals in the category "Neurosciences".


Sharp waves and ripples

Sharp waves and ripples (SWRs) are oscillatory patterns in the mammalian brain hippocampus seen on an EEG during immobility and sleep. There are three major network oscillation patterns in the hippocampus: theta waves, SWRs and gamma waves. Gamma oscillations are found in all major brain structures, whereas theta and sharp waves are specific to the hippocampus and its neighbouring areas. SWRs are composed of large amplitude sharp waves in local field potential and associated fast field oscillations known as ripples. SWRs are shown to be involved in memory consolidation and the replay of wakefulness-acquired memory. These network oscillations are the most synchronous patterns in the brain, making them susceptible to pathological patterns such as epilepsy.
History and background.
Neuronal oscillations are important components of neuroscience research. During the last two decades, hippocampal oscillations have been a major focus in the research of neuronal oscillations. Among different oscillations present in the brain, SWRs are the first and only population activity that start in the developing hippocampus, but they are the least understood network pattern of the hippocampus.
Originally, these large waves were observed by Cornelius Vanderwolf in 1969, and later John O'Keefe investigated SPW-Rs in more detail in 1978 while studying the spatial memory of rats. György Buzsáki and his collaborators studied and characterized SWRs in detail and described their physiological functions and role in different states of the animal.
These patterns are large amplitude, aperiodic recurrent oscillations occurring in the apical dendritic layer of the CA1 regions of the hippocampus. Sharp waves are followed by synchronous fast field oscillations (140–200 Hz frequency), named ripples.
Features of these oscillations provided evidences for their role in inducing synaptic plasticity and memory consolidation. Among these features are their widespread effect on the population neurons in the hippocampus, and the experience-dependent content of participating neurons. Studies have shown that elimination of SWRs by electrical stimulation interfered with rats ability to recall the spatial memory information. These features support functional role of sharp waves and ripples in memory consolidation.
Hippocampal formation.
Structures.
Circuit.
The trisynaptic loop, as the main circuit of the hippocampus responsible for information transfer between the hippocampus and the cortex, is also the circuit producing SWRs. This circuit provides the pathway by which SWRs affect the cortical areas, and also receive inputs from them. Consequently, this loop is shown to be the pathway responsible for conversion of short term memory to long term memory. The trisynaptic loop of the hippocampus is one of the most thoroughly studied circuits for long-term potentiation.
Participant neuronal populations.
Emergence of these self-organized hippocampal events are dependent on interactions between various pyramidal and granule neurons with different types of the interneurons in this circuit. Pyramidal cells of CA3 and CA1 dendritic layer region are important in generating these waves, and they affect the subiculum, parasubiculum, entorhinal cortex, and ultimately neurons of the neocortex.
During SWRs, which last approximately 100 milliseconds, 50,000-100,000 neurons discharge in synchrony, making SWRs the most synchronous event in the brain.
An important concept about the neuronal populations participating in these events is the fact that they are experience-dependent. Sequences that have been active during the animal's activity are the ones participating in SWRs. Activity naturally spreads along the pathways that have stronger synapses. This is one of the features of SWRs providing evidence for their role in memory consolidation.
Network mechanisms of generation.
Self-emergent network.
Population bursts of pyramidal cells in the CA3 region of the hippocampus via CA3 collaterals cause depolarization of pyramidal cells in the dendritic layer of the CA1 which give rise to extracellular negative waves–the sharp waves–followed by fast ripples.
Discharge of pyramidal cells of CA3 region also activates the GABAergic interneurons. Sparse firing of CA1 pyramidal cells and in-phase inhibition from the activated interneurons, give rise to high frequency (200 Hz) network oscillations, which are the ripples. CA1 population bursts lead to highly synchronized activity in the target population of parahippocampal structures.
Effects of neocortical inputs.
In spite of the self-emergent nature of the SWRs, their activity could be altered by inputs from the neocortex via the trisynaptic loop to the hippocampus. Activity of the neocortex during slow wave sleep is deterministic of inputs to the hippocampus; thalamocortical sleep spindles and delta waves are the sleep patterns of the neocortex. These inputs contribute to the selection of different neuronal assemblies for initiation of SWRs, and affect the timing of the SWRs. Different thalamocortical neuronal assemblies give rise to sleep spindles, and these cell assemblies affect the burst initiator for the sharp waves. In this manner, thalamocortical inputs affect the content of the SWRs going to neocortex.
Memory consolidation.
Sharp waves and associated ripples are present in the mammalian brains of the species that have been investigated for this purpose, including mice, rats, rabbits, monkeys and humans. In all of these species, they have been shown primarily to be involved in consolidation of recently acquired memories during the immobility and slow wave sleep. Characteristics of these oscillations, such as having experience dependent neuronal content, being affected by the cortical input, and reactivating neocortical pathways formed through recent experiences, provides evidences for their role in memory consolidation. Besides, some direct evidences for their role come from studies, investigating effects of their removal.
Animal studies indicated that depletion of ripple activity by electrical stimulation, would impair formation of new memories in rats. Furthermore, in spatially non-demanding tasks, such as passive exploration, optogenetic disruption of SPW-R events interferes with the stabilisation of the newly formed hippocampal place cell code (ref, but see ref).
As for humans, what is currently known is that the hippocampus as a whole is important for memory consolidation. The most famous human patient with hippocampal lesion is H.M., whose hippocampus has been removed from both sides of his brain. Studies conducted on HM have clearly proven the role of the hippocampus in shaping the long-term memory. Investigations also provide strong evidence supporting role of the hippocampus in consolidation of specific types of memories such as declarative and spatial memories. However, clear evidence for the role of SPW-R events in memory consolidation in the hippocampus of humans is still missing.
Two stage model of memory.
Based on the research findings about SPW-Rs, in 1989 an influential two stage model of memory proposed by Buzsáki, that subsequent evidences supported it.
Based on this model initial memories of the events are formed during the acquisition and reinforced during replay. Acquisition occurs by theta and gamma waves activating a neuronal pathway for initial formation of the memory. Later this pathway would get replayed following the SPW-Rs propagation to neocortex. Neuronal sequences during replay happen in a faster rate and are in both forward and reverse direction of the initial formation.
Ripples and fast gamma.
In spite of the fact that hippocampal ripples (140–220 Hz) and fast gamma (90–150 Hz) oscillations have similar mechanisms of generation, they are two distinct patterns in the hippocampus. They are both produced as the response of the CA1 region to inputs from the CA3 region. Ripples are only present when theta waves are relatively absent during sharp waves, whereas fast gamma waves occur during theta waves and sharp waves. The magnitude and frequency of both ripples and fast gamma patterns are dependent on the magnitude of hippocampal sharp waves. Stronger excitation from sharp waves results in ripple oscillations, whereas weaker stimulations generate fast gamma patterns. Besides they are shown to be region dependent, ripples that are the fastest oscillations are present in the CA1 region pyramidal cells while gamma oscillations dominate in CA3 region and parahippocampal structures.
Disease state.
Epilepsy.
In addition to ongoing research on the role of SPW-R complexes in memory consolidation and neuronal plasticity, another major area of the attention is their role in development of epilepsy. As mentioned before, SPW-Rs are the most synchronous oscillations observed in the brain; which implies any abnormal activity in this network would bring significant consequences. One of the deviations from normal activity is fast ripples. Fast ripples are a pathologic pattern that emerges from the physiologic ripples. These fast ripples are field potentials of hypersynchronous bursting of excitatory neurons pyramidal cells at frequencies between 250–600 Hz.
Fast ripples activities in the hippocampus considered as pathologic patterns directly associated with epilepsy, but they appear as both physiologic and pathologic activity in neocortex. Although underlying physiology and identifying contributions of fast ripples in generation of seizures are still under investigation and further research, studies are suggesting that fast ripples could be used as a biomarker of epileptogenic tissues.


