Prevalence of abnormal upper limb arterial anatomy and its correlation with access failure during transradial coronary angiography

ObjectiveThe study aimed at to find out prevalence of abnormal upper limb arterial anatomy and its correlation with access failure during transradial coronary angiography.MethodThis was a prospective observational study of 1512 patients who had undergone transradial coronary angiography (CAG). Angiographic assessment of upper limb arterial tree was performed when the angiographic guidewire or the diagnostic catheter followed an abnormal path or got stuck in its course.ResultsAbout 5.29% patients (80/1512) were noted to have abnormal upper limb arterial anatomy. The most common abnormality detected were radio-ulnar loop in 22 (1.46%) patients, tortuous upper limb arteries 19 (1.25%) and abnormal high origin of radial artery 10 (0.66%) patients. Access failure was encountered in 4.4% (67/1512) of total patients and 64.17% (43/67) access failure was due to abnormal upper limb arterial anatomy.ConclusionAbnormal upper limb arterial anatomy was the most common cause of access failure in transradial coronary angiography in this study.     

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats,Dogs, and Humans

Enterohepatic recirculation (EHC) can greatly enhance plasma drug exposures and therapeutic effects. This study aimed to develop a population pharmacokinetic model that can simultaneously characterize the extent and time-course of EHC in three species using fimasartan, a novel angiotensin II receptor blocker, as a model drug. All fimasartan plasma concentration profiles in 32 rats (intravenous doses, 0.3–3 mg/kg; oral doses, 1–10 mg/kg), 34 dogs (intravenous doses, 0.3–1 mg/kg; oral doses, 1–10 mg/kg), and 42 healthy volunteers (single or multiple oral doses, 20–480 mg) were determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS) and simultaneously modeled in S-ADAPT. The proposed model quantitatively characterized EHC in three species after oral and intravenous dosing. The median (range) fraction of drug undergoing recirculation was 76.3% (64.9–88.7%) in rats, 33.3% (24.0–45.9%) in dogs, and 65.6% (56.5–72.0%) in humans. In the presence compared with the absence of EHC, the area under the curve in plasma was predicted to be 4.22-fold (2.85–8.85) as high in rats, 1.50-fold (1.32–1.85) in dogs, and 2.91-fold (2.30–3.57) in humans. The modeled oral bioavailability in rats (median (range), 38.7% (20.0–59.8%)) and dogs (median, 7.13% to 15.4%, depending on the formulation) matched the non-compartmental estimates well. In humans, the predicted oral bioavailability was 25.1% (15.1–43.9%) under fasting and 18.2% (12.2–31.0%) under fed conditions. The allometrically scaled area under the curve predicted from rats was 420 ng ⋅ h/mL for 60 mg fimasartan compared with 424 ± 63 ng ⋅ h/mL observed in humans. The developed population pharmacokinetic model can be utilized to characterize the impact of EHC on plasma drug exposure in animals and humans.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9764-2) contains supplementary material, which is available to authorized users.KEY WORDS: animal to human scaling, enterohepatic recirculation, fimasartan, population pharmacokinetics, S-ADAPT     

Mimicry between neurokinin-1 and fibronectin may explain the transport and stability of increased substance P immunoreactivity in patients with bone marrow fibrosis

Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases. In this study, the role of substance P (SP), a peptide with pleiotropic functions, was examined. Some of its functions-angiogenesis, fibroblast proliferation, and stimulation of BM progenitors-are amenable to inducing BM fibrosis. Indeed, a significant increase was found in SP-immunoreactivity (SP-IR) in the sera of patients with BM fibrosis (n = 44) compared with the sera of patients with hematologic disorders and no histologic evidence of fibrosis (n = 46) (140 +/-12 vs 18 +/-3; P <.01). Immunoprecipitation of sera SP indicated that this peptide exists in the form of a complex with other molecule(s). It was, therefore, hypothesized that SP might be complexed with NK-1, its natural receptor, or with a molecule homologous to NK-1. To address this, 3 cDNA libraries were screened that were constructed from pooled BM stroma or mononuclear cells with an NK-1 cDNA probe. A partial clone (clone 1) was retrieved that was 97% homologous to the ED-A region of fibronectin (FN). Furthermore, sequence analyses indicated that clone 1 shared significant homology with exon 5 of NK-1. Immunoprecipitation and Western blot analysis indicated co-migration of SP and FN in 27 of 31 patients with BM fibrosis. Computer-assisted molecular modeling suggested that similar secondary structural features between FN and NK-1 and the relative electrostatic charge might explain a complex formed between FN (negative) and SP (positive). This study suggests that SP may be implicated in the pathophysiology of myelofibrosis, though its role would have to be substantiated in future research. (Blood. 2001;97:3025-3031)     

Aminoacidopathies: A review of 3 years experience of investigations in a Kuwait hospital

Summary We present a summary of the results of quantitative amino acid analysis in 800 subjects over a three-year period in Al-Sabah Hospital, Kuwait. Thirty-five patients with aminoacidopathy were identified, all but two of whom were the offspring of first-degree consanguineous marriages: nine cases of phenylketonuria, one benign hyperphenylalaninaemia, seven non-ketotic hyperglycinaemia, five tyrosinaemia, five homocystinuria, four citrullinaemia, two cystinuria, one hyperprolinaemia, and one maple syrup urine disease. The clinical and biochemical findings in these cases are described.     

