Renal Effects of Multiple Infusion of Pyridoxalated-Hemoglobin-Polyoxyethylene Conjugate (PHP) Solution in Dogs

Abstract: Pyridoxalated-hemoglobin-polyoxyethylene conjugate (PHP), which is made from out-dated human red blood cells by two major chemical modifications, namely pyridoxalation and conjugation with polyoxyethylene (POE), is currently under development as a physiological oxygen carrier. This study assessed the effects of PHP-88 solution, which contains 8% (wt/vol) each of hemoglobin (Hb) and maltose, on renal function when it was infused 3 times every other day into the intact circulation of 8 dogs (5 dogs for the PHP group and 3 for the control group; 20 ml/kg for the first infusion, and 10 ml/kg each for the second and third infusions, at the rate of 2.5 ml/h/kg). Serial determinations of glomerular filtration rate (GFR) and renal plasma flow (RPF) were carried out pre- and postinfusion for up to 3 months along with measurements of blood and urine analyses, urine output rate, fractional excretion of sodium (FES), and free water clearance (C_H2O). The results showed that plasma colloid osmotic pressure (COP) elevated an average of 3.3 mm Hg (p = 0.0085), and GFR and RPF tended to increase by 13% (NS) and 38% (NS), respectively, immediately after the third infusion with PHP solution. Urine output rate increased during and after the infusion, and FES and C_H2O also increased for 24 h after the infusion in both groups. Blood urea nitrogen, serum creatinine, and serum Na⁺ concentrations were not affected greatly by the infusions, but hematocrit was decreased by 8% in the PHP group, indicating approximately a 42% expansion of plasma volume. These changes were observed to return to their preinfusion levels by 1 week postinfusion. Renal histology of the PHP group obtained at 2 weeks postinfusion revealed vacuole formation in the proximal tubules which was not associated with any pathologic changes indicative of cell death or regeneration. In 4 out of 5 dogs at 3 months postinfusion (necropsy), the vacuoles were not present. Though urinary N-acetyl β-glucosaminidase (NAG) activity had significantly increased after infusion, it returned to the preinfusion level by 1 month postinfusion. No detrimental effect of vacuoles on the assessed renal tubular functions was confirmed in the present study. The result demonstrated that multiple infusions of PHP solutions were well tolerated in normal dogs, and the observed effects were conceived predominantly attributable to the physiological response of the kidneys to an oncotic load into the circulation, which produced plasma volume expansion.     

A simple in vitro system for comparing the bactericidal activity of antibiotics at variable concentrations

An in vitro device is described that allows the study of bactericidal activity of decreasing antibiotic concentrations. This simple and easily set up device was found to be accurate and reliable. The bactericidal kinetics of three antibacterial compounds (cephalothin, norfloxacin and pristinamycin) on Staphylococcus aureus were compared in a system simulating serum concentration and half-life of each antibacterial compound. The results show the importance of pharmacokinetic parameters on antibacterial activity and their usefulness in new antibiotics evaluation.     

Low‐density lipoprotein cholesterol lowering in real‐world patients treated with evolocumab

BackgroundLow‐density lipoprotein cholesterol (LDL‐C) is a risk factor for atherosclerotic cardiovascular disease (ASCVD). There are limited real‐world data on LDL‐C lowering with evolocumab in United States clinical practice.HypothesisWe assessed LDL‐C lowering during 1 year of evolocumab therapy.MethodsThis retrospective cohort study used linked laboratory (Prognos) and medical claims (IQVIA Dx/LRx and PharMetrics Plus^®) data. Patients with a first fill for evolocumab between 7/1/2015 and 10/31/2019 (index event) and LDL‐C ≥ 70 mg/dL were included (overall cohort; N = 5897). Additionally, a patient subgroup with a recent myocardial infarction (MI) within 12 months (median 130 days) before the first evolocumab fill was identified (N = 152). Reduction from baseline LDL‐C was calculated based on the lowest LDL‐C value recorded during a 12‐month follow‐up period.ResultsThe mean (SD) age was 65 (10) years; 61.9% of patients had ASCVD diagnoses and 70.7% of patients were in receipt of lipid‐lowering therapy. Following evolocumab treatment, changes in LDL‐C from baseline were −60% in the overall cohort (median [interquartile range (IQR)] 146 [115–180] mg/dL to 58 [36–84] mg/dL) and −65% in the recent MI subgroup (median [IQR] 137 [109–165] mg/dL to 48 [30–78] mg/dL). In the overall cohort and recent MI subgroup, 62.1% and 69.7% of patients achieved LDL‐C < 70 mg/dL, respectively.ConclusionsIn this real‐world analysis, evolocumab was associated with significant reductions in LDL‐C comparable to that seen in the FOURIER clinical trial, which were durable over 1 year of treatment.     

