Comparing antiviral strategies against COVID-19 via multiscale within-host modelling.

Within-host models of COVID-19 infection dynamics enable the merits of different forms of antiviral therapy to be assessed in individual patients. A stochastic agent-based model of COVID-19 intracellular dynamics is introduced here, that incorporates essential steps of the viral life cycle targeted by treatment options. Integration of model predictions with an intercellular ODE model of within-host infection dynamics, fitted to patient data, generates a generic profile of disease progression in patients that have recovered in the absence of treatment. This is contrasted with the profiles obtained after variation of model parameters pertinent to the immune response, such as effector cell and antibody proliferation rates, mimicking disease progression in immunocompromised patients. These profiles are then compared with disease progression in the presence of antiviral and convalescent plasma therapy against COVID-19 infections. The model reveals that using both therapies in combination can be very effective in reducing the length of infection, but these synergistic effects decline with a delayed treatment start. Conversely, early treatment with either therapy alone can actually increase the duration of infection, with infectious virions still present after the decline of other markers of infection. This suggests that usage of these treatments should remain carefully controlled in a clinical environment.

Adult-onset very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD).

BACKGROUND AND PURPOSE: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a hereditary disorder of mitochondrial long-chain fatty acid oxidation that has variable presentations, including exercise intolerance, cardiomyopathy and liver disease. The aim of this study was to describe the clinical and genetic manifestations of six patients with adult-onset VLCADD. METHODS: In this study, the clinical, pathological and genetic findings of six adult patients (four from Iran and two from Serbia) with VLCADD and their response to treatment are described. RESULTS: The median (range) age of patients at first visit was 31 (27-38) years, and the median (range) age of onset was 26.5 (19-33) years. Parental consanguinity was present for four patients. Four patients had a history of rhabdomyolysis, and the recorded CK level ranged between 67 and 90 000 IU/l. Three patients had a history of exertional myalgia, and one patient had a non-fluctuating weakness. Through next-generation sequencing analysis, we identified six cases with variants in the ACADVL gene and a confirmed diagnosis of VLCADD. Of the total six variants identified, five were missense, and one was a novel frameshift mutation identified in two unrelated individuals. Two variants were novel, and three were previously reported. We treated the patients with a combination of L-carnitine, Coenzyme Q10 and riboflavin. Three patients responded favorably to the treatment. CONCLUSION: Adult-onset VLCADD is a rare entity with various presentations. Patients may respond favorably to a cocktail of L-carnitine, Coenzyme Q10, and riboflavin.

Neuromuscular manifestations of lead poisoning in opium and herbal users in Iran.

Opium sale is prohibited in Iran, and sellers mix it with lead to increase the weight. Herein, we describe neuromuscular findings in nine patients who developed lead poisoning due to opium/drug consumption. The mean age of patients was 53±3.5 years and their mean blood lead level was 122.6±20.8µg/dL. Most of the patients had an acute/subacute course presenting as axonal or demyelinating sensorimotor polyneuropathy, motor neuron disease, and multiple mononeuropathies with favorable response to the chelation therapy. Lead poisoning should be considered in patients with a history of opium use and neuromuscular symptoms.

Metabolisable energy of grass and red clover silages fed to sheep at maintenance level.

