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An intranasal formulation of midazolam, Nayzilam, has been FDA-approved to treat intermittent, stereotypic episodes of frequent seizure activity. Nayzilam is easy to administer and can quickly treat seizures that occur outside of the hospital. The intra-nasal route of administration allows non-medical personal to administer the drug which makes it more accessible and user-friendly in the event of a seizure. Many studies have indicated quick cessation of seizures with Nayzilam compared to rectal diazepam, which has been the standard of care treatment. Nayzilam has been proven to be safe and effective for acute seizures in children, deeming it a revolutionary alternative in times where intravenous administration is not possible., Competing Interests: None of the authors report any conflicts of interest.

Parkinson's Disease (PD) is a common neurodegenerative disorder and the leading cause of disability. It causes significant morbidity and disability through a plethora of symptoms, including movement disorders, sleep disturbances, and cognitive and psychiatric symptoms. The traditional pathogenesis theory of PD involves the loss of dopaminergic neurons in the substantia nigra (SN). Classically, treatment is pursued with an assortment of medications that are directed at overcoming this deficiency with levodopa being central to most treatment plans. Patients taking levodopa tend to experience "off episodes" with decreasing medication levels, causing large fluctuations in their symptoms. These off episodes are disturbing and a source of morbidity for these patients. Opicapone is a novel, peripherally acting Catechol-O-methyl transferase (COMT) inhibitor that is used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of "off episodes." It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in duration of "off episodes." The main side effect demonstrated was dyskinesia, mostly with the 100mg dose, which is higher than the approved, effective dose of 50mg. Post-marketing surveillance and analysis are required to further elucidate its safety profile and contribute to patient selection. This paper reviews the seminal and latest evidence in the treatment of PD "off episodes" with the novel drug Opicapone, including efficacy, safety, and clinical indications.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that causes significant functional impairment and is related to altered stress response and reinforced learned fear behavior. PTSD has been found to impact three functional networks in the brain: default mode, executive control, and salience. The executive control network includes the dorsolateral prefrontal cortex (DLPFC) and lateral PPC. The salience network involves the anterior cingulate cortex, anterior insula, and amygdala. This latter network has been found to have increased functional connectivity in PTSD. Transcranial Magnetic Stimulation (TMS) is a technique used in treating PTSD and involves stimulating specific portions of the brain through electromagnetic induction. Currently, high-frequency TMS applied to the left dorsolateral prefrontal cortex (DLPFC) is approved for use in treating major depressive disorder (MDD) in patients who have failed at least one medication trial. In current studies, high-frequency stimulation has been shown to be more effective in PTSD rating scales posttreatment than low-frequency stimulation. The most common side effect is headache and scalp pain treated by mild analgesics. Seizures are a rare side effect and are usually due to predisposing factors. Studies have been done to assess the overall efficacy of TMS. However, results have been conflicting, and sample sizes were small. More research should be done with larger sample sizes to test the efficacy of TMS in the treatment of PTSD. Overall, TMS is a relatively safe treatment. Currently, the only FDA- approved to treat refractory depression, but with the potential to treat many other conditions., Competing Interests: OV was employed by Valley Anesthesiology and Pain Consultants. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Edinoff, Hegefeld, Petersen, Patterson, Yossi, Slizewski, Osumi, Cornett, Kaye, Kaye, Javalkar, Viswanath, Urits and Kaye.)

