A case of a single intracranial vertebral artery and cerebral infarct.

The vertebral arteries are commonly affected by anatomical variation. This variation ranges from slight asymmetry in arterial diameter between the right and left sides to complete absence of a vertebral artery on one side. Asymmetry in diameter is a common observation, although complete absence of the artery is rare. Herein, we report on a 79-year-old male anatomical donor who, upon brain removal, was found to have a single intracranial vertebral artery which was the sole source of the basilar artery. During dissection of the neck, both right and left vertebral arteries were identified arising from the subclavian arteries. The vertebral arteries were dissected from the transverse foramina and followed into the skull. The right vertebral artery terminated by supplying the spinal cord, consistent with the distribution of the posterior spinal artery. Such vascular anomalies are clinically significant, as they may lead to abnormal patterns of sensory-motor deficiencies in stroke and are at risk of iatrogenic injury during surgical procedures.

Walleye Sander vitreus (Mitchill) are relatively resistant to experimental infection with VHSV IVb and extant walleye strains vary in susceptibility.

Compared to fathead minnow, walleye demonstrate low susceptibility to experimental infection with VHSV IVb, regardless of route of exposure or water temperature at time of infection. In triplicate and duplicate groups, walleye were intraperitoneally (i.p.) injected (102 -108  pfu/fish) or waterborne-exposed (w; 1.4 × 107  pfu mL-1 ) with VHSV IVb. High cumulative mortality (64-100%) and severe gross lesions associated with VHSV IVb infection were evident only in fish i.p. injected with 108  pfu at 12 °C. These fish had multifocal necrosis of several tissues including the gill and heart. There was no difference in mortality between walleye infected (w or i.p.) at 12 °C (spring stocking) compared with a declining temperature profile from 18 to 12 °C (fall stocking). There were significant differences (P < 0.05) in mortality between four extant walleye strains following i.p. infection, indicating that the choice of walleye strain for stocking might be an important consideration. Viral antigen was found in both i.p. and w-exposed walleye using immunohistochemistry, mostly within the gill and skin of w-exposed fish and most prominently in dermal fibrocytes. VHSV IVb was detected in multiple tissues from 6 to 21 days post-infection using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR).

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Quantitative proteomic analysis of the tizoxanide effect in vero cells.

Nitazoxanide (NTZ) is effective against helminths and numerous microorganisms, including bacteria and viruses. In vivo, NTZ is metabolized into Tizoxanide (TIZ), which is the active circulating metabolite. With the emergence of SARS-Cov-2 as a Pandemic agent, NTZ became one of the molecules already approved for human use to engage clinical trials, due to results in vitro showing that NTZ was highly effective against the SARS-Cov-2, agent of COVID-19. There are currently several ongoing clinical trials mainly in the USA and Brazil involving NTZ due not only to the in vitro results, but also for its long-known safety. Here, we study the response of Vero cells to TIZ treatment and unveil possible mechanisms for its antimicrobial effect, using a label-free proteomic approach (LC/MS/MS) analysis to compare the proteomic profile between untreated- and TIZ-treated cells. Fifteen differentially expressed proteins were observed related to various biological processes, including translation, intracellular trafficking, RNA processing and modification, and signal transduction. The broad antimicrobial range of TIZ points towards its overall effect in lowering cell metabolism and RNA processing and modification. The decreased levels of FASN, HNRNPH and HNRNPK with the treatment appear to be important for antiviral activity.

Autoimmunity to munc-18 in Rasmussen's encephalitis.

Rasmussen's encephalitis (RE) is a rare disease of the central nervous system characterized by severe epileptic seizures, progressive degeneration of a single cerebral hemisphere, and autoimmunity directed against glutamate receptor subunit, GluR3. We report here the identification of high-titer autoantibodies directed against munc-18 in the serum of a single patient with RE previously shown to have anti-GluR3 antibodies. Munc-18 is an intracellular protein residing in presynaptic terminals, which is required for secretion of neurotransmitters. These findings are consistent with the possibility of intermolecular epitope spreading between GluR3, a postsynaptic cell surface protein, and munc-18, a presynaptic intracellular protein. Immune attack on these two proteins, which participate at distinct steps of synaptic transmission, could act in an additive or synergistic manner to impair synaptic function and lead to seizures and neuronal death.

Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer's Disease.