Nilvadipine

Nilvadipine is a calcium channel blocker (CCB) used for the treatment of hypertension and chronic major cerebral artery occlusion.
Pathohistochemical studies have revealed that the volume of the infarction in the middle cerebral artery occlusion model could be decreased by nilvadipine.
Experimental research.
Nilvadipine was tested in clinical trial as a possible treatment for Alzheimer's disease in Ireland by the Roskamp Institute, Florida, USA and Trinity College, Ireland. Following this study, an international research consortium led by Trinity College Dublin (Ireland) in May 2011 announced the selection for funding of a large-scale European clinical trial of nilvadipine. More than 500 Alzheimer's disease patients will participate in the multicenter phase III clinical trial designed to study the effectiveness of nilvadipine.


Hexestrol

Hexestrol, sold under the brand name Synestrol among others, is a nonsteroidal estrogen which was previously used for estrogen replacement therapy and in the treatment of certain hormone-dependent cancers as well as gynecological disorders but is mostly no longer marketed. It has also been used in the form of esters such as hexestrol diacetate (brand name Sintestrol) and hexestrol dipropionate (brand name Hexanoestrol). Hexestrol and its esters are taken by mouth, held under the tongue, or via injection into muscle.
Medical uses.
Hexestrol has been used in estrogen replacement therapy, for the treatment of breast cancer in women and prostate cancer in men, and for the treatment of certain gynecological disorders.
Pharmacology.
Pharmacodynamics.
Hexestrol has approximately 302% and 234% of the affinity of estradiol for the estrogen receptors (ERs) ERα and ERβ, respectively. The affinity of hexestrol for the ERs is said to be similar to or slightly higher than that of estradiol. Along with diethylstilbestrol, hexestrol has been said to be one of the most potent estrogens known. The total endometrial proliferation dose per cycle of different forms of hexestrol are 70 to 100 mg for oral hexestrol, 45 mg for sublingual hexestrol diacetate, and 25 mg for hexestrol dipropionate by intramuscular injection. These doses are fairly similar to those of estradiol and its esters. Hexestrol induces mammary gland development in rodents similarly to other estrogens.
Pharmacokinetics.
The pharmacokinetics and distribution of hexestrol have been studied with intravenous injection of aqueous solution in women and with subcutaneous injection of oil solution in female goats and sheep.
Chemistry.
Hexestrol, also known as dihydrodiethylstilbestrol, is a synthetic nonsteroidal estrogen of the stilbestrol group related to diethylstilbestrol. Esters of hexestrol include hexestrol diacetate, hexestrol dicaprylate, hexestrol diphosphate, and hexestrol dipropionate.
History.
Hexestrol was first described by Campbell, Dodds, and Lawson in 1938. It was isolated from the demethylation products of anethole.
Society and culture.
Generic names.
"Hexestrol" is the generic name of the drug and its .
Brand names.
Hexestrol has been marketed under a variety of brand names including Synestrol, Synoestrol, Estrifar, and Estronal, among others.
Availability.
Hexestrol has mostly been discontinued and remains available in only a handful of countries. Esters of hexestrol which have been marketed include hexestrol diacetate, hexestrol dicaprylate, hexestrol diphosphate, and hexestrol dipropionate.