This study investigated the effect of forage type (grass or red clover) and harvesting time (primary growth or regrowth) of silage on energy and N utilisation by sheep fed at maintenance level. Specifically, the assumption of constant loss of energy of digestible organic matter from energy losses in urine and CH4 applied in evaluation of silage metabolisable energy (ME) was investigated. Urinary excretion of high-energy phenolic compounds related to solubilisation of lignin was assumed to affect urinary energy (UE) losses from sheep fed highly digestible grass silage (GS). A total of 25 primary growth and regrowth silages of timothy (Phleum pratense) and meadow fescue (Festuca pratensis) grass mixtures and red clover (Trifolium pratense) samples collected in digestibility trials with sheep, including faecal and urine samples, were used for energy and N determinations. Urinary concentration of monophenolic compounds and CH4 emissions in vitro were also analysed. Daily faecal N output, CH4 yield (MJ/kg DM intake), proportion of CH4 energy in digestible energy (DE) and proportion of UE in DE were greater (P ≤ 0.03) in sheep fed red clover silage (RCS) than GS. Furthermore, less (P = 0.01) energy was lost as UE of DE in sheep fed primary growth GS compared with the other treatments. The relationship between UE and silage N intake or urinary N output for both silage types (i.e. grass v. red clover) was strong, but the fit of the regressions was better for GS than RCS. The CH4/DE ratio decreased (P < 0.05) and the UE/DE ratio increased (P < 0.05) with increasing organic matter digestibility in RCS. These relationships were not significant (P < 0.05) for the GS diets. The regression coefficient was higher (P < 0.05) for GS than RCS when regressing ME concentration on digestible organic matter. The results of this study imply that ME/DE ratio is not constant across first-cut GS of different maturities. The ME production response may be smaller from highly digestible first-cut GS but could not be clearly related to urinary excretion of monophenols derived from solubilisation of lignin. Furthermore, energy lost in urine was not clearly defined for RCS and was much more predictable for GS from silage N concentration.

Effect of dietary supplementation with heat-treated canola meal on ruminal nutrient metabolism in lactating dairy cows.

An experiment was conducted to quantify the effects of incremental levels of heat-moisture-treated canola meal (TCM) fed to dairy cows on the relationship between ruminal nutrient digestion and milk production. Experimental diets were fed to 4 multiparous rumen-cannulated Nordic Red cows, averaging (mean ± standard deviation) 681 ± 54.8 kg of body weight, 111 ± 16 d in milk, and 29.1 ± 9.1 kg of milk/d at the start of the study, in a Latin square design with four 21-d periods. The 4 experimental dietary treatments consisted of a basal diet of grass silage and crimped barley, and 3 diets in which the crimped barley was replaced with TCM, giving 3 incremental levels of protein supplementation. Nutrient flow was quantified by the omasal sampling technique using 3 markers (Cr, Yb, and indigestible neutral detergent fiber). Continuous infusion of 15N was used to label bacterial crude protein. Additionally, ruminal sampling and evacuations and measurements of total-tract digestibility were conducted. The experimental diets provided 132, 148, 164, and 180 g of crude protein/kg of dry matter. The increased level of TCM linearly increased dry matter intake from 15.1 to 16.6 kg/d and energy-corrected milk yield from 21.0 to 25.6 kg/d. The increased proportion of TCM when substituting barley with TCM was associated with greater total-tract digestibility of neutral detergent fiber and potentially digestible neutral detergent fiber, which could be explained by increased digestion rate of potentially digestible neutral detergent fiber. Omasal flow of nonammonia N naturally increased with greater dietary TCM inclusion, but the increased intestinal supply of rumen-undegradable protein was partly offset by diminished microbial protein synthesis when feeding more TCM. This was also reflected in a decreased proportion of milk protein from ruminal bacterial protein when TCM supplementation increased.

The effect of the ginger on the apoptosis of hippochampal cells according to the expression of BAX and Cyclin D1 genes and histological characteristics of brain in streptozotocin male diabetic rats.

Diabetes is the most common endocrine disorder in humans with multiple complications including nervous system damages. The aim of the present study was to determine the effect of ginger extract on apoptosis of the neurons of hippocampus, via evaluation of BAX and Cyclin D1 and also histological analysis, in male diabetic rats. In this experimental study, 60 Wistar rats (220 ± 30gr) were conducted in 5 groups as follow: diabetic group treated with saline (group 1), normal group treated with saline (group 2), diabetic group treated with ginger (group 3), diabetic group treated with ginger-insulin (group 4), diabetic group treated with insulin (group 5). STZ (60 mg/kg) was intraperitoneally used to induce the diabetes. Expression levels of BAX and Cyclin D1 were examined using Real-Time PCR technique and the normality of neurons was evaluated using H&E staining method. The results showed that blood glucose level significantly decreased in group 4 when compared to group 1. In molecular analysis, there was no significant difference between groups regarding the expression of BAX gens, while, the expression of Cyclin D1 were significantly decreased in group 4 compared with group 1. Histological analysis revealed that pathological symptoms were lower in group 4 than the other diabetic groups. The results of present study showed that the ginger in addition to lowering blood sugar level, changes the expression of Cyclin D1 gene and histological characteristics in a positive manner. This means that the ginger may protects neurons of the hippocampus from apoptosis in diabetic patients.