Neflamapimod (previously code named VX-745) is a clinical phase 2b-ready highly specific inhibitor of the intra-cellular enzyme p38 mitogen activated protein kinase alpha ("p38α") that is being developed as a disease-modifying drug for Alzheimer's disease (AD) that acts via targeting synaptic dysfunction. Neflamapimod was discovered through a proprietary structure-based drug discovery platform at Vertex Pharmaceuticals, and developed previously by Vertex through to phase 2a in rheumatoid arthritis. EIP Pharma licensed the compound in 2014 for development and commercialization as a treatment of central nervous system (CNS) disorders. Neflamapimod is the most advanced in the clinic drug that targets specific molecular mechanisms within neurons that leads to synaptic dysfunction, the pathogenic process that is now considered to be a major driver of the development of memory deficits and disease progression in the early stages of AD. Based on the scientific rationale of targeting synaptic dysfunction and the preclinical data, neflamapimod has the potential to both reverse memory deficits and slow disease progression. Phase 2a clinical data in patients with early-stage AD (MMSE 20-28, biomarker positive) provides evidence that the preclinical science may be translatable to human Alzheimer's, as 6- to 12-weeks of neflamapimod treatment led to significant improvement in episodic memory, the best clinical measure of synaptic dysfunction in AD. A phase 2b six-month placebo-controlled 150-patient clinical study is anticipated to start by end of 2017. This study is designed to definitively demonstrate that neflamapimod reverses memory deficits, and also to provide preliminary evidence that the drug slows disease progression.

Identification of four proteins from the small subunit of the mammalian mitochondrial ribosome using a proteomics approach.

Proteins in the small subunit of the mammalian mitochondrial ribosome were separated by two-dimensional polyacrylamide gel electrophoresis. Four individual proteins were subjected to in-gel Endoprotease Lys-C digestion. The sequences of selected proteolytic peptides were obtained by electrospray tandem mass spectrometry. Peptide sequences obtained from in-gel digestion of individual spots were used to screen human, mouse, and rat expressed sequence tag databases, and complete consensus cDNAs for these species were deduced in silico. The corresponding protein sequences were characterized by comparison to known ribosomal proteins in protein databases. Four different classes of mammalian mitochondrial small subunit ribosomal proteins were identified. Only two of these proteins have significant sequence similarities to ribosomal proteins from prokaryotes. These proteins are homologs to Escherichia coli S9 and S5 proteins. The presence of these newly identified mitochondrial ribosomal proteins are also investigated in the Drosophila melanogaster, Caenorhabditis elegans, and in the genomes of several fungi.

A new face on apoptosis: death-associated protein 3 and PDCD9 are mitochondrial ribosomal proteins.

Two proteins known to be involved in promoting apoptosis in mammalian cells have been identified as components of the mammalian mitochondrial ribosome. Proteolytic digestion of whole mitochondrial ribosomal subunits followed by analysis of the peptides present using liquid chromatography-tandem mass spectrometry revealed that the proapoptotic proteins, death-associated protein 3 (DAP3) and the programmed cell death protein 9, are both components of the mitochondrial ribosome. DAP3 has motifs characteristic of guanine nucleotide binding proteins and is probably the protein that accounts for the nucleotide binding activity of mammalian mitochondrial ribosomes. The observations reported here implicate mitochondrial protein synthesis as a major component in cellular apoptotic signaling pathways.

Long-acting dihydropyridine calcium antagonists. 1. 2-Alkoxymethyl derivatives incorporating basic substituents.

A series of dihydropyridines substituted at the 2-position by basic side chains are described and their potencies as calcium antagonists listed. One compound, 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine (17, amlodipine) was found to be comparable in potency to nifedipine and to have an elimination half-life of 30 h in dogs. Oral bioavailability approached 100%, and hemodynamic responses were gradual in onset and long-lasting in effect. The two enantiomers have been prepared, and the bulk of the activity was found to reside with the (-) isomer, 18. X-ray crystallographic studies, carried out on a close analogue of 17, suggest the existence of a weak hydrogen bond between the side-chain oxygen and the proton on the ring nitrogen.

Electropharmacology of dofetilide, a new class III agent, in anaesthetised dogs.

In open chest anaesthetised dogs, dofetilide increased the ventricular effective refractory period over the dose range 1-100 micrograms/kg i.v. and the ventricular fibrillation threshold at doses between 3-100 micrograms/kg and was 80-1000 times more potent than sematilide, racemic sotalol, d-sotalol or quinidine. The maximal increases in ventricular fibrillation threshold induced by sematilide and quinidine were less than that induced by the other drugs. A change in the character of the induced arrhythmia from true ventricular fibrillation to a rapid ventricular flutter, with frequent spontaneous conversion, was observed following all drugs. No adverse haemodynamic effects of dofetilide, sematilide or d-sotalol were observed, but quinidine induced marked cardiac depression and racemic sotalol also impaired left ventricular contractility. All drugs reduced heart rate, though the effect of racemic sotalol was clearly greater than that of the other agents. Dofetilide is a potent class III antiarrhythmic agent with antifibrillatory properties and a favourable haemodynamic profile.