Instruction selection

In computer science, "instruction selection" is the stage of a compiler backend that transforms its middle-level intermediate representation (IR) into a low-level IR. In a typical compiler, instruction selection precedes both instruction scheduling and register allocation; hence its output IR has an infinite set of pseudo-registers (often known as "temporaries") and may still be – and typically is – subject to peephole optimization. Otherwise, it closely resembles the target machine code, bytecode, or assembly language.
For example, for the following sequence of middle-level IR code
a good instruction sequence for the x86 architecture is
MOV EAX, a
XCHG EAX, b
ADD a, EAX
For a comprehensive survey on instruction selection, see.
Macro expansion.
The simplest approach to instruction selection is known as "macro expansion" or "interpretative code generation". A macro-expanding instruction selector operates by matching "templates" over the middle-level IR. Upon a match the corresponding "macro" is executed, using the matched portion of the IR as input, which emits the appropriate target instructions. Macro expansion can be done either directly on the textual representation of the middle-level IR, or the IR can first be transformed into a graphical representation which is then traversed depth-first. In the latter, a template matches one or more adjacent nodes in the graph.
Unless the target machine is very simple, macro expansion in isolation typically generates inefficient code. To mitigate this limitation, compilers that apply this approach typically combine it with peephole optimization to replace combinations of simple instructions with more complex equivalents that increase performance and reduce code size. This is known as the "Davidson-Fraser approach" and is currently applied in GCC.
Graph covering.
Another approach is to first transform the middle-level IR into a graphical representation and then "cover" the graph using "patterns". A pattern is a template that matches a portion of the graph and can be implemented with a single instruction provided by the target machine. The goal is to cover the graph such that the total cost of the selected patterns is minimized, where the cost typically represents the number of cycles it takes to execute the instruction. For tree-shaped graphs, the least-cost cover can be found in linear time using dynamic programming, but for DAGs and full-fledged graphs the problem becomes NP-complete and thus is most often solved using either greedy algorithms or methods from combinatorial optimization.
Lowest common denominator strategy.
The "lowest common denominator strategy" is an instruction selection technique used on platforms where processor-supplementary instructions exist to make executable programs portable across a wide range of computers. Under a lowest common denominator strategy, the default behaviour of the compiler is to build for the lowest common architecture. Use of any available processor extension is switched off by default, unless explicitly switched on by command line switches.
The use of a lowest common denominator strategy means that processor-supplementary instructions and capabilities are not used by default.


Agraphesthesia

Agraphesthesia is a disorder of directional cutaneous kinesthesia or a disorientation of the skin's sensation across its space. It is a difficulty recognizing a written number or letter traced on the skin after parietal damage.
Causes.
Agraphesthesia, or the lack of graphesthesia ability, results from brain damage, particularly to the parietal lobe, thalamus, and secondary somatosensory cortex.
A significant relationship has been found between agraphesthesia and people living with Alzheimer's disease. Alzheimer's patients typically experience the lack of sensation in both their dominant and non-dominant hands. Astereognosis, the inability to identify a physical object solely by touch, is commonly found in conjunction with agraphesthesia in Alzheimer's patients. Some research suggest that agraphesthesia can be used to track the cognitive decline in Alzheimer's patients once the disease is diagnosed.
Studies also show that patients diagnosed with schizophrenia and their immediate relatives have a decreased ability to perform graphesthesia tasks in comparison to people without relatives diagnosed with schizophrenia. Therefore, researchers have suggested that somatosensory dysfunction in the parietal cortex is a potential cause of graphesthesia impairments.
Diagnosis.
A diagnosis of agraphesthesia is determined using a variety of tests, such as the Palm Writing subtest. The Palm Writing subtest involves a series of trials where patients are asked to identify whether an X or an O was written on the palm of their hand. Just as numbers and shapes may be used in addition to letters, similar neurological tests can be carried out on other parts of the body, such as the forearm and the abdomen. For tests of graphesthesia like the Palm Writing subtest, it is important that subjects do not see what is being traced on their palm because this can bias the subjects’ responses. Subjects can be blindfolded or a screen can be used to obstruct the subject's view of the area being tested.


Ocular straylight

Ocular straylight is a phenomenon where parts of the eye scatter light, creating glare. It is analogous to stray light in other optical systems; scattered light reaches the retina but does not contribute to forming a correct image.
One can observe the effect of straylight by looking at a distant bright light source against a dark background. If the source is small, it would look like a small bright spot if the eye imaged it perfectly. Scattering in the eye makes the source appear spread out, surrounded by glare. The disability glare caused by such a situation has been found to correspond precisely to the effect of true light. As a consequence, disability glare was subsequently defined by this true light, called "straylight".
Individual differences.
Straylight can differ considerably between individuals. Aging of the crystalline lens of the human eye causes straylight to become worse. Lens extraction and artificial lens implantation is an effective treatment.
Less common causes for straylight include:


