Impact of deintensifying hypoglycaemic drugs in older adults with type 2 diabetes: protocol for an emulation of a target trial.

INTRODUCTION: In older adults with type 2 diabetes (T2D), overtreatment with hypoglycaemic drugs (HDs: sulfonylureas, glinides and/or insulins) is frequent and associated with increased 1-year mortality. Deintensification of HD is thus a key issue, for which evidence is though limited. The primary objective of this study will be to estimate the effect of deintensifying HD on clinical outcomes (hospital admission or death) within 3 months in older adults (≥75 years) with T2D. METHODS: We will emulate with real-world data a target trial, within The Health Improvement Network cohort, a large-scale database of data collected from electronic medical records of 2000 general practitioners in France. From 1 January 2010 to 28 February 2019, we will include eligible patients ≥75 years who will have T2D, a stable dose of HDs, glycated haemoglobin A1c (HbA1c) value <75 mmol/mol (9.0%) and no deintensification in the past year. The target trial will be sequentially emulated (ie, eligibility assessed) every month in the database. Patients will be classified at baseline of each sequential trial in the intervention arm (deintensification of HDs: decrease of ≥50% in the total dose of HDs, including complete cessation) or control arm (no deintensification of HDs). The pooled dataset for all sequential emulated trials will be analysed. The primary outcome will be time to first occurrence of hospital admission or death, within 3 months. Secondary outcomes will be hospitalisation, death, appropriateness of glycaemic control and occurrence of HbA1c >75 mmol/mol within 1 year. Participants will be followed from baseline to 12 months after randomisation, administrative censoring, or death, whichever occurs first. A pooled logistic regression will be used to estimate the treatment effect on the incidence of the outcomes. DISSEMINATION AND ETHICS: No ethical approval is needed for using retrospectively this fully anonymised database. The results will be disseminated during conferences and through publications in scientific journals.

Supplementation of conventional anti-diabetic therapy with alpha-lipoic acid prevents early development and progression of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Current pharmacological interventions only retard DN progression. Alpha-lipoic acid (ALA) is a potent antioxidant with beneficial effect in other diabetic complications. This study investigates whether ALA supplementation prevents early development and progression of DN. METHOD: Fifty-eight male Sprague-Dawley rats were randomly assigned to healthy control and diabetic groups and subjected to overnight fasting. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). On day 3 after T2DM induction, diabetic rats received oral daily administration of ALA (60 mg/kg), gliclazide (15 mg/kg), ramipril (10 mg/kg) or drug combinations for 6 weeks. Untreated diabetic rats served as diabetic control. Blood, kidneys and pancreas were harvested for biochemical and histological analyses. RESULT: Induction of T2DM resulted in hypoinsulinemia, hyperglycemia and renal pathology. ALA supplementation maintained ß-cell function, normoinsulinemia and normoglycemia in diabetic rats, and prevented renal pathology (PAS, KIM-1, plasma creatinine, total protein, blood urea nitrogen, uric acid and urine albumin/creatinine ratio) and triglycerides level compared to diabetic control (p < 0.001). Additionally, ALA supplementation significantly prevented elevated serum and tissue malondialdehyde, collagen deposition, α-SMA expression, apoptosis and serum IL-1ß and IL-6 levels while it markedly increased renal glutathione content and plasma HDL-C compared to diabetic control group (p < 0.001). CONCLUSION: ALA supplementation prevents early development and progression of DN by exerting anti-hyperglycemic, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Our findings provide additional option for clinical treatment of DN in T2DM patients.

Polyphenols in cassava leaves (Manihot esculenta Crantz) and their stability in antioxidant potential after in vitro gastrointestinal digestion.

