Compression Behavior of Orthorhombic Paracetamol

Purpose. Orthorhombic crystals of paracetamol exhibit good technological properties during compression. The purpose of this study was to investigate the compression behavior of this substance and to compare it to that of monoclinic paracetamol. From the crystal structure, it could be hypothesized that sliding planes are present in the orthorhombic form, and could be responsible for an increase in crystal plasticity. Methods. Compression of pure orthorhombic or monoclinic paracetamol tablets was carried out on a fully instrumented single punch machine. Data was used to establish Heckel's profiles. Images of compressed crystals were obtained by scanning electron microscopy. Results. Tabletability of the orthorhombic crystals was far better than that of the monoclinic ones, and capping was not observed even at high compression pressure. Compared to the monoclinic form, orthorhombic paracetamol exhibited greater fragmentation at low pressure, increased plastic deformation at higher pressure, and lower elastic recovery during decompression. Plastic behavior was confirmed by SEM - micrographs showing that crystals folded under pressure. A compactibility study showed that the nature of interparticle bonds was similar for both polymorphs, the number of bonds being greater for orthorhombic paracetamol. Conclusions. Unlike the monoclinic form, orthorhombic paracetamol is suitable for the direct compression process. The crystalline structure accounts for its better compression behavior, because of the presence of sliding planes.     

Intravenous administration of the food-derived opioid peptide gluten exorphin B5 stimulates prolactin secretion in rats.

Gluten Exorphin B5 (GE-B5) is a food-derived opioid peptide, identified in vitro in enzymatic digests of wheat gluten. It has been suggested that this peptide may play a regulatory role on pituitary secretion, since it stimulates prolactin (PRL) secretion when administered in the cerebral ventricles in rats.It is not known, however, if GE-B5 can exert this stimulatory action after peripheral administration. In order to clarify this aspect, we gave the following treatments to four groups of male rats: intravenous (i.v.) vehicle, GE-B5 3 mg/kg body weight i.v., naloxone intraperitoneally (i.p.) followed by vehicle i.v., naloxone i.p. followed by GE-B5 i.v. Blood samples for PRL were taken at intervals for 60 min after vehicle or GE-B5 administration. At the dose of 3 mg/kg body weight, GE-B5 induced a significant increase in PRL levels; naloxone completely abolished any effect of GE-B5 on PRL secretion.The present study indicates that GE-B5 stimulates PRL secretion after peripheral administration and that its action is mediated via classical opioid receptors; moreover, it identifies the minimum peptide dose which must reach the blood in order to exert its action on PRL secretion.     

On the spectrum of leprosy neuropathies: Multifocal inflammatory neuropathy heralding leprosy relapse

We report a 52 year-old woman with a past history of lepromatous leprosy (14 years prior to our first evaluation) who presented with progressive weakness and severe arm/leg pain. CSF analysis revealed elevated protein level with normal cell count. Skin and sural nerve biopsy showed no bacilli. Immunomodulatory treatment led to major improvement on clinical, CSF and electrodiagnostic grounds, but after one year of treatment, skin test revealed leprosy relapse. To our knowledge, this is the first report of a multifocal inflammatory neuropathy heralding leprosy relapse. Extended neurological work-up may be important in unexplained neuropathy progression after leprosy treatment.     

Critical Re-Evaluation of a Failure Mode Effect Analysis in a Radiation Therapy Department After 10 Years