Parkinson's disease (PD) is a common neurodegenerative disorder. It is also the fastest-growing neurodegenerative disorder and has more than doubled between 1990 and 2016. Parkinson's disease causes significant morbidity and disability from motor dysfunction, sleep disturbances, and cognitive and psychiatric symptoms. This paper reviews recent evidence in the treatment of PD "off" episodes with the novel drug opicapone, including its efficacy, safety, and clinical indications. Opicapone is a novel, peripherally acting catechol-O-methyl transferase (COMT) inhibitor used as adjunctive therapy to carbidopa/levodopa for treatment and prevention of "off" episodes. It has been approved for use as an adjunct to levodopa since 2016 in Europe and has recently (April 2020) gained FDA approval for use in the USA. By inhibiting COMT, opicapone slows levodopa metabolism and increases its availability. Several clinical studies demonstrated significant improvement in treatment efficacy and reduction in the duration of "off" episodes The main side effect demonstrated was dyskinesia, mostly with the 100 mg dose, which is higher than the approved, effective dose of 50 mg., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Mood and psychotic disorders are a group of illnesses that affect behavior and cognition. Schizophrenia is characterized by positive symptoms, such as delusions and hallucinations, as well as negative symptoms. Major depressive disorder (MDD) is a mood disorder that affects the patient's emotions, energy, and motivation. Brexpiprazole works as a partial agonist at serotonin 5-hydroxytryptamine1A and dopamine D2 receptors and an antagonist at serotonin 5-hydroxytryptamine2A. Schizophrenia and MDD have a wide range of risk factors, both biological and environmental. Third generation antipsychotics, which include brexpiprazole, are the latest group of drugs to reach the market, demonstrating efficacy and tolerability. Patients with acute schizophrenia have responded well to brexpiprazole. In this regard, in patients who have MDD plus anxiety symptoms, brexpiprazole can be effective as an adjunctive therapy and can reduce anxiety symptoms. In summary, brexpiprazole has proved to be an effective alternative to typical or first and second-generation atypical antipsychotics., (Copyright © 1964–2021 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Stevens-Johnson Syndrome (SJS) is a rare life-threatening condition characterized by severe mucocutaneous epidermal necrolysis and detachment of the epidermis. The condition centers around a delayed-type hypersensitivity reaction with a complex etiology stemming from a variety of causes. The number one cause is medication-related-common ones including sulfonamides, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs. Genetics also play a role as several human leukocyte antigen (HLA) genotypes within certain ethnic groups have been implicated in adverse reactions to specific drugs. HLAB*15:02 has been identified in the Chinese and others of Southeast Asian origin to increase susceptibility to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese origin with HLAB*31:01 and Koreans with HLA-B*44:03 are also at increased risk of SJS after receiving the same two drugs. Of the antiepileptics, one most commonly associated with SJS is lamotrigine, a pre-synaptic voltage-gated sodium channel inhibitor. Lamotrigine is an antiepileptic drug of the phenyltriazine class that is indicated for the prevention of focal and generalized seizures in epileptic patients as well as monotherapy or adjunctive maintenance treatment for Bipolar disorder. The occurrence of SJS is not a rigid contraindication to lamotrigine reintroduction in the same patient. To facilitate this, manufacturers have developed a strict re-challenge dosing regimen to facilitate successful reintroduction of lamotrigine. In order to prevent the recurrence of SJS during a re-challenge, timing of re-dose and initial rash severity must be considered. Therefore, to prevent SJS recurrence, prime lamotrigine re-challenge patients are those with mild initial rash that has not occurred within the previous 4 weeks. The Federal Food and Drug Administration recommends the testing HLA subtypes for those associated with SJS prior to starting lamotrigine., (Copyright © 1964–2021 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Infertility, the inability to establish a clinical pregnancy after 12 months of regular unprotected sexual intercourse, is caused by a wide variety of both male and female factors. Infertility is estimated to affect between 8-12% of couples trying to conceive globally. Female factor infertility can be subdivided into the following broad categories: ovulatory dysfunction, fallopian tubal disease, uterine causes, and oocyte quality. Hyperprolactinemia causes ovulary dysfunction along with other hormonal abnormalities, such as decreased estrogen, which can lead to infertility. In this regard, antipsychotics are commonly used for both schizophrenia and bipolar disorder. The use of these medications can be associated with hyperprolactinemia and hyperprolactinemia associated infertility. Antipsychotic-induced hyperprolactinemia occurs through blockade of D 2 receptors on lactotroph cells of the anterior pituitary gland. Discontinuation of the hyperprolactinemia-inducing antipsychotic is an option, but this may worsen the patient's psychosis or mood. If antipsychotics are determined to be the culprit of infertility, the degree of hyperprolactinemia symptoms, length of treatment with the antipsychotic, and risk of relapse should be assessed prior to discontinuation, reduction, or switching of antipsychotic medications. The treatment of a women's mental health and her desire to have children should always be considered as treatment may influence fertility while on the medication., (Copyright © 1964–2021 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Migraine is a neurobiological headache disorder that affects around 16% of adults in the United States. Medical treatment of mild to moderate migraines include non-prescription non-steroidal anti-inflammatory drugs, acetaminophen, or aspirin and caffeine-containing combination analgesics. Additionally, moderate to severe migraines and those that are mild to moderate that have not responded to analgesics can be treated with triptans, which are drugs specific for migraine treatment. Non-pharmacological treatments include cognitive behavioral therapy and relaxation training. Medications for the prevention of migraines have also been developed since they are more affective in offsetting the symptoms. Ubrogepant's high specificity and selectivity for calcitonin gene-related peptide (CGRP) sets it apart from certain other drugs, which previously limited the treatment of migraines with or without aura due to their decreased selectivity. The most frequently reported side effects are oropharyngeal pain, nasopharyngitis, and headache. Most studies found that participants receiving Ubrogepant were free from pain within 2 h when compared to placebo. Patients taking Ubrogepant should avoid taking it when pregnant or with end stage renal disease. In summary, Ubrogepant has good tolerability and an overall favorable safety profile. It appears to hold promise for the acute treatment of migraines with or without aura in adults.