The study was carried out to assess the effect of variety on polyphenols in cassava leaves and their stability in antioxidant activity before and after in vitro gastrointestinal digestion. The results showed that individual and total polyphenols content (TPC) and antioxidant activity of bound, free and bioaccessible polyphenols were significantly (p < 0.05) influenced by variety at harvesting maturity. The bound polyphenols had lower TPC (5.00-19.16 mg GAE/g) than free (39.16-89.61 mg GAE/g) throughout harvesting maturity. The polyphenols were strongly affected after in vitro digestion, however, salicylic, syringic and benzoic acids are the most bioaccessible. The free polyphenols of variety IRAD4115 had the highest value of FRAP (35.17 µg TE/g) at 12 months after planting (MAP), while, bound polyphenols showed the lowest DPPH (6.59 µg TE/g, variety EN at 12MAP). The antioxidant activity value evaluated by DPPH method was decreased significantly after in vitro gastrointestinal digestion. However, there was no significant difference between antioxidant activity of bioaccessible polyphenols (77.71 µg TE/g) and methanolic polyphenols (79.17 µg TE/g) assessed by FRAP method. These findings showed the stability of antioxidant potential of polyphenols in cassava leaves harvested at different periods after in vitro digestion. Thus cassava leaves harvested at appropriate maturity can be used as ingredient of functional food for nutraceutical benefits.

Ratio of fetal choroid plexus to head size: simple sonographic marker of open spina bifida at 11-13 weeks' gestation.

OBJECTIVES: To measure the ratio of choroid plexus (CP) size to head size in normal fetuses and to compare it to that in fetuses with open spina bifida (OSB) and quantify the subjective sign of a 'dry brain'. METHODS: This was a retrospective study of ultrasound images, obtained during first-trimester screening between 11 and 13 weeks of gestation, from 34 fetuses with OSB and 160 normal fetuses. From the hospital databases, we retrieved images of the fetal head in the transventricular axial plane. We measured the areas of both CPs and the head and calculated the ratio between them. We also measured the longest diameter of each CP and calculated their mean (CP length), and measured the occipitofrontal diameter (OFD) and calculated the ratio of CP length to OFD. Measurements from the OSB fetuses were plotted on crown-rump length (CRL) reference ranges constructed using data from the normal fetuses, and Z-scores were calculated. RESULTS: In the normal fetuses, the CP area increased, while the ratios of CP area to head area and CP length to OFD decreased, with increasing CRL. In 30 of the 34 (88%) fetuses with OSB, both ratios were increased significantly and the CPs filled the entirety of the head, giving the impression of a dry brain. In these cases, the borders of the lateral ventricles could not be identified. CONCLUSIONS: At 11-13 weeks, the majority of fetuses with OSB have reduced fluid in the lateral ventricles such that the CPs fill the head. The dry brain sign is easily visualized during routine first-trimester ultrasound examination while measuring the biparietal diameter, and can be quantified by comparing the size of the CPs to the head size. Until prospective data confirm the usefulness of this sign in screening for OSB, it should be considered as a hint to prompt the examiner to assess thoroughly the posterior fossa and spine. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

In Vitro Antioxidant Potential and Effect of a Glutathione-Enhancer Dietary Supplement on Selected Rat Liver Cytochrome P450 Enzyme Activity.

BACKGROUND: There is considerable evidence that many people take dietary supplements including those of herbal origin as an alternative therapy to improve their health. One such supplement, with an amalgam of constituents, is CellGevity®. However, the effect of this dietary supplement on drug-metabolizing enzymes is poorly understood, as it has not been studied extensively. Therefore, we investigated the effect of CellGevity dietary supplement on selected rat liver microsomal cytochrome P450 (CYP) enzymes, the most common drug-metabolizing enzymes. We also determined the total antioxidant potential of this dietary supplement in vitro. METHODS: To determine the antioxidant potential of CellGevity dietary supplement, 2,2-diphenyl-2-picryl-hydrazyl (DPPH), total phenolic, and flavonoid assays were used after initial preparation of a solution form of the supplement (low dose, LD; 4 mg/kg and high dose, HD; 8 mg/kg). Rats received oral administration of these doses of the supplement for 7 days, after which the effect of the supplement on selected liver CYP enzymes was assessed using probe substrates and spectroscopic and high-performance liquid chromatographic methods. Rats which received daily administration of 80 mg/kg of phenobarbitone and distilled water served as positive and negative controls, respectively. RESULTS: The IC50 value of the supplement 0.34 ± 0.07 mg/ml compared to 0.076 ± 0.03 mg/ml of the BHT (positive control). The total phenolic content of the supplement at a concentration of 2.5 mg/ml was 34.97 g gallic acid equivalent (GAE)/100 g while its total flavonoid content at a concentration of 2.5 mg/ml was 6 g quercetin equivalent (QE)/100 g. The supplement significantly inhibited rat CYP2B1/2B2 (LDT 92.4%; HDT 100%), CYP3A4 (LDT 81.2%; HDT 71.7%), and CYP2C9 (LDT 21.7%; HDT 28.5%) while it had no significant inhibitory effect on CYPs 1A1/1A2, CYP1A2, and CYP2D6. CONCLUSION: CellGevity dietary supplement possesses moderate antioxidant activity in vitro and has an inhibitory effect on selected rat liver CYP enzymes, suggesting its potential interaction with drugs metabolized by CYP enzymes.