Reduction of beta cell mass: partial insulin secretory compensation from the residual beta cell population in the nicotinamide–streptozotocin Göttingen minipig after oral glucose in vivo and in the perfused pancreas

Aims/hypothesis A progressive loss of beta cell function and mass are important contributory factors in the development and progression of type 2 diabetes. The aim of this study was to evaluate the effects of a primary reduction in beta cell mass on beta cell function in vivo and in the perfused pancreas and to relate these characteristics to beta cell mass.Methods The beta cell mass of six Göttingen minipigs was reduced chemically (using 67 mg/kg nicotinamide and 125 mg/kg streptozotocin). Six untreated minipigs were kept as control animals. Insulin responses were evaluated in vivo using the mixed meal tolerance test (2 g/kg oral glucose) and in the isolated perfused pancreata from the same animals by stimulation with glucose, glucagon-like peptide-1 or arginine.Results Beta cell mass was reduced in the beta-cell-reduced animals compared with the control minipigs (182±76 vs 464±156 mg, p<0.01). AUC_glucose was increased in the beta-cell-reduced animals (1383±385 vs 853±113 mmol·l^–1·min in control minipigs, p<0.01), as was the insulin response to oral glucose per unit of beta cell mass (123±84 vs 56±24 pmol·l^–1·min·mg^–1, p<0.05). Total in vitro insulin secretion was increased per unit of beta cell mass in nicotinamide + streptozotocin pancreata compared to controls (83.7±45.9 vs 34.6±14.4 nmol/mg beta cells, p<0.05) with responses to glucose and glucagon-like peptide-1 showing a partial compensation for reduced beta cell mass, whereas no compensation was seen in response to arginine.Conclusions/interpretation A primary reduction in beta cell mass impairs glucose tolerance and leads to a compensatory increase in insulin secretion from the remaining beta cells after oral glucose in vivo, which is even more apparent in the perfused pancreas. It remains to be determined whether this compensation can be maintained in the long term.Conflict of interest statement: M.O. Larsen, B. Rolin, C.F. Gotfredsen and R.D. Carr are all employees and shareholders at Novo Nordisk. J.J. Holst has been on advisory boards for Novo Nordisk.     

Les abdomens chirurgicaux dus au traitement traditionnel. À propos de cinq cas au Centre hospitalier Yalgado Ouédraogo de Ouagadougou

The traditional products used to treat some pains can cause serious complications of which surgical abdomen. We listed in two years five cases of surgical abdomen complicating a traditional treatment in the service of digestive and general surgery of the hospital complex Yalgado Ouédraogo. There were two men and three women with an average age of 34,4 years. These traditional products were used to treat constipation, sexual impotence, sterility and to “posses” her husband. Oral and rectal routes were used by one and three patients respectively, another patient used triple routes (oral, rectal and vaginal). The digestive lesions were in the upper tract in one case (gastric phytobezoar), two patients presented acute intestinal occlusion and two others acute generalized peritonitis. All the five patients underwent laparotomy. Two patients died in immediately post-operative course. The prevention of severe surgical complications of the digestive tract induced by traditional treatments has to be broadcasted through information, education and communication.     

Intracranial suppurations in the African child: a severe but preventable complication

Introduction

Intracranial suppurations (ICS) are collections of pus of infectious origin in the skull. The authors present their experience.

Patients and method

All children operated for ICS at the Central Hospital of Yaoundé from January 2000 to December 2008 were retrospectively included.