Muscle MRI of facioscapulohumeral dystrophy (FSHD): A growing demand and a promising approach.

Facioscapulohumeral muscular dystrophy (FSHD), an inherited and progressive muscle disorder, is among the most common hereditary muscle disorders. From a clinical vantage point, FSHD is characterized by weakness of the facial, shoulder (often with scapular winging), arm (including biceps and triceps) and abdominal muscles. Forearm muscles are usually spared and weakness is usually asymmetrical. Over the past few decades, muscle magnetic resonance imaging (MRI) has become established as a reliable and accurate noninvasive tool for the diagnosis and assessment of progression in neuromuscular diseases, showing specific patterns of muscle involvement for a number of myopathies. More recently, MRI has been used to noninvasively identify quantitative biomarkers, allowing evaluation of the natural progression of disease and assessment of therapeutic interventions. In the present review, the intention was to present the most significant MRI developments related to diagnosis and pattern recognition in FSHD and to discuss its capacity to provide outcome measures.

A comparison of ruminal or reticular digesta sampling as an alternative to sampling from the omasum of lactating dairy cows.

The objective of this study was to develop and compare techniques for determining nutrient flow based on digesta samples collected from the reticulum or rumen of lactating dairy cows with estimates generated by the omasal sampling technique. Pre-experimental method development suggested, after comparing with the particle size distribution of feces, application of primary sieving of ruminal and reticular digesta from lactating cows through an 11.6-mm sieve, implying that digesta particles smaller than this were eligible to flow out of the rumen. For flow measurements at the different sampling sites 4 multiparous, lactating Nordic Red cows fitted with ruminal cannulas were used in a Latin square design with 4 dietary treatments, in which crimped barley was replaced with 3 incremental levels of protein supplementation of canola meal. Digesta was collected from the rumen, reticulum, and omasum to represent a 24-h feeding cycle. Nutrient flow was calculated using the reconstitution system based on Cr, Yb, and indigestible neutral detergent fiber and using (15)N as microbial marker. Large and small particles and the fluid phase were recovered from digesta collected at all sampling sites. Bacterial samples were isolated from the digesta collected from the omasum. Several differences existed for digesta composition, nutrient flows, and estimates of ruminal digestibility among the 3 different sampling sites. Sampling site × diet interactions were not significant. The estimated flows of DM, potentially digestible neutral detergent fiber, nonammonia N, and microbial N were significantly different between all sampling sites. However, the difference between DM flow based on sampling from the reticulum and the omasum was small (0.13kg/d greater in the omasum). The equality between the reticulum and the omasum as sampling sites was supported by the following regression: omasal DM flow=0.37 (±0.649) + 0.94 (±0.054) reticular DM flow (R(2)=0.96 and root mean square error=0.438kg/d). More deviating nutrient-flow estimates when sampling digesta from the rumen than the reticulum compared with the omasum suggested that sampling from the reticulum is the most promising alternative to the omasal sampling technique. To definitively promote sampling from the reticulum as an alternative to the omasal sampling technique, more research is needed to determine selection criteria of reticular digesta for accurate and precise flow estimates across a range of diets.

Review of the relationship between milk urea nitrogen and days in milk, parity, and monthly temperature mean in Iranian Holstein cows.

The objectives of this study were to determine the relationships between milk urea N and days in milk, parity, and season in Iranian Holstein cows. Twelve Iranian commercial dairy herds participated in a 13-mo study from December 1, 2008, to December 31, 2009. All cows were milked 3 times daily, housed in freestalls, and fed a total mixed ration twice a day. Mean milk urea N over the study period was 16.0mg/dL. Mean milk urea N, categorized by 30-d increments of days in milk, paralleled changes in milk values and followed a curvilinear shape. However, milk urea N concentration reached a maximum at the fifth month of days in milk, but milk production reached a maximum at the third month. The concentration of milk urea N was lower during the first 30 d in milk category compared with all other days in milk categories. Overall mean milk urea N concentration of Holstein cows in the third and greater lactations was lower than in the first or second lactation. Milk urea N was at its lowest level in December (13 mg/dL), increased in the spring and summer months, and reached a maximum in July (18.8 mg/dL). From that point, milk urea N concentration progressively diminished to the autumn-winter level. In this study, milk urea N concentration was positively correlated with monthly temperature mean and may be a reason for the lower reproductive performance during the summer months. It has been recommended that milk urea N concentration should be evaluated in association with parity, days in milk, and season (or month). These variables should be considered potential sources of misinterpretation when exploring the relationship between milk urea N and nutritional management or measures of performance.