First-Trimester Crown-Rump Length and Embryonic Volume of Fetuses with Structural Congenital Abnormalities Measured in Virtual Reality: An Observational Study.

Background. With the introduction of three-dimensional (3D) ultrasound it has become possible to measure volumes. The relative increase in embryonic volume (EV) is much larger than that of the crown-rump length (CRL) over the same time period. We examined whether EV is a better parameter to determine growth restriction in fetuses with structural congenital abnormalities. Study Design, Subjects, and Outcome Measures. CRL and EV were measured using a Virtual Reality (VR) system in prospectively collected 3D ultrasound volumes of 56 fetuses diagnosed with structural congenital abnormalities in the first trimester of pregnancy (gestational age 7+5 to 14+5 weeks). Measured CRL and EV were converted to z-scores and to percentages of the expected mean using previously published reference curves of euploid fetuses. The one-sample t-test was performed to test significance. Results. The EV was smaller than expected for GA in fetuses with structural congenital abnormalities (-35% p < 0.001, z-score -1.44 p < 0.001), whereas CRL was not (-6.43% p = 0.118, z-score -0.43 p = 0.605). Conclusions. CRL is a less reliable parameter to determine growth restriction in fetuses with structural congenital abnormalities as compared with EV. By measuring EV, growth restriction in first-trimester fetuses with structural congenital abnormalities becomes more evident and enables an earlier detection of these cases.

Neurophysiological assessment of acute pain in infants: a scoping review of research methods.

A systematic scoping search to describe the neurophysiological methods used in infant acute pain assessment research was conducted. Of the 2411 abstracts screened, 19 articles were retained. Nine studies utilised near-infrared spectroscopy (NIRS), two utilised functional magnetic resonance imaging (fMRI), and eight utilised electroencephalography (EEG). There was methodological variability in studies utilising NIRS, whereas EEG and fMRI studies reported consistent methods. Of the eight EEG studies, six identified a nociceptive-specific event-related potential. CONCLUSION: While more methodologically rigorous studies are needed, ERPs appear to hold some promise as indicators of infant nociception during clinical procedures to supplement existing measures.

Long-term continuous administration of a hydro-ethanolic extract of Synedrella nodiflora (L) Gaertn in male Sprague-Dawley rats: biochemical, haematological and histopathological changes.

BACKGROUND: Conflicting reports about the toxicity of Synedrella nodiflora (L) Gaertn (family Asteraceae), a plant traditionally used in Ghana for the management of epilepsy, abound in literature. The present study evaluates the effect of a 90-day continuous oral administration of a hydro-ethanolic whole plant extract of Synedrella nodiflora (SNE) in male Sprague-Dawley rats. METHODS: The toxicological evaluation of the extract (100, 300 and 1000 mgkg-1) was focused on haematological, serum biochemical parameters and histopathological changes of some isolated organs. RESULTS: The extract produced no mortality in the rats treated during the study period. Only SNE 100 mgkg-1 produced significant decrease in white blood cell and neutrophil counts and an increase in albumin, globulin, total bilirubin, total protein and potassium levels. The higher doses (SNE 300 and 1000 mgkg-1) had no significant effect on all the haematological and biochemical parameters measured. Histopathological assessment of the liver, kidney and heart revealed no abnormalities in rats treated with the extracts. Only the SNE 1000 mgkg-1 produced distortions of the branching arrangements of the myocardial fibres and a congested vessel which indicates a healed infarction. CONCLUSIONS: The findings suggest hydro-ethanolic extract of Synedrella nodiflora (L) Gaertn generally has a low toxicity profile following a 90-day continuous oral administration in male Sprague-Dawley rats under the present laboratory conditions. However patients with renal or cardiac problems should use the plant with caution. FUNDING: Jointly supported by the International Foundation for Science, Stockholm, Sweden, through a grant (# F/5191-1) to Dr. Patrick Amoateng and the Office of Research, Innovation and Development (ORID), University of Ghana, Accra, Ghana, grant awarded to Dr. Patrick Amoateng (reference number: URF/6/ILG-002/2012-2013).

