Operating Cooperatively (OC) Sensor for Highly Specific Recognition of Nucleic Acids

Molecular Beacon (MB) probes have been extensively used for nucleic acid analysis because of their ability to produce fluorescent signal in solution instantly after hybridization. The indirect binding of MB probe to a target analyte offers several advantages, including: improved genotyping accuracy and the possibility to analyse folded nucleic acids. Here we report on a new design for MB-based sensor, called \u27Operating Cooperatively\u27 (OC), which takes advantage of indirect binding of MB probe to a target analyte. The sensor consists of two unmodified DNA strands, which hybridize to a universal MB probe and a nucleic acid analyte to form a fluorescent complex. OC sensors were designed to analyze two human SNPs and E.coli 16S rRNA. High specificity of the approach was demonstrated by the detection of true analyte in over 100 times excess amount of single base substituted analytes. Taking into account the flexibility in the design and the simplicity in optimization, we conclude that OC sensors may become versatile and efficient tools for instant DNA and RNA analysis in homogeneous solution

Clozapine and Constipation: A Review of Clinical Considerations and Treatment Options

Psychosis, a break in reality which is manifested as hallucinations, delusions or the disruption in thought process, is the hallmark of schizophrenia. Despite novel pharmacotherapy advancements of antipsychotic medications that have resulted in some patients having the ability to return to social settings and thereby decreasing psychotic symptoms and reducing hospital admissions, there is still a sub-population of patients who remain symptomatic. Treatment-resistant schizophrenia is defined as failure of treatment with at least two different antipsychotics with the proper length of treatment and titration. Clozapine has been heralded as a drug to resolve the puzzle of treatment-resistant schizophrenia. Clozapine has one side effect that is well known, being the development of agranulocytosis. However, there is another side effect that can limit clozapine’s use and can also be life-threatening. Recently, at the end of January 2020, the FDA issued a communications statement which “[strengthened] an existing warning that constipation caused by the schizophrenia medicine clozapine can, uncommonly, progress to serious bowel complications.” After identifying ten cases of constipation from between 2006 to 2016 that progressed to hospitalization, surgery, and even death, the FDA focused their attention on this often overlooked, common side effect, especially when considering the strong anticholinergic effects of clozapine. Although patients are screened by their physicians for agranulocytosis by weekly lab monitoring, constipation is also a complication that needs to be identified and treated. Much like opioid-induced constipation, constipation can also be reduced with the use of laxatives and reduction in the co-prescribing of anticholinergic therapies with clozapine

Isolated X-ray -- infrared sources in the region of interaction of the supernova remnant IC 443 with a molecular cloud

The nature of the extended hard X-ray source XMMU J061804.3+222732 and its surroundings is investigated using XMM-Newton, Chandra, and Spitzer observations. This source is located in an interaction region of the IC 443 supernova remnant with a neighboring molecular cloud. The X-ray emission consists of a number of bright clumps embedded in an extended structured non-thermal X-ray nebula larger than 30" in size. Some clumps show evidence for line emission at ~1.9 keV and ~3.7 keV at the 99% confidence level. Large-scale diffuse radio emission of IC 443 passes over the source region, with an enhancement near the source. An IR source of about 14" x 7" size is prominent in the 24 um, 70 um, and 2.2 um bands, adjacent to a putative Si K-shell X-ray line emission region. The observed IR/X-ray morphology and spectra are consistent with those expected for J/C-type shocks of different velocities driven by fragmented supernova ejecta colliding with the dense medium of a molecular cloud. The IR emission of the source detected by Spitzer can be attributed to both continuum emission from an HII region created by the ejecta fragment and line emission excited by shocks. This source region in IC 443 may be an example of a rather numerous population of hard X-ray/IR sources created by supernova explosions in the dense environment of star-forming regions. Alternative Galactic and extragalactic interpretations of the observed source are also discussed.Comment: The Astrophysical Journal, v. 677 (April 2008), in pres

A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing.