Multiple sclerosis (MS) is a prevalent and debilitating neurologic condition characterized by widespread neurodegeneration and the formation of focal demyelinating plaques in the central nervous system. Current therapeutic options are complex and attempt to manage acute relapse, modify disease, and manage symptoms. Such therapies often prove insufficient alone and highlight the need for more targeted MS treatments with reduced systemic side effect profiles. Ozanimod is a novel S1P (sphingosine-1-phosphate) receptor modulator used for the treatment of clinically isolated syndrome, relapsing-remitting, and secondary progressive forms of multiple sclerosis. It selectively modulates S1P1 and S1P5 receptors to prevent autoreactive lymphocytes from entering the CNS where they can promote nerve damage and inflammation. Ozanimod was approved by the US Food and Drug Administration (US FDA) for the management of multiple sclerosis in March 2020 and has been proved to be both effective and well tolerated. Of note, ozanimod is associated with the following complications: increased risk of infections, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, and posterior reversible encephalopathy syndrome, among others. Further investigation including head-to-head clinical trials is warranted to evaluate the efficacy of ozanimod compared with other S1P1 receptor modulators.

Neurological disorders, including Parkinson's disease (PD), have increased in prevalence and are expected to further increase in the coming decades. In this regard, PD affects around 3% of the population by age 65 and up to 5% of people over the age of 85. PD is a widely described, physically and mentally disabling neurodegenerative disorder. One symptom often poorly recognized and under-treated by health care providers despite being reported as the most common non-motor symptom is the finding of chronic pain. Compared to the general population of similar age, PD patients suffer from a significantly higher level and prevalence of pain. The most common form of pain reported by Parkinson's patients is of musculoskeletal origin. One of the most used combination drugs for PD is Levodopa-Carbidopa, a dopamine precursor that is converted to dopamine by the action of a naturally occurring enzyme called DOPA decarboxylase. Pramipexole, a D2 dopamine agonist, and apomorphine, a dopamine agonist, and Rotigotine, a dopamine receptor agonist, have showed efficacy on PD-associated pain. Other treatments that have shown efficacy in treating pain of diverse etiologies are acetaminophen, Nonsteroidal anti-inflammatory drugs (NSAIDs), and cyclooxygenase-2 (COX-2) inhibitors. Opioids and opioid-like medications such as oxycodone, morphine, tramadol, and codeine are also commonly employed in treatment of chronic pain in PD. Other opioid related medications such as Tapentadol, a central-acting oral analgesic with combined opioid and noradrenergic properties, and Targinact, a combination of the opioid agonist oxycodone and the opioid antagonist naloxone have shown improvement in pain. Anticonvulsants such as gabapentin, pregabalin, lamotrigine, carbamazepine and tricyclic antidepressants (TCAs) can be trialed when attempting to manage chronic pain in PD. The selective serotonin and noradrenaline reuptake inhibitors (SNRIs) also possess pain relieving and antidepressant properties, but carry less of the risk of anticholinergic side effects seen in TCAs. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown in multiple studies to be effective against various types of PD associated pain symptoms. Massage therapy (MT) is one of the most common forms of complementary and alternative medicine. Studies have shown that pressure applied during MT may stimulate vagal activity, promoting reduced anxiety and pain, as well as increasing levels of serotonin. In a survey study of PD patients, rehabilitative therapy and physical therapy were rated as the most effective for pain reduction, though with only temporary relief but these studies were uncontrolled. Yoga has been studied for patients with a wide array of neurological disorders. In summary, PD pathology is thought to have a modulating effect on pain sensation, which could amplify pain. This could help explain a portion of the higher incidence of chronic pain felt by PD patients. A treatment plan can be devised that may include dopaminergic agents, acetaminophen, NSAIDs, opioids, antidepressants, physical therapies, DBS and other options discussed in this review. A thorough assessment of patient history and physical examination should be made in patients with PD so chronic pain may be managed effectively.