Optimization of vegetable milk extraction from whole and dehulled Mucuna pruriens (Var Cochinchinensis) flours using central composite design.

Extraction conditions for maximum values of protein yield, protein content, sugar content and dry matter of vegetable milk extracts from dehulled Mucuna cochinchinensis bean flour and whole Mucuna cochinchinensis bean flour were investigated using response surface methodology. A Central Composite Design (CCFD) with three factors: temperature (25 to 95 °C); extraction time (6 to 74 min.) and water to flour ratio (6 to 24 mL/g) were used. Data analysis showed that all the factors significantly (p < 0.05) affected the responses variables. The optimal conditions determined for extraction were temperature 63-66 °C, water to flour ratio 12-13 mL/g and extraction time of 57-67 min. At these optimum points the protein and sugar contents, extraction yield of protein and dry matter were respectively 14.0 g/100 mL, 4.8 g/100 mL, 53.8 g/100 g, 12.1 g/100 g for vegetable milk produced from dehulled M. cochinchinensis bean flour and 6.4 g/100 mL, 3.5 g/100 mL, 50.0 g/100 g and 8.0 g/100 g for vegetable milk extracted from whole M. cochinchinensis bean flour milk. The optimal condition was verified at the optimum points for model validation and the response values were not significantly different from the predicted values.

Supraphysiological expression of survival motor neuron protein from an adenovirus vector does not adversely affect cell function.

Spinal muscular atrophy (SMA) is the most common inherited neurodegenerative disease that leads to infant mortality. It is caused by mutations in the survival motor neuron (SMN) protein resulting in death of alpha motor neurons. Increasing evidence suggests that several other tissues are also affected in SMA, including skeletal and cardiac muscle, liver, and pancreas, indicating that systemic delivery of therapeutics may be necessary for true disease correction. Due to the natural biodistribution of therapeutics, a level of SMN several-fold above physiological levels can be achieved in some tissues. In this study, we address whether supraphysiological levels of SMN adversely affects cell function. Infection of a variety of cell types with an adenovirus (Ad) vector encoding SMN leads to very high expression, but the resulting protein correctly localizes within the cell, and associates with normal cellular partners. Although SMN affects transcription of certain target genes and can alter the splicing pattern of others, we did not observe any difference in select target gene splicing or expression in cells overexpressing SMN. However, normal human fibroblasts treated with Ad-SMN showed a slight reduction in growth rate, suggesting that certain cell types may be differently impacted by high levels of SMN.

Heterotopic ossification following total hip replacement for acetabular fractures.

Early total hip replacement (THR) for acetabular fractures offers accelerated rehabilitation, but a high risk of heterotopic ossification (HO) has been reported. The purpose of this study was to evaluate the incidence of HO, its associated risk factors and functional impact. A total of 40 patients with acetabular fractures treated with a THR weres retrospectively reviewed. The incidence and severity of HO were evaluated using the modified Brooker classification, and the functional outcome assessed. The overall incidence of HO was 38% (n = 15), with nine severe grade III cases. Patients who underwent surgery early after injury had a fourfold increased chance of developing HO. The mean blood loss and operating time were more than twice that of those whose surgery was delayed (p = 0.002 and p < 0.001, respectively). In those undergoing early THR, the incidence of grade III HO was eight times higher than in those in whom THR was delayed (p = 0.01). Only three of the seven patients with severe HO showed good or excellent Harris hip scores compared with eight of nine with class 0, I or II HO (p = 0.049). Associated musculoskeletal injuries, high-energy trauma and head injuries were associated with the development of grade III HO.The incidence of HO was significantly higher in patients with a displaced acetabular fracture undergoing THR early compared with those undergoing THR later and this had an adverse effect on the functional outcome.