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143

Selective serotonin reuptake inhibitors and adverse effects: A narrative review

Depression is the most prevalent psychiatric disorder in the world, affecting 4.4% of the global population. Despite an array of treatment modalities, depressive disorders remain difficult to manage due to many factors. Beginning with the introduction of fluoxetine to the United States in 1988, selective serotonin reuptake inhibitors (SSRIs) quickly became a mainstay of treatment for a variety of psychiatric disorders. The primary mechanism of action of SSRIs is to inhibit presynaptic reuptake of serotonin at the serotonin transporter, subsequently increasing serotonin at the postsynaptic membrane in the serotonergic synapse. The six major SSRIs that are marketed in the USA today, fluoxetine, citalopram, escitalopram, paroxetine, sertraline, and fluvoxamine, are a group of structurally unrelated molecules that share a similar mechanism of action. While their primary mechanism of action is similar, each SSRI has unique pharmacokinetics, pharmacodynamics, and side effect profile. One of the more controversial adverse effects of SSRIs is the black box warning for increased risk of suicidality in children and young adults aged 18–24. There is a lack of understanding of the complexities and interactions between SSRIs in the developing brain of a young person with depression. Adults, who do not have certain risk factors, which could be confounding factors, do not seem to carry this increased risk of suicidality. Ultimately, when prescribing SSRIs to any patient, a risk–benefit analysis must factor in the potential treatment effects, adverse effects, and dangers of the illness to be treated. The aim of this review is to educate clinicians on potential adverse effects of SSRIs

Collision of millimetre droplets induces DNA and protein transfection into cells

Nonperturbing and simple transfection methods are important for modern techniques used in biotechnology. Recently, we reported that electrospraying can be applied to DNA transfection in cell lines, bacteria, and chicken embryos. However, the transfection efficiency was only about 2%. To improve the transfection rate, physical properties of the sprayed droplets were studied in different variations of the method. We describe a highly efficient technique (30–93%) for introduction of materials such as DNA and protein into living cells by electrospraying droplets of a high conductivity liquid onto cells incubated with the material for transfection. Electric conductivity has a sizable influence on the success of transfection. In contrast, molecular weight of the transfected material, types of ions in the electrospray solution, and the osmotic pressure do not influence transfection efficiency. The physical analysis revealed that collision of cells with millimetre-sized droplets activates intracellular uptake

An update on treatment modalities for ulnar nerve entrapment: A literature review

Context: Ulnar nerve entrapment is a relatively common entrapment syndrome second only in prevalence to carpal tunnel syndrome. The potential anatomic locations for entrapment include the brachial plexus, cubital tunnel, and Guyon�s canal. Ulnar nerve entrapment is more so prevalent in pregnancy, diabetes, rheumatoid arthritis, and patients with occupations involving periods of prolonged elbow flexion and/or wrist dorsiflexion. Cyclists are particularly at risk of Guyon�s canal neuropathy. Patients typically present with sensory deficits of the palmar aspect of the fourth and fifth digits, followed by motor symptoms, including decreased pinch strength and difficulty fastening shirt buttons or opening bottles. Evidence Acquisition: Literature searches were performed using the belowMeSHTerms using Mendeley version 1.19.4. Search fields were varied until further searches revealed no new articles. All articles were screened by title and abstract. Decision was made to include an article based on its relevance and the list of final articles was approved three of the authors. This included reading the entirety of the artice. Anyquestion regarding the inclusion of anarticlewasdiscussed by all authors untilanagreementwasreached. Results: X-rayandCTplay a role in diagnosiswhenabonyinjury is thought to be related to the pathogenesis (i.e., fracture of thehook of the hamate.) MRI plays a role where soft tissue is thought to be related to the pathogenesis (i.e., tumor or swelling.) Electromyography and nerve conduction also play a role in diagnosis. Medicalmanagement, in conjunction with physical therapy, shows limited promise. However, minimally invasive techniques, including peripheral percutaneous electrode placement and ultrasound-guided electrode placement, have all been recently studied and show great promise. When these techniques fail, clinicians should resort to decompression, which can be done endoscopically or through an open incision. Endoscopic ulnar decompression shows great promise as a surgical option with minimal incisions. Conclusions: Clinical diagnosis of ulnar nerve entrapment can often be delayed and requires the suspicion as well as a thorough neurological exam. Early recognition and diagnois are important for early institution of treatment. A wide array of diagnostic imaging can be useful in ruling out bony, soft tissue, or vascular etiologies, respectively. However, clinicians should resort to electrodiagnostic testing when a definitive diagnois is needed. Many new minimally invasive techniques are in the literature and show great promise; however, further large scale trials are needed to validate these techniques. Surgical options remains as a gold standard when adequate symptom relief is not achieved through minimally invasive means. © 2020, Author(s)