The development of young infants' ability to detect stimuli in the nasal visual field.

We compared infants' ability to detect single lines of varying width in the temporal and nasal visual fields. The smallest lines detected by 1-month-olds at 20 degrees in the nasal visual field were more than eight times wider than those detected at 30 degrees in the temporal visual field. In contrast, 2-month-olds detected smaller lines at 20 degrees in the nasal visual field than at 30 degrees in the temporal visual field. Converging evidence suggests that the observed improvement between 1 and 2 months in detection in the nasal visual field reflects the maturation of a projection from the retina through the visual cortex to the superior colliculus.

Effects of trichloroethylene exposure on male reproductive function in rats.

The present study was designed to evaluate the influences of trichloroethylene (TCE) on the reproductive system of male rats. In addition, information was obtained on the distribution and metabolism of TCE. At 100 days of age, male rats were allowed to copulate with ovariectomized, hormonally primed females and copulatory behaviors scored. Fifteen minutes post-ejaculation, females were sacrificed and ejaculate and semen plug recovered from the uterus and vagina for evaluation. These data served as a pre-exposure baseline for each animal. TCE exposure was then initiated with animals intubated with either 0, 10, 100, or 1000 mg/kg of TCE (10 males/group) for 5 days/week for 6 weeks. Copulatory behaviors and semen evaluations were conducted at Weeks 1 and 5 as well as 4 weeks post-exposure. Three males/group were sacrificed at the end of the sixth week of exposure and levels of TCE and its metabolites measured in various organs and blood. The remaining animals were sacrificed at the end of Week 10. TCE-related effects were seen primarily in the 1000 mg/kg group as reduced body weight gain, elevated liver/body weight ratios, and impaired copulatory behavior. However, the copulatory performance of the "affected" males had returned to normal by the fifth week of exposure. Although TCE and its metabolites concentrated to a significant extent in the male reproductive organs, semen evaluations failed to reveal any indices of spermatotoxicity. The initial alterations in copulatory behavior may be attributed to the narcotic properties of TCE. Tolerance to this pharmacological effect may explain the absence of these effects by the fifth week of exposure.

A new animal model of binge eating: key synergistic role of past caloric restriction and stress.

Dieting and stress are important in the etiology and maintenance of eating disorders, and dieting strongly predicts stress-induced overeating in humans. We hypothesized that caloric restriction and stress interact in a unique manner to promote binge eating. To test this hypothesis, a group of young female rats were cycled through a restriction period (4 days of 66% of control food intake) followed by 6 days of free feeding prior to being stressed by acute foot shock. After three of these cycles, the food intake of rats exposed only to restriction (R), or only to stress (S), did not differ from controls. However, R+S rats that were restricted and refed, despite normal body weight and food intake after free feeding, engaged in a powerful bout of hyperphagia when stressed (Experiment 1). The R + S effect was replicated in an older group of rats (Experiment 2). The hyperphagia was characteristically binge-like, it constituted a 40% selective increase in highly palatable (HP) food (P < .001) over a discrete period of time (within 24 h post-stress), and reflected feeding for reward (higher HP:chow ratio) over metabolic need as occurred after restriction (higher chow:HP ratio). Subsequent experiments revealed that binge eating did not occur if only chow was available (Experiment 3) or if restriction-refeeding (R-R) did not proximally precede stress (Experiment 4). Experiment 5 revealed that a history of R-R cycles followed by only one stress episode was sufficient to increase intake to 53% above controls as early as 2 h after stress (P < .001). This animal model of binge eating should facilitate investigations into the neurochemical changes induced by dieting and environmental stress to produce disordered eating and provide a preclinical tool to test preventive strategies and treatments more relevant to bulimia nervosa, multiple cases of binge eating disorder (BED) and binge-purge type anorexia nervosa.

Roles of advanced practice nurses in oncology.

Managed care is a process of health-care management that integrates financing, cost-containment strategies, and business principles with the delivery of health care. Managed care's rapid transformation of specialty practices, such as oncology, is redirecting classic nursing functions toward market initiatives that value the design of care/case management systems and the implementation of multidisciplinary "patient-centered" care models. As health-care systems continue to evolve, advanced practice nurses (APNs) are redefining their roles and enhancing their skills to meet the demands of the marketplace. Advanced practice nurses are defined as registered nurses who have met advanced educational and practice requirements and are prepared at the graduate level. This paper will identify the four established APN roles: nurse practitioner (NP), nurse anesthetist, nurse midwife, and clinical nurse specialist (CNS), as well as highlight the nurse practitioner and clinical nurse specialist as the leadership APN roles within oncology practice. The adaption to managed care has identified new functions and created opportunities for these APN specialties that are being viewed both competitively by other oncology health-care providers and creatively by managed-care organizations. The integration of these emerging roles within the new advanced nursing market and their contributions to oncology care are also discussed.