PurposeFailure mode effect analysis (FMEA) is a proactive methodology that allows one to analyze a process, regardless of whether an adverse event occurs. In our radiation therapy (RT) department, a first FMEA was performed in 2009. In this paper we critically re-evaluate the RT process after 10 years and present it in terms of a lesson learned.Methods and MaterialsA working group (WG), led by a qualified clinical risk engineer, which included radiation oncologists, physicists, a radiation therapist, and a nurse, evaluated the possible failure modes (FMs) of the RT process. For each FM, the estimated frequency of occurrence (O, range 1-4), the expected severity of the damage (S, range 1-5), and the detectability lack (D, range 1-4) were scored. A risk priority number (RPN) was obtained as RPN = OxSxD. The data were compared with the 2009 edition.ResultsIn the 2020 analysis, 67 FMs were identified (27 in the 2009 series). The absolute risk values of the previous 3 highest FMs were generally reduced. The patient identification risk (highest value in the 2009 analysis) was reduced from 48.0 to 6.9, becoming the 51st RPN score, thanks to a patient barcode recognition within the bunker. The 2020 highest risk values regarded: (i-2020) the patient’s inadequate recollection and reporting of his/her medical history (ie, anamnesis) during the first medical examination and (ii-2020) the incorrect interpretation of tumor and normal tissue in computed tomography images. The WG proposed corrective actions.ConclusionsIn this single institution experience, the 10-year FMEA analysis showed a reduction in the previous higher RPN values thanks to the corrective actions taken. The new FMs and subsequent RPNs reveal the need for a continuous iterative improvement process.     

Genotype probabilities of pairs of individuals for X-chromosome markers

BACKGROUND: The usual set of autosomal markers (A-STRs) available in commercial kits is often insufficient to discriminate between close relationships when only two subjects are available for analysis. X-chromosome markers (X-STRs) provide higher statistical power in special cases. STUDY DESIGN AND METHODS: Formulas are derived for the probabilities of all possible genotype pairs for X-STRs of any sex combination for seven common relationships. The power of exclusion (PE) of X-STRs in parentage analysis is compared with that of A-STRs of equivalent distribution of allele frequency. RESULTS: Seventy-three equations were obtained, from which the likelihood ratio of any two alternative hypotheses about the relationship between two individuals can be obtained by division and simplification. For father-daughter and mother-son duos, the PE of X-STRs is almost twice the corresponding value of A-STRs for moderately low values of heterozygosity (0.6-0.75); for alleged pairs of sisters and pairs of half-sisters the PE is equivalent to that of A-STRs in parent-child duos. Considering four real unlinked X-STRs, the cumulative PE for father-daughter and mother-son duos was 99 percent, compared with 94 percent if they were autosomal. CONCLUSIONS: X-STRs can substantially increase the discrimination capacity of standard A-STRs in parentage analyses involving pairs of individuals. Up to four unlinked X-STRs may be treated as independent loci. When linked loci are included, computer programs that calculate pedigree likelihoods can be used.     

Comparison between men and women of volume regulating hormones and aquaporin-2 excretion following graded central hypovolemia

Central hypovolemia induced by orthostatic loading causes reno-vascular changes that can lead to orthostatic intolerance. In this study, we investigated volume regulating hormonal responses and reno-vascular changes in male and female subjects as they underwent central hypovolemia, induced by graded lower body negative pressure (LBNP). Aquaporin-2 (AQP2) excretion was measured as a biomarker for the renal system response to vasopressin. 37 young healthy subjects (n = 19 males; n = 18 females) were subjected to graded LBNP until − 40 mmHg LBNP. Under resting conditions, males had significantly higher copeptin (a stable peptide derived from vasopressin) levels compared with females. Adrenocorticotropin (ACTH), adrenomedullin (ADM), vasopressin (AVP) and brain natriuretic peptide (BNP) were not affected by our experimental protocol. Nevertheless, an analysis of ADM and BNP with the data normalized as percentages of the baseline value data showed an increase from baseline to 10 min after recovery in the males in ADM and in the females in BNP. Analysis of BNP and ADM raises the possibility of a preferential adaptive vascular response to central hypovolemia in males as shown by the normalized increase in ADM, whereas females showed a preferential renal response as shown by the normalized increase in BNP. Furthermore, our results suggest that there might be a difference between men and women in the copeptin response to alterations in orthostatic loading, simulated either using LBNP or during posture changes.