The soft tissues of many fossil vertebrates preserve evidence of melanosomes-micron-scale organelles that inform on integumentary coloration and communication strategies. In extant vertebrates, however, melanosomes also occur in internal tissues. Hence, fossil melanosomes may not derive solely from the integument and its appendages. Here, by analyzing extant and fossil frogs, we show that non-integumentary melanosomes have high fossilization potential, vastly outnumber those from the skin, and potentially dominate the melanosome films preserved in some fossil vertebrates. Our decay experiments show that non-integumentary melanosomes usually remain in situ provided that carcasses are undisturbed. Micron-scale study of fossils, however, demonstrates that non-integumentary melanosomes can redistribute through parts of the body if carcasses are disturbed by currents. Collectively, these data indicate that fossil melanosomes do not always relate to integumentary coloration. Integumentary and non-integumentary melanosomes can be discriminated using melanosome geometry and distribution. This is essential to accurate reconstructions of the integumentary colours of fossil vertebrates.

We have studied the chromatin structure of a 16-kb region of the chicken genome containing the 3'-terminal 2 kb of the ovalbumin pre-mRNA coding sequence and the 14-kb segment located immediately downstream from the main mRNA polyadenylation site. Using the indirect end-labelling technique, four major and two minor DNase I-hypersensitive regions were found in the oviduct chromatin, whereas they were not present in liver, kidney or erythrocyte chromatin. The first hypersensitive region (region A) was present in chromatin of oviducts from laying hen and estrogen- or progesterone-stimulated immature chicks, in which the ovalbumin gene is expressed, but not in the chromatin of 'acute withdrawn' chicks where the gene is no longer transcribed. Region A spans 1.3 kb, from 7.2 to 8.5 kb downstream from the ovalbumin gene capsite (position +1), and encompasses the 3' moiety of the last exon including the major polyadenylation signal and polyadenylation site located at +7546 and +7564, respectively. Region A also contains a minor polyadenylation signal present at +7294 and the corresponding polyadenylation site at +7368. Two putative termination sequences at +8445 and +8483 are also found at the 3' extremity of region A in a 170-bp DNA segment within which 90% of the ovalbumin primary transcripts apparently terminate. Two minor hormone-independent DNase I-hypersensitive regions (a1 and a2) located at +8.6 and +8.8 kb are also specific to oviduct chromatin.(ABSTRACT TRUNCATED AT 250 WORDS)

The aggregation of chromatin during spermiogenesis in the house cricket and many other animals is an orderly process involving the formation of a series of long, thick, well defined structures. The differentiation of chromatin preliminary to the development of such unusual structures is given attention here. Examination of nuclei after lysis and spreading indicated that fibers with closely spaced nucleosomes, like the fibers of somatic chromatin, make up the chromatin in all stages of early spermiogenesis and most of middle spermiogenesis. The thick structures of late spermatids cannot be formed by aggregation of fibers of this somatic type, however; just before thick structures form, chromatin fibers lose the nucleosomal structure. During the process, fibers with nucleosomes spaced at irregular intervals and with long stretches of smooth thin fiber are found, as if nucleosomes at one site on a fiber are broken down independently of those at adjacent sites. Since prior studies of cricket proteins have indicated that somatic histones persist during the stages when nucleosome structure disappears, the observations imply that the histones which are organized in nucleosomes during early stages must become incorporated into different kinds of nucleoprotein complexes during succeeding stages of spermiogenesis.

The organization of chromatin was analysed in a segment of the chicken ovalbumin gene extending 6.5 kb upstream from the start site of transcription. Nuclei of chicken oviduct cells and of erythrocytes, and preparations of 'naked' DNA were digested with DNase I and with micrococcal nuclease. The locations of specific nuclease cleavage sites were determined by analyzing the fragments obtained with an indirect end-labeling technique. In oviduct nuclei there are four regions of DNase I hypersensitivity centered at approximately 0.15, 0.80, 3.2 and 6.0 kb upstream from the mRNA cap site. DNase I hypersensitive regions are absent from the 5'-flanking regions of erythrocyte nuclei. Micrococcal nuclease cleavage sites were found that are unique to oviduct nuclei and others that are enhanced in oviduct nuclei, relative to erythrocyte nuclei and to naked DNA. The locations of these micrococcal nuclease cleavage sites are closely associated with the DNase I hypersensitive regions. Nuclease hypersensitivity in the 5'-flanking region of oviduct nuclei reflects alterations in chromatin structure that are specifically correlated with gene expression. Our results suggest the presence at hypersensitive regions of specific proteins which alter the chromatin structure, making the DNA more accessible to nuclease attack.