The cytologic evaluation of lipid-laden alveolar macrophages as an indicator of aspiration pneumonia in young children.

Gastroesophageal reflux with aspiration of feedings in infants and young children may be involved in the development of chronic lung damage. Our laboratory has utilized tracheal aspirates stained with oil red O to identify and quantitate lipid-laden alveolar macrophages as a marker of such aspiration. During the last 10 years, we have evaluated 244 tracheal aspiration smears in children. Although a few patients were up to 3 years old, the vast majority were infants. The cytologist looked for the presence of and the number of oil red O-positive macrophages on tracheal aspirate smears. The specimens were easily assigned grades of absent (grade = 0), low positive (grade 1: 1-25 lipid-laden macrophages), moderate positive (grade 2: 26-50 lipid-laden macrophages), and high positive (grade 3: > 50 lipid-laden macrophages). The grade was then correlated with the positive or negative clinical diagnosis of gastroesophageal reflux with aspiration. We believe the cytologic evaluation and grading of oil red O-stained tracheal aspirates for lipid-laden macrophages is valuable in identifying these patients with gastroesophageal reflux and aspiration.

Avermectin B1, Isazofos, and Fenamiphos for Control of Hoplolaimus galeatus and Tylenchorhynchus dubius Infesting Poa annua.

Avermectin B, isazofos, and fenamiphos were evaluated in greenhouse experiments for efficacy against two common turfgrass parasites, Hoplolaimus galeatus and Tylenchorhynchus dubius. Treatments in all experiments were arranged in a completely randomized design and replicated four times. In the first experiment, avermectin B at rates of 0.2 and 0.4 kg a.i./ha and isazofos at rates of 2.3 and 23 kg a.i./ha significantly reduced populations of both species of parasitic nematodes compared to controls at 14 and 28 days after treatment (P

High-pressure Liquid Injection of Isazofos for Management of Hoplolaimus galeatus and Tylenchorhynchus dubius Infesting Turfgrasses.

Three high-pressure liquid injection machines were used to inject isazofos into the root zone of tuff;grass plots to evaluate its potential for control of Hoplolaimus galeatus and Tylenchorhynchus dubius. A Rogers root zone injector delivering isazofos at 2.3 kg a.i./ha through 30 degrees and 60 degrees spray tips at 5,000 psi (3.45 x 10 Pascals) significantly reduced nematode populations at 32 days after a single application and 33 days after a second application. In a second experiment with the Rogers injector at 2.3 kg a.i./ha, H. galeatus populations were significantly lower at 16 days after a single application and at 42 and 61 days after a second application with the 60 degrees spray angle tips. An Envirojet turfgrass injector used to inject isazofos at 1.15 kg a.i./ha and 2.88 kg a.i./ha at 3,000 psi (1.38 x 107 Pascals) significantly reduced nematode populations at 7 days after treatment at the low rate and at 63 days after treatment with both application rates. A Landpride material injector applying isazofos at 6.9 and 13.8 kg a.i./ha at 2,000 psi (1.38 x 10 Pascals) significantly reduced nematode populations at 7, 14, and 63 days after treatment at the high rate and at 63 days after the low-rate application. Although suppression of nematodes with isazofos was found, the degree of suppression is probably not enough to warrant recommendation of high-pressure delivery of isazofos for control of H. galeatus and T. dubius populations infesting turfgrasses.

Redesigning the care of carotid endarterectomy patients.

Recent studies have supported the effectiveness of carotid endarterectomy (CEA) as a treatment for significant carotid stenosis. While the efficacy of CEA has been established, it is important to review the processes and outcomes of care to ensure high-quality, cost-effective care. As part of a quality-improvement process, our hospital's Vascular Surgery Quality Improvement Team redesigned the care for patients having CEA surgery. Practice changes, implemented in January 1995, included routine discharge on the first postoperative day; a new critical pathway supported by a computerized order set, a switch from general anesthesia to a regional block approach, and the use of an algorithm in treating postoperative hypertension. The impact of these changes on cost and quality were then analyzed. A retrospective chart audit was completed on 185 CEA surgeries performed in 1995. Length of stay decreased by 1.15 days, and costs were reduced by $1900 per case, with no change in postoperative morbidity or mortality rates. The incidence and severity of postoperative hypertension, bradycardia, and hypotension were also analyzed, supporting the practice changes and the current level of nursing care.