Utilization of intravenous lidocaine infusion for the treatment of refractory chronic pain

Context: Chronic pain accounts for one of the most common reasons patients seek medical care. The financial burden of chronic pain on health care is seen by direct financial cost and resource utilization. Many risk factors may contribute to chronic pain, but there is no definite risk. Managing chronic pain is a balance between maximally alleviating symptoms by utilizing a therapeutic regimen that is safe for long-term use. Currently, non-opioid analgesics, NSAIDs, and opioids are some of the medical treatment options, but these have numerous adverse effects and may not be the best option for long-term use. However, Lidocaine can achieve both central and peripheral analgesic effects with relatively few side effects, whichmaybe an idealcompoundfor managing chronic pain. Evidence Acquisition: This is a Narrative Review. Results: Infusion of lidocaine (2-(diethylamino)-N-(2,6-dimethylphenyl)acetamide), an amino-amide compound, is emerging as a promising option to fill the therapeutic void for treatment of chronic pain. Numerous studies have outlined dosing protocols for lidocaine infusion for the management of perioperative pain, outlined below. While there are slight variations in these different protocols, they all center around a similar dosing regimen to administer a bolus to reach a rapid steady state, followed by infusion for up to 72 hours to maintain the therapeutic analgesic effects. Conclusions: Lidocaine may be a promising pharmacologic solution with a low side effect profile that provides central and peripheral analgesia. Even though the multifaceted mechanism is not entirely understood yet, lidocainemaybe a promising novel remedy in treating chronic pain in various conditions. © 2020, Author(s)

Peripheral neuromodulation for the management of headache

Context: Neuromodulation is an expanding field of study for headache treatment to reduce pain by targeting structures within the nervous system that are commonly involved in headache pathophysiology, such as the vagus nerve (VNS), occipital nerves, or sphenopalatine ganglion (SPG) for stimulation. Pharmaceutical medical therapies for abortive and prophylactic treatment, such as triptans, NSAIDs, beta-blockers, TCAs, and antiepileptics, are effective for some individuals, but the role that technology plays in investigating other therapeutic modalities is essential. Peripheral neuromodulation has gained popularity and FDA approval for use in treating certain headaches and migraine headache conditions, particularly in those who are refractory to treatment. Early trials found FDA approved neurostimulatory implant devices, including Cephaly and SpringTMS, improved patient-oriented outcomes with reductions in headaches per month (frequency) and severity. Evidence Acquisition: This was a narrative review. The sources for this review are as follows: Searching on PubMed, Google Scholar, Medline, and ScienceDirect from 1990 - 2019 using keywords: Peripheral Neuromodulation, Headache, vagus nerve, occipital nerves, sphenopalatine ganglion. Results: The first noninvasive neurostimulator device approved for migraine treatment was the Cefaly device, an external trigeminal nerve stimulation device (e-TNS) that transcutaneously excites the supratrochlear and supraorbital branches of the ophthalmic nerve. The second noninvasive neurostimulation device receiving FDA approval was the single-pulse transcranial magnetic stimulator, SpringTMS, positioned at the occiput to treat migraine with aura. GammaCore is a handheld transcutaneous vagal nerve stimulator applied directly to the neck at home by the patient for treatment of cluster headache (CH) and migraine. Several other devices are in development for the treatment of headaches and target headache evolution at different levels and inputs. The Scion device is a caloric vestibular stimulator (CVS) which interfaces with the user through a set of small cones resting in the ear canal on either side and held in place by modified over-ear headphones. The pulsante SPG Microstimulator is a patient-controlled device implanted in the patient�s upper jaw via an hour-long oral procedure to target the sphenopalatine ganglion. The occipital nerve stimulator (ONS) is an invasive neuromodulation device for headache treatment that consists of an implanted pulse generator on the chest wall connected to a subcutaneous lead with 4 - 8 electrodes that is tunneled the occiput. Conclusions: The aim of this review is to provide a comprehensive overview of the efficacy, preliminary outcomes, and limitations of neurostimulatory implants available for use in the US and those pending further development. © 2020, Author(s)