Superior salivatory nucleus


Tax on the stupid


Nu Rho Psi

Nu Rho Psi (ΝΡΨ or NRP) is the National Honor Society in Neuroscience, founded in 2006 by the Faculty for Undergraduate Neuroscience and now an independent honor society. Nu Rho Psi is a non-profit, grass-roots organization of neuroscientists and is governed by a National Council elected by the members. Charters have been awarded to chapters at colleges and universities in all regions of the United States of America. Nu Rho Psi currently consists of 80+ chapters and 5,100+ lifetime members. Prominent honorary members include Dr. Larry Squire (University of California – San Diego), Dr. Robert Sapolsky (Stanford University), Bruce McEwen (Rockefeller University) and the 14th Dalai Lama of Tibet.
Nu Rho Psi is a tax-exempt 501(c)(3) public charity incorporated in the state of Ohio, US. The Honor Society has a small part-time staff housed at Baldwin Wallace University (Berea, Ohio, US) and is managed by a member-elected national council consisting of student and faculty volunteers from many colleges and universities throughout the United States of America.
Mission, Greek letter designation, and insignia.
The official mission and purpose of Nu Rho Psi is to: (1) encourage professional interest and excellence in scholarship, particularly in neuroscience; (2) award recognition to students who have achieved such excellence in scholarship; (3) advance the discipline of neuroscience; (4) encourage intellectual and social interaction between students, faculty, and professionals in neuroscience and related fields; (5) promote career development in neuroscience and related fields; (6) increase public awareness of neuroscience and its benefits for the individual and society; and, (7) encourage service to the community.
The Greek letters of the honor society, “ΝΡΨ”, designates the interdisciplinary science that engages its members in the study of the brain and the rest of the nervous system. The Greek letter Nu (Ν, ν) stands for the noun Nous (pronounced “noose”), meaning “Mind”. The letter Rho (Ρ, ρ) stands for the verb Ρueaoai (pronounced “hruesthigh”) meaning, “to cure”. The letter Psi (Ψ, ψ) stands for the noun Psyche (pronounced “psuke”), meaning “life.”
History.
Nu Rho Psi, the National Honor Society in Neuroscience, was founded in 2006, but its history can be traced to the early 1990s with the founding of the Faculty for Undergraduate Neuroscience (FUN). In its formative years, Nu Rho Psi was governed by the FUN Council but, as the society grew, FUN decided that Nu Rho Psi would be better served by its own separate council. In 2006 Nu Rho Psi became an independent tax-exempt [501(c)(3)] public charity incorporated in the state of Ohio, US. The first Nu Rho Psi National Council was elected in 2011. The first charters were awarded in 2006 to Baldwin Wallace University (application dated 16 Jun 2006), Baylor University (application dated 6 Nov 2006) and Macalester College (application dated 8 Dec 2006). A full history of Nu Rho Psi can be found here.
Membership requirements.
Membership is by invitation and is open to undergraduate and graduate students who are making the study of neuroscience one of their major interests and who meet the other academic qualifications. Nu Rho Psi is also open to qualifying neuroscience faculty and alumni of neuroscience programs. Requirements for membership include:
The National Council of Nu Rho Psi awards charters to colleges and universities in the United States that have qualified based on their neuroscience curriculum, faculty expertise, and student research opportunities – among other factors. Students and faculty are elected to membership by the chapter at participating institutions, according to the provisions in the national Nu Rho Psi Constitution and locally adopted by-laws. Any chapter, at its discretion, may establish higher academic standards for eligibility, but may not require lower standards for eligibility. Membership in Nu Rho Psi is open to qualified candidates regardless of age, sex, sexual orientation, race handicap or disability, color, religion, or national or ethnic origin.
The current one-time membership induction fee is $40.00 for students and $50.00 for faculty. At the discretion of individual chapters, there may be additional chapter dues which are determined at the local level. No further fees go to the national organization as membership is for life.
Membership benefits.
Nu Rho Psi membership provides recognition of verified academic excellence in the interdisciplinary field of neuroscience. Students who become members of Nu Rho Psi are selected based on their superior scholarly accomplishments as well as their excellent work in the laboratory. Nu Rho Psi membership is for life and it is often a springboard for the networking and collaboration of like-minded colleagues throughout the U.S.A. interested in the study of the brain. Nu Rho Psi members are provided opportunities to form professional relationships that carry them through their careers in neuroscience. There are both regional and national Nu Rho Psi meetings where young neuroscientists from around the United States gather to share scientific findings. Nu Rho Psi offers competitive travel awards for members to attend and present their research at the annual Society for Neuroscience meeting. Nu Rho Psi also offers competitive small grants to facilitate member's senior theses or summer research projects. Nu Rho Psi mentors members through publications (e.g. The Nu Rho Psi Guide to Graduate School in Neuroscience ) and other outreach activities of the society. News and additional information about benefits are available to members via the Nu Rho Psi online newsletter. Members receive membership certificates and lapel pins as an indication of the honor they have earned.
Activities and regional/national meetings.
As documented in the Nu Rho Psi News, individual Nu Rho Psi chapters organize a variety of service and educational activities throughout the year. Regional Vice-Presidents provide leadership of the federation of chapters in the region where they reside and represent their region through service on the national council. They are also responsible for promoting Nu Rho Psi activities during the regional undergraduate neuroscience meetings (e.g. mGluRs, NEURON, SYNAPSE, MIDBRAINS). Nu Rho Psi holds an annual National Membership meeting during the Society for Neuroscience conference.
In 2014 the national council established an annual theme for its chapters. Nu Rho Psi chapters use this theme as a focal point in planning educational and service activities for the academic year.
List of current chapters.
Nu Rho Psi chapters are divided into four regional areas in the United States (Northeast, Midwest, South, and West), each with their own representative vice-president.
National council.
Members of the national council are elected by the Nu Rho Psi membership.


David Capel

David John Capel (6 February 19632 September 2020) was an English cricketer who played for Northamptonshire and England. Cricket writer Colin Bateman noted that "Capel was one of those unfortunate cricketers who became tagged as being the next all-rounder to fill Ian Botham's boots". He was well known for his long stint with Northamptonshire as a player as well as coach for nearly 32 years. He was regarded as one of the icons of the Northamptonshire club. He died on 2 September 2020, at the age of 57, after being diagnosed with a brain tumour in 2018.
Playing career.
An irrepressible enthusiast, Capel was a batsman who bowled but, because of his dual role, found himself pushed down the order. He joined Northampton county in 1980 as an "apprentice cricketer" without much experience and made his first-class debut in 1981 against the visiting Sri Lankans. He played in 313 first-class matches, scoring 12,202 runs and taking 546 wickets. Capel also featured in 345 List A matches scoring 7,011 runs and taking 237 wickets. He spent most of his playing career with Northamptonshire, representing the club in 270 first-class matches and 300 List A matches. He retired from first-class cricket in 1998.
He made his international Test match debut against Pakistan in 1987 at Headingley, becoming the first Northamptonshire-born cricketer in 77 years to represent England in test cricket after George Thompson. He walked to the crease when England were at 31 for 5 and scored a fifty against Imran Khan and Wasim Akram. He eventually top scored in England's first innings total of 136 with 53 off 161 balls. He registered his career best of 98 in punishing conditions in Karachi against Pakistan in 1987–88, in his fourth Test match in his career. However, he followed it up with a string of poor scores and was discarded with a batting average below 20 and a bowling average above 50 in both forms of the international game. He dismissed Viv Richards three times in his career, as well as forming part of the pace quartet which won in Jamaica in 1989–90. He ended up playing fifteen Tests and twenty-three One Day Internationals (ODIs) for England.
Later career.
After retiring from playing competitive cricket in 1998, Capel became the director of excellence of the Northamptonshire County Cricket Club in 1999. Capel also eventually took over the academy at Northamptonshire. He became the head coach of the Northamptonshire County Cricket Club in 2006, replacing Kepler Wessels. He served as the head coach of the county until 2012. On 2 July 2012, Northants Cricket sacked him from the position of head coach of the club following the conclusion of the 2012 Twenty20 Cup. It ended his 32-year-long association with the club.
After eight years as the head coach of Northamptonshire, Capel became the assistant coach of the England women's cricket team in 2013, staying in the role until 2015. In October 2016, he was appointed by the Bangladesh Cricket Board (BCB) as the head coach of the Bangladesh women's cricket team, initially for an agreed period of four months. However, his contract was extended by the BCB, and he served as Bangladesh women's team head coach until 2018. In May 2020, he was inducted into the Northamptonshire CCC Hall of Fame.
Capel underwent surgery in 2018 after being diagnosed with a brain tumour. Having battled the condition for two years, he died from complications on 2 September 2020.