Small biparietal diameter in fetuses with spina bifida on 11-13-week and mid-gestation ultrasound.

OBJECTIVES: To assess whether, at 11-13-week and mid-trimester ultrasound examinations, the biparietal diameter (BPD) in fetuses with open spina bifida is smaller than the reference range. METHODS: In a multicenter retrospective analysis of data from 23 fetuses with open spina bifida diagnosed at 16-24 weeks, BPD at diagnosis was compared with that measured at 11-13 weeks, before diagnosis. Z-scores were calculated for comparison of BPD deviations from the reference range within the groups at 11-13 weeks and 16-24 weeks, and between these two time intervals. RESULTS: BPD Z-scores at 11-13 weeks and 16-24 weeks were significantly lower (P < 0.0001) in fetuses with open spina bifida when compared to the reference range, with mean values of - 1.29 and - 2.14, respectively, corresponding to the 10(th) and 1.5(th) centiles, respectively. At 11-13 weeks only six of the 23 (26%) fetuses with open spina bifida had BPD below the 5(th) centile, in comparison to 16 (69%) at mid-gestation. This was confirmed by paired t-test comparing the first-trimester with the second-trimester BPD measurements, which showed significantly slower growth of the BPD in fetuses with spina bifida. CONCLUSION: In fetuses with open spina bifida, BPD is smaller not only in the second trimester, as previously reported, but also in the first trimester. This is most likely due to loss of cerebrospinal fluid. We suggest that a BPD value < 10(th) centile in an otherwise normally grown fetus at 11-13 weeks' gestation should be considered as a potential subtle early marker for open spina bifida.

Prospective detection of open spina bifida at 11-13 weeks by assessing intracranial translucency and posterior brain.

We describe a case series of six fetuses with open spina bifida (OSB) from four different prenatal units, where the anomaly was detected at the routine 11-13-week ultrasound examination. Crown-rump length ranged from 49 to 78 mm. All cases were first suspected during nuchal translucency thickness measurement in the mid-sagittal plane of the face. OSB was lumbosacral in five fetuses and cervical in one. The intracranial translucency (IT) was obliterated in two cases, but some fluid was found in the other four cases. However, in all cases the typical landmarks of a normal posterior brain and normal IT were absent. In all six cases the ratio of brainstem diameter to brainstem-occipital bone distance was increased (≥ 1). This detection of an abnormal posterior brain led to a targeted examination and detection of the spinal lesion during the same examination in five cases, whereas in one suspicious case the patient was recalled at 17 weeks, when the abnormality was detected. Two fetuses had both multiple anomalies and trisomy 18. These prospective cases demonstrate the feasibility of using the standard mid-sagittal plane commonly used for NT measurement to assess the IT and the posterior brain and to determine the presence of OSB during NT screening.

Internal fixation of osteopenic acetabular fractures involving the quadrilateral plate.

BACKGROUND: Older patients tend to have acetabular fractures with medial displacement patterns and associated comminution, particularly of the quadrilateral surface. Our goal was to investigate the appropriateness of open reduction and internal fixation using an infra-pectineal buttress plate for osteopenic acetabular fractures. MATERIALS AND METHOD: We conducted a retrospective review involving twenty one consecutive patients over the course of 4 years with an acetabular fracture in an academic level 1 trauma centre. We performed the modified Stoppa approach with buttress plating of the quadrilateral surface. Clinical examination radiographs was done using criteria described by Matta. Functional outcome was evaluated using surveys including SF-12, WOMAC, Harris Hip score and modified Postel Merle D'Aubigne. RESULTS: Average follow-up was 4.2 years with a minimum of 2 years. Mean age for patients was 64.3 years. We obtained anatomic reduction in 52.4% (11/21) of cases, imperfect reduction in 38.1% (8/21) of cases and poor reduction in 9.5% (2/21) of cases. Significant loss of reduction was seen in 2 patients. A superior dome impaction (a Gull sign) was correlated to arthroplasty (p=0.02) and reduced quality of initial reduction (p=0.02). Two patients required re-intervention with a total hip arthroplasty. There was one traumatic injury to the obturator nerve and 2 patients were noted to have temporary weakness of the hip adductors postoperatively. CONCLUSION: Internal fixation using the modified Stoppa approach to buttress the quadrilateral plate should be considered a viable alternative to total hip arthroplasty for the initial treatment of acetabular fractures in the elderly.