Four DNase I-hypersensitive regions (I-IV) occur in the 5'-flanking region of the ovalbumin gene in hen oviducts. One is centered close to the cap site (position +1) of transcription and the others at -0.8, -3.3 and -6.0 kb. The correlation of hypersensitivity with transcription was determined for each region in oviducts of chicks, where expression of the ovalbumin gene can be controlled by administration and withdrawal of steroid hormones. DNase I-hypersensitive regions were mapped by the indirect end-labeling technique and ovalbumin mRNA levels were determined by the dot blot assay. Diethylstilbestrol (DES) induces the appearance of hypersensitive regions I-IV whereas progesterone induces regions I, II and IV, but not region III. Upon withdrawal, regions II and III, and most of regions I and IV, disappear. A weak zone of hypersensitivity in region I near the cap site persists during withdrawal and a new zone of hypersensitivity appears between regions I and II. There is strong correlation between hypersensitivity at regions I-IV and gene transcription; ovalbumin mRNA levels are high in stimulated chicks, where hypersensitive regions are present, and drop to very low levels in withdrawn chicks, where the hypersensitivity is absent. We suggest that proteins, perhaps hormone receptors acting together with tissue-specific factors, induce DNAse I-hypersensitive regions I-IV of the ovalbumin gene.

Flagellar structure in spermatids of several species of cricket was studied with the electron microscope. The flagella of mid-spermatids contain the usual 9 + 2 set of fibers and a set of nine accessory fibers. At first all are hollow, then the lumina become filled with an electron-opaque matrix material in which narrow electron-lucent microcylinders are embedded. The accessory fibers and one central fiber become filled first, then the B subfibers and the other central fiber, and finally the A subfiber. In all but the B subfibers, microcylinders are arranged in a circular or oval group that lies against the wall of the lumen and encloses one or several additional microcylinders. In accessory fibers there are 9-11 microcylinders in the outer group and 4-5 in the inner group. In the central fibers and the A subfibers there are 7-9 microcylinders that enclose one or two more. In the B subfibers there is a crescentic group of 6-7 microcylinders that partially encloses 2-3 more. Microcylinders become packed as though they are independent units; the matrix appears to be an amorphous substance that fills the spaces around the microcylinders. The mean diameter of the microcylinders is 36 A, and they have a center-to-center distance of 56 A. In both respects they resemble wall subunits of flagellar fibers and microtubules and they may be similar structures but with a different localization. The diameter of accessory fibers is about 350 A, which is 25% greater than that of the other flagellar fibers and of cytoplasmic microtubules. Rotation tests suggest that the accessory fibers have 16 wall-subunits.

The early stages of nuclear differentiation in spermatids of the house cricket are described with regard to the fine structural elements and chemical components which occur. Particular attention is given to the loss of nonhistone protein from the nucleus and its relation to chromatin structure. Granular elements about 25 to 80 mmicro in diameter, and fibers about 8 mmicro in diameter occur in the earliest spermatid nucleus. The fibers are found in diffuse and condensed chromatin while granules are found only in diffuse material. DNA and histone parallel the chromatin fibers in distribution, while nonhistone protein and RNA parallel the granules in distribution. The granules and most of the nonhistone protein are lost, simultaneously, after the early spermatid stage. The protein loss occurs without detectable change in the structure of chromatin fibers. Chromatin fibers first show a structural change in mid spermiogenesis, when they become thicker and very contorted. Unusually thin fibers (about 5 mmicro) also appear in mid spermatid nuclei; they are apparently composed of nonhistone protein and free of DNA and histone.

Acrosome formation during spermatogenesis in the house cricket was studied with the electron microscope. In the early spermatid there is a single Golgi body, called the acroblast, which is cup-shaped, the walls being composed of a number of parallel membranes. A pro-acrosomal granule then appears within the acroblast. Next, the granule migrates to the nucleus, where it becomes attached. The acroblast then migrates away from the attached granule and is eventually sloughed off. In the first stage of acrosome differentiation the granule assumes the shape of a blunt cone and its base invaginates deeply so that it becomes hollowed. Within the space created by the invagination a new structure forms which, from the first, has the shape of a hollow cone. The two cones constitute the mature acrosome. Both have a biconvex cross-section.