Drug resistant Haemophilus influenzae from respiratory tract infection in a tertiary care hospital in north India

Haemophilus influenzae is an important respiratory pathogen. Emergence of resistance to various antibiotics is a major problem in patient management. A total of 90 strains of H. influenzae were characterized from specimens obtained from patients of acute respiratory tract infection; 13 (14.4%) belonged to type beta. On biotyping, 90% strains belonged to biotype II. The frequency of resistance to various antibiotics was as follows: cotrimoxazole 33.3% ampicillin 21.1%, cephalexin 7.8%, chloramphenicol 7.8%, ciprofloxacin 2.5% erythromycin and tetracycline 5% each. All the ampicillin-resistant strains produced beta-lactamase as detected by nitrocefin disc method. None of the strains exhibited resistance to cefaclor and third generation cephalosporins. The present study showed emergence of variable resistance to ampicillin, cotrimoxazole and other antibiotics. It is important for the clinical microbiology laboratory to monitor drug resistant strains for instituting appropriate antibiotic therapy of respiratory infections due to H. influenzae.     

Structural basis for substrate discrimination by E. coli repair enzyme,AlkB

E. coli AlkB, a repair enzyme of the dioxygenase family, catalyses the removal of mutagenic methylated nucleotides from the genome. Known for substrate promiscuity, AlkB''s catalytic mechanism and conformational changes accompanying substrate binding have been extensively dissected. However, the structural parameters of various substrates governing their recognition by AlkB still remain elusive. In this work, through solution-state vibrational spectra of methylated substrates bound to AlkB in combination with computational analysis, we show that the recognition specificity is dictated by the protonation states of the substrates. Specificity is conferred predominantly through hydrogen bonding and cation–π interactions. Furthermore, we report on the interaction of AlkB with normal, unmodified nucleotides, wherein the presence of an exocyclic amino group serves as an essential criterion for the initial process of substrate recognition. Taken together, these results provide a rationale for structural determinants of substrate specificity as well as mode of lesion discrimination employed by AlkB.

Positive charge on methylated nucleotides is a prime criterion for substrate recognition by E. coli AlkB.     

Rifaximin,a pregnane X receptor (PXR) activator regulates apoptosis in a murine model of breast cancer

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats. Animals were randomized and divided among four groups of six animals each. Group I (control 0.9% normal saline, 3 ml kg⁻¹, p.o.); Group II (toxic control, MNU 47 mg kg⁻¹, i.v.); Group III (RFX, 25 mg kg⁻¹, p.o.); Group IV (RFX, 50 mg kg⁻¹, p.o.). Toxicity was induced by single i.v. injection of MNU. MNU treatment was evident with increased alveolar bud count, differentiation score, up-regulated inflammatory enzyme markers (COX, LOX, NO and H₂S) and oxidative stress markers (TBAR''s, protein carbonyl, SOD, catalase and Ach). The mammary gland surface architecture was studied using SEM, carmine staining and H&E staining. The treatment with RFX elicited noticeable restoration of the overall histological architecture in the experimental animals similar to the control. In the MNU treated toxic group, the levels of oxidative stress markers significantly increased in comparison to the control, which was subsequently restored after RFX treatment. Furthermore, RFX up regulated the levels of caspase 3 and caspase 8, when compared to the MNU treated animals. MNU associated toxicity was also ascertained, when determined for UCHL-1, COX, NF-κBp65, BAD, and BCL-xl expression, while RFX demonstrated modulation of the same.

The present study was proposed to investigate the effect of rifaximin (RFX) on methyl nitrosourea (MNU) induced mammary gland carcinoma in albino wistar rats.     

Sensitivity and specificity of CT scan in revealing skull fracture in medico-legal head injury victims

Background

Emergency departments rely on CT scans to manage trauma victims, especially for head injuries. Although the detection of an undisplaced fracture on a CT scan of the head without significant intracranial findings may be insignificant for a clinician, such cases are of paramount importance for medico-legal purposes because they help ascertain the nature, manner, and cause of the head injury.

Aims

The study was conducted with the objective of knowing the sensitivity and specificity of ante-mortem CT scan findings indicating the presence or absence of skull fractures.

Methods

Findings were confirmed during post-mortem examination of the subjects who had died during management but who had not had any surgical intervention. A comparative study of ante-mortem CT scan and autopsy findings with respect to fracture in traumatic head injuries was undertaken on 60 deceased individuals brought in for medico-legal post-mortem examination over a period of two years.

Results

Considering the autopsy findings as the gold standard, we have concluded that 14.6 per cent of the fractures were missed on CT scan findings compared to fractures found during autopsy. The sensitivity of CT scan for skull fractures was found to be 85.4 per cent and specificity was 100 per cent. Kappa was 0.787, which shows good agreement with p<0.001, which was highly significant.

Conclusion

In developing countries, images are interpreted in the axial plane only on a CT scan of the head, which may be due to a lack of financial and human resources. For better delineation of fractures, the use of techniques like multi-detector CT with sagittal and coronal reformations should be considered in the routine interpretation of a CT scan of the head.     

Cost-Effective Isolation of a Process Impurity of Pregabalin

Cost-effective isolation methods were developed on preparative HPLC, flash LC, and simulated moving bed (SMB) to prepare the process impurity, 3-(aminomethyl)-5-methylhex-4-enoic acid (4-ene impurity), of pregabalin. By a thorough experimental study on the different isolation techniques available, it was concluded that SMB was the most cost-effective. Hence, it was a continuous chromatography that utilized the advantage of SMB so that a high quantity of the impurity was generated in a short period of time. SMB was equipped with eight reversed-phased columns and was used to separate the process impurity of pregabalin. The effects of flow rate in zone 2 (Q2) and 3 (Q3), as well as switching time, on the operating performance parameters like purity, productivity, and desorbent consumption were studied. Operating conditions leading to more than 90% purity in the raffinate outlet stream were identified, together with those achieving optimal performance. All of these developed methods are novel, cost-effective, and can be applied to the isolation of other process- and stability-related impurities of pregabalin.