Longitudinal striae

In human neuroanatomy, the longitudinal striae (also striae lancisi or nerves of Lancisi) are two bundles of fibres embedded in the indusium griseum running along the corpus callosum of the brain. They were originally described by Italian physician, epidemiologist and anatomist Giovanni Maria Lancisi. The striae are categorized as medial longitudinal stria and lateral longitudinal stria; the area between the striae is a useful neurosurgical mark of the middle of the corpus callosum.
After the indisium griseum curves along the rostrum of the corpus callosum the combined striae continue toward the amygdala as part of the diagonal band of Broca.


International Neuroethics Society

The International Neuroethics Society (INS) is a professional organization that studies the social, legal, ethical, and policy implications of advances in neuroscience. Its mission is to encourage and inspire research and dialogue on the responsible use of advances in brain science.
History.
The INS was formed as the Neuroethics Society in May 2006 in Asilomar, California by a multidisciplinary group of 13 members, including neuroscientists, psychologists, philosophers, bioethicists and lawyers. This group formed the INS following the first meeting solely devoted to neuroethics held in San Francisco in 2002, entitled 'Neuroethics: Mapping the Field'. This meeting was co-hosted by Stanford University and the University of California, San Francisco (UCSF), and sponsored by the Dana Foundation. This event prompted the attending and future founders of the INS to meet again and discuss the creation of a society devoted to neuroethics. The formation of the Neuroethics Society was formally announced in July 2006.
The founding president of the INS was Professor Steven Hyman, who served as President from 2006 to 2014. Hyman stated that the role of the Society was to study the issues related to the nervous system that are not neatly contained within traditional bioethics, as well as to bridge the gap between advances in neuroscience and the world of policy and ethics.
The Neuroethics Society was renamed the International Neuroethics Society in 2011, prior to the Society's 2011 Annual Meeting, to reflect its international membership and mission.
The official journal of the INS is the "American Journal of Bioethics-Neuroscience" (AJOB-Neuroscience), which has Paul Root Wolpe as its Editor-in-Chief. The journal launched in 2007 as a section of the American Journal of Bioethics and became an independent journal in 2010, publishing four issues a year.
Members.
The INS is an international organisation, with over 300 members. Membership is open to anyone with an interest in neuroethics, including students, for whom there is a discounted rate.
Governance.
The INS is a non-profit organisation and was formed by a grant from the Dana Foundation. The society has its headquarters in Bethesda, Maryland, USA.
Annual Meeting.
In May 2007, the INS sponsored a forum on the ethics of neuroenhancement in Washington, DD, which was hosted by the Dana Foundation. This was followed by the first Annual Meeting of the INS in 2008, also held in Washington, DC. This 2-day meeting was held prior to the Society for Neuroscience (SfN) annual conference was attended by over 200 people.
Since 2010, the INS has continuously held a meeting annually as a satellite of the Society for Neuroscience conference. In addition to plenary speakers, panel discussions, networking and mentoring sessions, researchers are invited to present posters of their work. The dates, locations, themes and program information for past INS annual meetings are as follows:
In addition to the Annual Meeting, the INS collaborates with other organizations in programs on neuroethics and related topics each year, including events at the Federation of European Neuroscience Societies (FENS) and the British Neuroscience Association.
Response to the Presidential Commission for the Study of Bioethical Issues.
In 2014, the Presidential Commission for the Study of Bioethical Issues, which advises the President of the United States on bioethical issues arising from advances in biomedicine and related areas of science and technology, asked for public comment on the ethical considerations of neuroscience research and the application of neuroscience research findings. In response, the INS listed the top 12 areas of importance for consideration by the Commission, which were published in the "Journal of Law and the Biosciences". The INS detailed the top 5 important areas that will have an ethical impact on society as the Human Brain Projects (both the UK and USA versions), human enhancement (the use of 'smart drugs' by healthy people), neurotechnology, responsibility and the law and mental health and brain disorders. Members of the Presidential Commission attended the INS Annual Meeting in November 2014 to further discuss the ethical issues surrounding neuroscience research.