Results

Thirty-five patients were recruited: 26 (74.29 %) males and 9 (25.71 %) females. These represent 82.9 % of all ICS operated in our institution. ICS represented 14.3 % of intracranial space-occupying lesions. The mean age was 8.34 years. They presented with headaches (80.77 %), altered consciousness (20 %), convulsions (76 %), vomiting (20 %), unilateral motor deficit (69.23 %), speech disorders (12 %), and fever (89.29 %). Bergman’s triad (51.86 %) was frequent. The primary infection was: meningitis, eight cases (22.85 %); sinusitis, six cases (17.14 %); head trauma, five cases (14.28 %); otitis media, one case (2.85 %); suppurations of the face, three cases (8.56 %); cardiopathy, one case (2.85 %); and craniotomy, one case (2.85 %). In seven cases (20 %), the origin was unknown. The lesions were empyema in 23 cases (65.71 %), cerebral abscess in 8 cases (22.85 %) and pyoventriculitis in 2 cases (5.72 %). The surgical procedures were burr holes (88.89 % of empyemas) and trepano-puncture–aspiration (75 % of abscesses). The mortality (21.42 %) and morbidity (42.85 %) were recorded.

Conclusion

ICS are frequent but preventable (early treatment of the primary infection) pathologies of childhood in developing countries. Burr hole drainage (empyemas) and puncture–aspiration (abscesses) are simple, safe, and effective techniques.     

Surgical management of lumbar spinal stenosis in patients over 80: is there an increased risk?

Neurosurgical Review - Management of lumbar spinal stenosis (LSS) represents the first cause of spinal surgery for the elderly and will increase with the aging population. Although the surgery...     

First detection of Theileria parva in cattle from Cameroon in the absence of the main tick vector Rhipicephalus appendiculatus

A major risk factor for the spread of livestock diseases and their vectors is the uncontrolled transboundary movement of live animals for trade and grazing. Such movements constrain effective control of tick‐transmitted pathogens, including Theileria parva. Only limited studies have been undertaken to identify ticks and tick‐borne diseases (TTBDs) affecting cattle in central African countries, including Cameroon. We hereby report the collection of baseline data on the prevalence of T. parva in Cameroon through a countrywide cross‐sectional survey, conducted in 2016, involving collection of blood samples from cattle from 63 sites across the five agro‐ecological zones (AEZs) of the country. ELISA‐based surveillance of infected cattle was performed on 479 randomly selected samples and revealed specific antibodies to T. parva in 22.7% and T. mutans in 41.1% of cattle. Screening of 1,340 representative DNA samples for the presence of T. parva identified 25 (1.86%) positives using a p104 antigen gene‐based nested PCR assay. The positives were distributed across agro‐ecological zones I, II, III and V. None of the p104 positive cattle exhibited clinical symptoms of East Coast fever (ECF). Using reverse line blot (RLB), 58 (4.3%) and 1,139 (85%) of the samples reacted with the T. parva and T. mutans oligonucleotide probes, respectively. This represents the first report of T. parva from Cameroon. Surprisingly, no Rhipicephalus appendiculatus ticks, the main vector of T. parva, were identified in a parallel study involving comprehensive morphological and molecular survey of tick species present in the country. Only two of the 25 p104 positive cattle were PCR‐positive for the CD8+ T‐cell target schizont‐expressed antigen gene Tp1. Cloning and sequencing of Tp1 amplicons revealed sequence identity with the reference T. parva Muguga. This new finding raises serious concerns of a potential spread of ECF into the central African region.     

Therapeutic potential of thromboxane inhibitors in asthma

This paper reviews the role of thromboxane A(2) (TXA(2)) in the pathogenesis of pulmonary allergies, particularly asthma. The potential of TXA(2) modifiers in the prevention and/or treatment of pulmonary allergies is also discussed. Bronchial asthma is characterised by reversible airway obstruction, bronchial hyperresponsiveness and inflammation. Several studies have elucidated the role of arachidonic acid metabolites (leukotrienes, prostaglandins and TXA(2)) in the pathogenesis of asthma. Among those mediators, TXA(2) has attracted attention due to its strong physiological activity. Indeed, TXA(2) demonstrates not only potent bronchoconstrictive activity but is also believed to be involved both in late asthmatic responses and in bronchial hyperresponsiveness, a typical feature of this disease. Several thromboxane receptor antagonists (TXRAs) and thromboxane synthase inhibitors (TXSIs) have been studied with the aim of reducing or preventing asthma. As double-blind, placebo-controlled clinical trials have proven the efficiency of some TXA(2) modifiers in treating asthma, the TP receptor antagonist seratrodast (AA-2414) and the thromboxane synthase inhibitor ozagrel hydrochloride (OKY-046) are now available as anti-asthmatic agents in Japan. Moreover, seratrodast and ramatroban (BAY-U-3405), another thromboxane receptor antagonist, are currently under Phase III clinical evaluation in the US for the treatment of asthma.