Decreased plasma levels of ceruloplasmin after diet-induced weight loss in obese women.

BACKGROUND: Plasma ceruloplasmin (Cp) has been shown to be a risk factor for cardiovascular disease and also to be associated with obesity. However, it is not known whether weight loss could decrease the plasma Cp levels. AIM: To investigate the effect of diet-induced weight loss on plasma Cp in obese women. SUBJECTS AND METHODS: Sixty-seven healthy obese women [age =33.4±8.7 yr, body mass index (BMI) =36.0±4.8 kg/m2] were entered into a medically supervised program aimed at reducing body weight by 10% or more. Weight loss was achieved through a diet providing a daily energy deficit of 500-1000 kcal/day. In addition, all patients were prescribed to use 50 g of a fiber supplement per day. For all subjects, assessment of dietary intake, anthropometric indices, and plasma levels of C-reactive protein and Cp was performed at the first visit and repeated at 12th week of follow-up. RESULTS: By completing the program, weight (Δ=-9.5%, p<0.0001), BMI (Δ=-9.7%, p<0.0001), waist-circumference (Δ=-6.1%, p<0.0001), and triceps skinfold thickness (Δ=-14.9%, p<0.0001) significantly decreased. Plasma Cp significantly decreased after 12 weeks of dietary intervention (33.6±5.6 mg/dl vs 25.2±5.8 mg/dl, p<0.0001). Percent change in Cp was correlated with percent change in waist-circumference (r=446, p=0.015). CONCLUSION: Our study suggests that an improved body composition induced by restriction of energy intake is associated with decreased serum concentrations of Cp in obese women which in turn might have reduced the subjects' risk of developing cardiovascular disease.

Association of pulp stones with coronary artery stenosis.

BACKGROUND: Dental pulp stones are discrete calcifications in the pulp chamber which are often seen in deciduous and permanent teeth. It has been hypothesised that atherosclerosis can be associated with their development. OBJECTIVE: To determine whether a higher prevalence of dental pulp stones is correlated with coronary artery stenosis. CLINICAL SETTING: Sixty-one patients aged 20-55 years referred to Afshar Heart Center for invasive coronary angiography were invited to undergo panoramic dental radiography. The panoramic radiographs were independently examined for the presence of pulp stones. RESULTS: Pulp stones were present in 82% (31/38) of patients with at least one clinically significant coronary artery stenosis and in 48% (11/23) of patients with normal coronary angiography. They were present in 13% of the teeth in the former group and in 5% of the teeth in the latter. The findings show a statistically significant association between coronary artery stenosis and presence of pulp stones (odds ratio 4.83, 95% confidence interval 1.5-15.4). CONCLUSION: Coronary artery stenosis and dental pulp calcification are significantly associated. Dental radiography has the potential to be used as a rapid screening method for the early detection of coronary artery stenosis.

Effect of eicosapentaenoic Acid (EPA) and vitamin e on the blood levels of inflammatory markers, antioxidant enzymes, and lipid peroxidation in Iranian basketball players.