Median raphe nucleus

The median raphe nucleus (MRN or MnR), also known as the nucleus raphes medianus (NRM) or superior central nucleus, is a brain region composed of polygonal, fusiform, and piriform neurons, which exists rostral to the nucleus raphes pontis. The MRN is located between the posterior end of the superior cerebellar peduncles and the V. Afferents of the motor nucleus. It is one of two nuclei, the other being the dorsal raphe nucleus (DnR), in the midbrain-pons.
The MRN projects extensively to the hippocampus, which is known to be essential for the formation of long-term memory. One recent study found that this raphe–hippocampus pathway plays a critical role in regulation of hippocampal activity and likely associated memory consolidation processes. It has also been found to play a role in anxiety and depression, as one of the few parts of the brain that creates tryptophan hydroxylase.
Description.
The median raphe nucleus contains 5-hydroxytryptamine (serotonin, 5-HT) cell bodies that give rise to the majority of the ascending 5-HT projections to the forebrain limbic areas that control emotional behavior. Because a dense population of neurons in the median raphe nucleus primarily contain serotonin, a prominent neurotransmitter in the median raphe nucleus is serotonin (5-HT). Projections from the MRN extend to forebrain structures. Distinct projection areas of the MnR innervates the medial septum, cingulate and dorsal hippocampus. According to a study by McKenna and Vertes, around 8–12% of cells of the MnR were retrogradely double-labeled after paired injections in the Medial septum CA1 region, Medial Septum CA3 region, Medial Septum Dentate Gyrus of the dorsal hippocampus, the lateral Medial Septum Dentate Gyrus, and the Medial Septum ventral hippocampus. These cells of the MnR that send collateral projections to the Medial Septum and hippocampus may serve a unique role in modulation of desynchronization of hippocampus EEG. Also, the MnR has significantly more single- and double-labeled cells after paired injections to the various Medial Septum and hippocampus regions than in DnR which demonstrate that MnR has more stronger projections to the Medial Septum and hippocampus than the DnR. MnR fibers are course and large with spherical varicosities. Neurotoxic 5-HT-releasing agents selectively destroy DnR projection fibers without affecting the dense coarse fibers from the MnR. Most of the fibers that distribute to the medial septum terminate selectively within the medial septum-vertical limb of the diagonal band nucleus (MS/DBv) and lateral aspects of lateral septum. Most of the pronounced projections to hippocampal formation (HF) distribute to the stratum lacunosum-molecular of Ammon’s horn and granule cell layer and adjacent inner molecular layer of the dentate gyrus (DG).
Projections stemming from the MRN modulate dopaminergic activity within the forebrain. Additionally MnR projections are part of a behavioral disinhibition/inhibition system that produces phenotypes resembling behavioral variations manifested during manic and depressive phases of bipolar disorder.
Inhibition of the MRN in cats by lysergic acid diethylamide (LSD) and psilocin, two serotonin agonist hallucinogens, leads to dose dependent behavioral changes, indicating the MRN may be an important site of action for humans hallucinations.
The MRN projects extensively to the hippocampus, which is known to be essential for the formation of long-term memory. One recent study found that this raphe–hippocampus pathway plays a critical role in regulation of hippocampal activity and likely associated memory consolidation processes. It has been shown that the MRN is a contributor of serotonergic agents, especially 5-HT to the hippocampus. These findings, together with the demonstration that serotonergic agents block Long Term Potentiation (LTP) and 5-HT antagonists enhance LTP and/or memory makes it clear that the MRN plays a part in formation of long term memory in the hippocampus.
The MRN was found to play a vital role in hippocampal desynchronization; it exerts an inhibitory effect on the mechanism for hippocampal theta wave generation. Also, median raphe nucleus suppresses theta bursts of the medial septal area neurons. Numerous studies reveal that lesions in the MRN continuously caused ongoing theta activity, and when the MRN was injected with pharmacological agents, the neurons displayed inhibited activity or reduced excitatory to drive them to produce theta at short latencies and for long durations. Therefore, MRN is a functional antagonist of the reticular formation which plays a critical role in hippocampal theta generation.
Function.
The MRN plays a role in the serotonin pathway. According to the study by Van De Kar and Lorens, it is the main source of 5-hydroxytryptamine (5-HT) to other parts of the brain"." 5-HT is another name for serotonin which is a neurotransmitter that is affected by many physical and emotional processes, including depression, mood, social functioning, exercise, and diet"." The MRN, when stimulated, significantly increases the amount of 5-HT present in the brain. This aided in forming the conclusion that the neurons in the MRN is the main contributor of 5-HT to the dorsal hippocampus as well as anterior and posterior cortical areas. Furthermore, the MRN was found to an area in the brain that relates to inhibitory control by GABA of serotonin (5-HT). The "gamma"-Aminobutyric acid (GABA) acts an inhibitory transmitter–when GABA antagonist were injected in the median raphe nucleus of rat, it was found that there was increase in serotonin turnover. Such relationship is also seen in when the MRN is electrically stimulated and as a result behavioral inhibition is induced in rats. These behaviors that are typically seen in rats during stressful situations involved crouching, teeth chattering, piloerection, and micturition. When the MRN is electrically stimulated, the behavioral response was not only suppressed but there was a counteraction with para-chlorophenylalanine (PCPA), a serotonin synthesis inhibitor. Such results demonstrate that the MRN is involved in behavioral inhibition as well.
Another function of the MRN is that it plays a role in depression. It has been discovered that the MRN is one of the few parts of the brain that creates tryptophan hydroxylase. Tryptophan hydroxylase is a rate-limiting enzyme that works with serotonin. When the levels of tryptophan hydroxylase 2 mRNA are elevated then more tryptophan hydroxylase is created. These elevated levels are associated with individuals who present as depressed suicides when compared to the nonpsychiatric controls.
Besides depression, MRN has been examined for its potential role in anxiety regulation. In examining the MRN, various animal models have shown that an inactivation of neurons containing the serotonin transmitter within the median raphe nucleus led to anxiolysis. Anxiolysis refers to medications or drugs, for example, that results in a calm and relaxed state; it can be used to relieve anxiety or as a sedative. Such relationship suggest that the MRN plays a regulatory function in anxiety.
Research.
The use of microdialysis and voltammetry in studies has indicated that neurotransmitter-mediated responses may be different, and chronic treatment with agonists may differentially regulate the MnR and DnR. Results from these studies have demonstrated  the selective vulnerability of MnR or DnR.