     

Functional evaluation of cerebral cortex in dementia with Lewy bodies

Neurochemical investigations have demonstrated central cholinergic dysfunction in patients with dementia with Lewy bodies (DLB). Central cholinergic circuits of the human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation of the contralateral motor cortex. This test, named short latency afferent inhibition has been shown in healthy subjects to be sensitive to the blockage of muscarinic acetylcholine receptors and it is impaired in patients with Alzheimer disease (AD), a cholinergic form of dementia, while it is normal in non-cholinergic forms of dementia such as fronto-temporal dementia. We evaluated short latency afferent inhibition in a group of patients with DLB and compared the data with that from a group of AD patients and a control group of age-matched healthy individuals. Short latency afferent inhibition was significantly reduced in DLB and AD patients. The findings suggest that this method can be used as a non-invasive test for the assessment of cholinergic pathways in patients with dementia and may represent a useful additional tool for discriminating between cholinergic and non-cholinergic forms of dementia.     

Efficacy and tolerability of enalapril (20 mg)/hydrochlorothiazide (12.5 mg) combination therapy in essential hypertension.

The efficacy and tolerability of a preconstituted formulation combining enalapril (20 mg) and hydrochlorothiazide (12.5 mg) were evaluated in patients with essential hypertension unresponsive to enalapril monotherapy (20 mg/day). The duration of this open-lable, multicenter, noncomparative trial was 12 weeks: a two-week washout period followed by ten weeks of active treatment. During the active treatment period, patients received enalapril alone (up to 20 mg/day) for six weeks. At the end of week 6, patients with supine diastolic blood pressure greater than 90 mmHg were treated with the enalapril/hydrochlorothiazide combination therapy (EN/HCTZ). Of the 147 patients who were entered into the study, 81 were not normalized with enalapril alone. At the end of the study period, blood pressure was normalized (supine diastolic blood pressure less than or equal to 90 mmHg) in 60 (74%) of the 81 patients who had received the EN/HCTZ combination. Overall, 86% of the patients achieved satisfactory blood pressure control with this therapeutic regimen. Adverse reactions were mild and transient. Six patients experienced undesirable effects, the most frequent of which was coughing (2 cases). Neither enalapril (20 mg/day) alone nor the EN/HCTZ combination had any significant influence on any of the metabolic parameters evaluated. No hypokalemia and no significant changes in serum lipids occurred in the course of the study.     

Inspiratory effort and measurement of dynamic intrinsic PEEP in COPD patients: Effects of ventilator triggering systems

Objective To investigate effects of ventilator triggering systems (pressure and flow triggering: PT and FT) on measurement of dynamic intrinsic PEEP (PEEPi_dyn) and patient-ventilator interaction in patients with chronic obstructive pulmonary disease during weaning from mechanical ventilation.Design Prospective study.Setting Medical/surgical intensive care unit of an academic hospital.Patients and participants 6 COPD patients with acute respiratory failure ready to wean.Measurements We measured flow, airway opening, esophageal and gastric pressures. Minute ventilation, breathing pattern and pressure time product (PTP) of the respiratory muscles and of the diaphragm were obtained during spontaneous ventilation through a mechanical ventilator (Puritan-Bennett 7200ae). Two triggering systems, namely PT and FT, were evaluated.Results The inspiratory muscles effort necessary to overcome the triggering system overestimated PEEPi_dyn measurement of an amount equal to 49±2 and 58±3% during respectively pressure and flow triggering. FT increased tidal volume and minute ventilation and decrease PTP/b and PTP/min of the respiratory muscles and diaphragm.Conclusions To correctly measure PEEPi_dyn, the inspiratory effort produced to overcome PEEPi and to trigger the ventilator must be discriminated. Application of flow triggering requires less effort to initiate inspiration and provide a positive end-expiratory pressure level that is able to unload the respiratory muscles by reducing PEEPi. With flow triggering higher minute ventilation are obtained in COPD patients during the weaning phase.Supported in part by the Ministero dell' Università e della Ricerca Scientifica e Tecnologica