Fetal interlens distance: normal values during pregnancy.

OBJECTIVES: The aims of this study were to establish normal ranges of values for interlens distance (ILD) during gestation, and to assess the correlation between ILD and growth of the orbits and other fetal biometric parameters. METHODS: A cross-sectional study of morphologically normal, singleton fetuses was carried out in low-risk pregnant women. We measured the distance between the centers of the fetal lenses from 12 to 37 completed weeks of gestation. An oblique anterior coronal section was used to measure the ILD. The biorbital diameter (BOD) was measured in the same plane. We analyzed the correlation between the ILD and gestational age (GA), BOD, biparietal diameter (BPD), head circumference (HC), femur length (FL) and abdominal circumference (AC). Fetal gender was assessed to evaluate possible significant differences. RESULTS: Four hundred and fifty normal fetuses were recruited for the study. In 427 fetuses appropriate ILD measurements were obtained, and complete evaluation of all parameters was accomplished in 377 of these. ILD demonstrated a high positive correlation with GA (r(2) = 0.969), BPD (r(2) = 0.959), HC (r(2) = 0.962), AC (r(2) = 0.949) and FL (r(2) = 0.956) as pregnancy advanced. The mean BOD : ILD ratio was 1.50 +/- 0.08, remaining constant throughout pregnancy (linear regression r(2) = 0.006). No statistically significant differences were found between genders for mean ILD and GA of the study population (P = 0.604 and 0.595, respectively). CONCLUSIONS: The results of this study confirm previous hypotheses regarding the close relationship between eyeball growth and growth of the surrounding bony structures. Measurement of fetal ILD, which can be used interchangeably with BOD measurement in either the axial or coronal plane, can be taken to reflect the expected development of the fetal orbits whilst simultaneously providing valuable information on eyeball development. It is likely that ILD could be used as a complementary tool in the elaboration of various severe abnormalities, mainly related to craniofacial and nervous system malformations.

Assessment of intracranial translucency (IT) in the detection of spina bifida at the 11-13-week scan.

OBJECTIVE: Prenatal diagnosis of open spina bifida is carried out by ultrasound examination in the second trimester of pregnancy. The diagnosis is suspected by the presence of a 'lemon-shaped' head and a 'banana-shaped' cerebellum, thought to be consequences of caudal displacement of the hindbrain. The aim of the study was to determine whether in fetuses with spina bifida this displacement of the brain is evident from the first trimester of pregnancy. METHODS: In women undergoing routine ultrasound examination at 11-13 weeks' gestation as part of screening for chromosomal abnormalities, a mid-sagittal view of the fetal face was obtained to measure nuchal translucency thickness and assess the nasal bone. In this view the fourth ventricle, which presents as an intracranial translucency (IT) between the brain stem and choroid plexus, is easily visible. We measured the anteroposterior diameter of the fourth ventricle in 200 normal fetuses and in four fetuses with spina bifida. RESULTS: In the normal fetuses the fourth ventricle was always visible and the median anteroposterior diameter increased from 1.5 mm at a crown-rump length (CRL) of 45 mm to 2.5 mm at a CRL of 84 mm. In the four fetuses with spina bifida the ventricle was compressed by the caudally displaced hindbrain and no IT could be seen. CONCLUSION: The mid-sagittal view of the face as routinely used in screening for chromosomal defects can also be used for early detection of open spina bifida.