Uncinate fasciculus

The uncinate fasciculus is a white matter association tract in the human brain that connects parts of the limbic system such as the temporal pole, anterior parahippocampus, and amygdala in the temporal lobe with inferior portions of the frontal lobe such as the orbitofrontal cortex. Its function is unknown though it is affected in several psychiatric conditions. It is one of the last white matter tracts to mature in the human brain.
Anatomy.
The uncinate fasciculus is a hook-shaped bundle of axons that links anterior portions of the temporal lobe with the inferior frontal gyrus and the lower surfaces of the frontal lobe. It arises in the anteriorior temporal lobe and amygdala,in the temporal lobe curving in an upward pathway behind the external capsule inward of the insular cortex and continuing up into the posterior part of the orbital gyrus. It does not appear to have cell bodies in the hippocampus proper.
The average length of the uncinate fasciculus is 45 mm with a range 40–49 mm. Its volume in adults is 1425.9±138.6 mm3, being slightly larger in men, at 1504.3±150.4, than women 1378.5±107.4.
It has three parts: a ventral or frontal extension, an intermediary segment called the isthmus or insular segment and a temporal or dorsal segment.
Function.
The uncinate fasciculus is a bi-directional pathway between the temporal lobe and frontal lobe; it is traditionally considered to be part of the limbic system. It has been proposed that the uncinate fasciclus allows mnemonic representations stored in the temporal lobe to interact with and guide decision making in the frontal lobe.
Diffusion tensor imaging, a reconstruction model available from a diffusion MRI scan, shows a greater fractional anisotropy on the left side than on the right. The difference in this measure of anisotropy has been linked to the left hemispheric specialization for language. However, the use of electrical brain stimulation upon it fails to disrupt language, suggesting it might not be involved in language, though it is possible that this disruption failed to happen because it was functionally compensated by alternative pathways.
The uncinate fasciculus appears to have a role in some, but not all, types of learning and memory. Reversal learning, in which a stimulus-reward association is learned over many trials, then reversed such that the initial stimulus is no longer is associated with a reward, is associated with individual variation in the uncinate fasciculus. In addition, the ability to learn associations through trial and error, such as the pairing of a name with a face, correlates with uncinate fasciculus microstructure. This relates to early work showing that surgical damage to the uncinate fasciculus is reliably associated with deficits in proper name retrieval.
Development.
The uncinate fasciculus has the longest period of development in terms of fractional anisotropy as it alone amongst the major white fibre tracks continues to develop until the age of 30. Developmental disorders with core problems relating to memory retrieval, reward and valuation computation, and impulsive decision making may be linked to aberrations in uncinate fasciculus microstructure, e.g. temporal lobe epilepsy and conduct disorder.
Moreover it seems to be developmentally vulnerable. In 12-year-old males that were preterm, abnormalities measured by fractional anisotropy in the left anterior uncinate correlated with verbal IQ, full-scale IQ, and Peabody Picture Vocabulary Test-Revised scores. In 10-year-old children who have suffered socioemotional deprivation, the left uncinate fasciculus shows reduced fractional anisotropy compared to that in other children, and this might underlie their cognitive, socioemotional, and behavioral difficulties.
Clinical significance.
Abnormalities within the fiber bundles of the uncinate fasciculus have been linked to a host of neuropsychiatric disorders, some consistently, some inconsistently. For instance, studies of individuals with social anxiety and schizophrenia have reported changed in diffusion metrics of the uncinate. Unfortunately these findings frequently fail to replicate, the directionality of effects is mixed, and there is no specificity between findings in the uncinate and these particular diseases. An in-depth review of the clinical literature noted that “the uncinate fasciculus per se plays either a small role, or no role, in anxiety disorders “ and that “the results of DTI studies measuring changes in uncinate fractional anisotropy values in schizophrenics are contradictory.” Future researchers should focus on using superior diffusion imaging methods as well correlating specific symptoms, rather than presence or absence of disease state, with changes in white matter.
In contrast, microstructural changes to the uncinate fasciculus have been consistently been linked to conduct disorder and psychopathy. This is consistent with studies of gray matter volume which reported that neural regions linked by the uncinate fasciculus—the orbitofrontal cortex and temporal polar cortex/Brodmann area 38 (also known as the temporal pole/temporal polar cortex/anterior temporal lobe)— have decreased volume in individuals with antisocial personality disorder /psychopathy relative to control. Interestingly, Phineas Gage, a railroad worker who had an iron bar go through his left frontal lobe also sustained damage to the uncinate fasciculus. After the accident, his personality was radically transformed, becoming impulsive, making poor decisions, and failing to follow social norms and conventions.
Last, consistent abnormalities in the uncinate fasciculus are found in Alzheimer's disease, semantic dementia, and temporal lobe epilepsy.


Olivopontocerebellar atrophy

Olivopontocerebellar atrophy (OPCA) is the degeneration of neurons in specific areas of the brain – the cerebellum, pons, and inferior olivary nucleus. OPCA is present in several neurodegenerative syndromes, including inherited and non-inherited forms of ataxia (such as the hereditary spinocerebellar ataxia known as Machado–Joseph disease) and multiple system atrophy (MSA), with which it is primarily associated.
OPCA may also be found in the brains of individuals with prion disorders and inherited metabolic diseases. The characteristic areas of brain damage that indicate OPCA can be seen by imaging the brain using CT scans or MRI studies.
The term was originally coined by Joseph Jules Dejerine and André Thomas.
Signs and symptoms.
OPCA is characterized by progressive cerebellar ataxia, leading to clumsiness in body movements, veering from midline when walking, wide-based stance, and falls without signs of paralysis or weakness. Clinical presentation can vary greatly between patients, but mostly affects speech, balance and walking. Other possible neurological problems include spasmodic dysphonia, hypertonia, hyperreflexia, rigidity, dysarthria, dysphagia and neck dystonic posture.
Cause.
Olivopontocerebellar atrophy is hereditary, but has an unknown genetic basis. There are two forms:
A few non-hereditary diseases formerly categorized as olivopontocerebellar atrophy have been reclassified as forms of multiple system atrophy as well as to four hereditary types, that have been currently reclassified as four different forms of spinocerebellar ataxia:
Diagnosis.
A diagnosis of olivopontocerebellar atrophy (OPCA) may be based on a thorough medical exam; the presence of signs and symptoms; imaging studies; various laboratory tests; and an evaluation of the family history.
MRI of the brain may show characteristics of OPCA, such as specific changes in the size of affected parts of the brain. This is more likely as the disease progresses; it is possible to have OPCA and have a normal brain MRI (especially within the first year of symptom onset).
Hereditary OPCA may be suspected based on having a family history, and may be diagnosed by genetic testing (when available) for the condition suspected or known to be present in the family. Sporadic OPCA may be diagnosed if hereditary forms of OPCA, and other conditions associated with OPCA, have been ruled out.
Treatment.
Physiotherapy intervention aims to improve balance and gait of OPCA patients, by stimulating neuroplastic changes in the atrophied neural structure. A challenge-oriented treatment program has previously been shown to be beneficial for individuals with ataxia from OPCA. The treatment program was composed of repetitive training with task challenges (e.g. obstacle course) and/or novel motor skills acquisition over a 12-week period under the supervision of a physiotherapist. Task challenges were progressed only when the patient showed mastery of a task.
Overground harness systems may be used to allow OPCA patients to challenge their balance without chance of falling. Furthermore, home exercise programs and/or aquatic exercises are used to allow more repetitions to facilitate balance learning. Treatment programs should be frequently monitored and adjusted based on a patient's progress. Outcome measures such as the Berg Balance Scale, Dynamic Gait Index and activities-specific balance confidence scales are useful to assess patient's progress over time.