BACKGROUND: Exercise can change the release of numerous cytokines and modulate their receptor systems. Dietary ω-3 lipids may decrease the levels of inflammatory cytokines and prostaglandins (PGs). Therefore, in this study, we investigated the effects of exercise and eicosapentaenoic acid (EPA) supplementation, with or without vitamin E, on the blood levels of IL-2, TNF-α, catalase, glutathione reductase, and MDA in male basketball players. METHODS: Thirty-four well-trained male basketball players were enrolled into the study. Venous blood samples were obtained from all subjects between 5:00 and 6:00 p.m., after intensive endurance exercising for 2 hours, at the baseline and after intervention. Subjects received 2g EPA and/or 400 IU vitamin E or placebo depends on their groups for 6 weeks. RESULTS: There were significant fall (paired t-test) in TNF-α in group1(P< 0.05), and in MDA in group 3 (P<0.05), whereas there were significant increase in glutathione reductase in groups1 and 3 (P< 0.05), and in MDA in group2 (P< 0.05).There were significant differences (Tukey) in glutathione reductase between groups 2 and 3 (P< 0.05), and in IL-2 between groups 1 and other groups (P< 0.01), but there were no significant differences in MDA, CAT, and TNF-α, among groups after 6 week of intervention. CONCLUSION: Six weeks of EPA+vitamin E supplementation enhances the plasma levels of IL-2 and erythrocytes glutathione reductase, whereas it reduces TNF-α, and 6 weeks of EPA supplementation alone enhances only the serum level of MDA.

Multiple sclerosis and neurofibromatosis type 1: report of seven patients from Iran.

INTRODUCTION: Co-occurrence of multiple sclerosis (MS) and neurofibromatosis type 1 (NF1) is rare. CASE REPORTS: In this study, we describe the clinical and neuroimaging features of seven patients with NF1 and MS. In our patients, six patients with MS were women, in all of them history of NF1 existed. Three of our patients had primary progressive, one had secondary progressive MS, and three relapsing-remitting MS. Optic neuritis as presenting symptoms was seen in three patients, and motor manifestation as presenting symptom was observed in three patients. The risk of having both NF1 and MS seemed to be higher than would be expected based on the prevalence rates of the two diseases in the general population. CONCLUSION: The findings of this study suggest a possible casual relationship between MS and NF1, indicating higher risk of MS among patients with NF1.

The effects of sour tea (Hibiscus sabdariffa) on hypertension in patients with type II diabetes.

To compare the antihypertensive effectiveness of sour tea (ST; Hibiscus sabdariffa) with black tea (BT) infusion in diabetic patients, this double-blind randomized controlled trial was carried out. Sixty diabetic patients with mild hypertension, without taking antihypertensive or antihyperlipidaemic medicines, were recruited in the study. The patients were randomly allocated to the ST and BT groups and instructed to drink ST and BT infusions two times a day for 1 month. Their blood pressure (BP) was measured on days 0, 15 and 30 of the study. The mean of systolic BP (SBP) in the ST group decreased from 134.4+/-11.8 mm Hg at the beginning of the study to 112.7+/-5.7 mm Hg after 1 month (P-value <0.001), whereas this measure changed from 118.6+/-14.9 to 127.3+/-8.7 mm Hg (P-value=0.002) in the BT group during the same period. The intervention had no statistically significant effect on the mean of diastolic BP (DBP) in either the ST or BT group. The mean pulse pressure (PP) of the patients in the ST group decreased from 52.2+/-12.2 to 34.5+/-9.3 mm Hg (P-value <0.001) during the study, whereas in the BT group, it increased from 41.9+/-11.7 to 47.3+/-9.6 mm Hg (P-value=0.01). In conclusion, consuming ST infusion had positive effects on BP in type II diabetic patients with mild hypertension. This study supports the results of similar studies in which antihypertensive effects have been shown for ST.

Effects of adenosine agents on apomorphine-induced yawning in rats.

In the present work, adenosine agonists and antagonists on apomorphine-induced yawning in rats was investigated. Subcutaneous (SC) injection of apomorphine (0.02, 0.05 and 0.1 mg/kg) induced dose-dependent yawning behaviour in rats. Intracerebroventricular (ICV) administration of different doses of the drug (1, 3, 5 micrograms/rat) also caused a dose-related yawning. ICV administration of the adenosine receptor agonists 5-N-ethylcarboxamidoadenosine (NECA) and N6-cyclohexyladenosine (CHA) decreased apomorphine-induced yawning. The response induced by the adenosine agonists was reduced by 8-phenyladenosine (8-PT) pretreatment. The yawning induced by SC and ICV administration of apomorphine was decreased by ICV or IP injection of theophylline, respectively. It is concluded that at least A1 adenosine receptors may exert negative influence on the apomorphine-induced yawning. However, the exact mechanism(s) of adenosine receptors in this behaviour remain to be established.