Nose flute

The nose flute is a popular musical instrument played in Polynesia and the Pacific Rim countries. Other versions are found in Africa.
Hawaii.
In the North Pacific, in the Hawaiian islands the nose flute was a common courting instrument. In Hawaiian, it is variously called "hano", "nose flute", by the more specific term "ʻohe hano ihu", "bamboo flute [for] nose," or "ʻohe hanu ihu", "bamboo [for] nose breath".
It is made from a single bamboo section. According to "Arts and Crafts of Hawai`i" by Te Rangi Hiroa, old flutes in the Bishop Museum collection have a hole at the nose area for the breath, and two or three fingering holes. In the three-finger-hole specimen, one fingering hole is placed near the breath hole. Lengths range from .
Oral tradition in various families states that numbers of fingering holes ranged from one to four, and location of the holes varied depending on the musical taste of the player. Though primarily a courting instrument played privately and for personal enjoyment, it also could be used in conjunction with chants, song, and hula. Kumu hula (dance masters), were said to be able to either make the flute sound as though it were chanting, or to chant as they played. Kumu hula Leilehua Yuen is one of the few contemporary Hawaiian musicians to perform with the nose flute in this manner.
Africa.
In the Congo, the nose flute is played by eight ethnic groups.
Philippines.
In the Philippines, the nose flute ("pitung ilong" in Tagalog), or the kalaleng of the northern Bontok people ("tongali" among the Kalinga people), is played with the extreme forward edge of the right or left nostril. Because the kalaleng is long and has a narrow internal diameter, it is possible to play different harmonics through overblowing—even with the rather weak airflow from one nostril. Thus, this nose flute can play notes in a range of two and a half octaves. Finger holes in the side of the bamboo tube change the operating length, giving various scales. Players plug the other nostril to increase the force of their breath through the flute.
Taiwan.
In Southern Taiwan, Paiwan people play twin-pipes nose flute. They also play twin-pipes mouth flute.
New Zealand.
Historically in New Zealand, the Māori carved nguru from wood, the stem of a gourd and whale's teeth. Nguru were often adorned with very elaborate carvings, befitting what is considered a sacred object. Although Nguru are commonly known as nose flutes, it is only the smaller instruments that can be played with the nose, more commonly Nguru are played with the mouth.
The Māori kōauau ponga ihu, a gourd nose flute, was also part of the nose flute tradition; note that a similarly constructed gourd nose flute, ipu ho kio kio was also used in Hawaii. The maker would form a nose hole in the neck (or stem) of the gourd, by cutting off the neck at a fairly small cross section. This small hole is placed under the player's nostril, in order to generate the flute-tone. The "kōauau ponga ihu" functions as an ocarina in its acoustic principles. Several notes of a scale can be obtained by drilling fingerholes into the "bowl" of the gourd.
Tonga.
A variation, the 'Fangufangu' nose flute of the island of Tonga is made with intact node walls at both ends of the bamboo tube, with the nostril holes on the side in front of the nodes (along with side finger holes) and a hole in the middle of the tube, acting as a vent hole, and taking the place of the open distal end. Thus the 'Fangufangu' can be played from either end, and the disposition of the fingerholes differ from node to vent hole so two alternating scales can be played, but only one scale at a time.


External granular layer (cerebral cortex)

The external granular layer of the cerebral cortex is commonly known as layer II. It is different from the internal granular layer of the cerebral cortex (commonly known as layer IV).
Layer II is often grouped together with layer III and referred to as layer II/III.
Layers I, II, and III are together referred to as the supragranular layers, because they are above layer IV.
Brodmann has this to say about layer II:
"The most inconstant or variable layers are Meynert's two so-called granular layers, layers II and IV of the basic pattern (the outer and inner granular layers). They alter their original cytoarchitectonic features so extensively during ontogeny that it is often only possible to correlate their mature structure with their primitive tectogenetic form by following the whole developmental sequence. Extreme variation, such as the disappearance or doubling of layers that we have already discussed, occur particularly in them, and their specific organisation also varies widely throughout the mammalian class, as we shall see.
The outer granular layer (layer II) is a major layer of the basic tectogenetic pattern, present over the whole extent of the cortex during foetal life and infancy. It stands out clearly as a thick, compact cellular lamina deep to the cell-spare molecular layer layers, as can be observed in Figures 1 to 3, 8 to 11 and 13 to 15 from man, cat, and wallaby (*69). ... As the individual grows older, the layer regresses and its essential transformation consists of its disappearance as an independent structure and its more or less complete fusion with the underlying pyramidal layer in most cortical areas of the mature brain... The outer granular layer maintains its independent character as a separate layer only in relatively few regions, where it represents a strip of densely packed, small polymorphic cells deep to the molecular layer, distinguished from the actual pyramidal layer by the density and small size of these cells. ...


Subcostal nerve

The subcostal nerve (anterior division of the twelfth thoracic nerve) is larger than the others. It runs along the lower border of the twelfth rib, often gives a communicating branch to the first lumbar nerve, and passes under the lateral lumbocostal arch.
It then runs in front of the quadratus lumborum, innervates the transversus, and passes forward between it and the abdominal internal oblique to be distributed in the same manner as the lower intercostal nerves.
It communicates with the iliohypogastric nerve and the ilioinguinal nerve of the lumbar plexus, and gives a branch to the pyramidalis muscle and the quadratus lumborum muscle. It also gives off a lateral cutaneous branch that supplies sensory innervation to the skin over the hip.