A novel homozygous SLC25A1 mutation with impaired mitochondrial complex V: Possible phenotypic expansion

SLC25A1 mutations are associated with combined D,L‐2‐hydroxyglutaric aciduria (DL‐ 2HGA; OMIM #615182), characterized by muscular hypotonia, severe neurodevelopmental dysfunction and intractable seizures. SLC25A1 encodes the mitochondrial citrate carrier (CIC), which mediates efflux of the mitochondrial tricarboxylic acid (TCA) cycle intermediates citrate and isocitrate in exchange for cytosolic malate. Only a single family with an SLC25A1 mutation has been described in which mitochondrial respiratory chain dysfunction was documented, specifically in complex IV. Five infants of two consanguineous Bedouin families of the same tribe presented with small head circumference and neonatal‐onset encephalopathy with severe muscular weakness, intractable seizures, respiratory distress, and lack of psychomotor development culminating in early death. Ventricular septal defects (VSD) were demonstrated in three patients. Blood and CSF lactate were elevated with normal levels of plasma amino acids and free carnitine and increased 2‐OH‐glutaric acid urinary exertion. EEG was compatible with white matter disorder. Brain MRI revealed ventriculomegaly, thin corpus callosum with increased lactate peak on spectroscopy. Mitochondrial complex V deficiency was demonstrated in skeletal muscle biopsy of one infant. Homozygosity mapping and sequencing ruled out homozygosity of affected individuals in all known complex V‐associated genes. Whole exome sequencing identified a novel homozygous SLC25A1 c.713A>G (p.Asn238Ser) mutation, segregating as expected in the affected kindred and not found in 220 control alleles. Thus, SLC25A1 mutations might be associated with mitochondrial complex V deficiency and should be considered in the differential diagnosis of mitochondrial respiratory chain defects.

     

Glycyrrhizic acid improved lipoprotein lipase expression,insulin sensitivity,serum lipid and lipid deposition in high-fat diet-induced obese rats

Background  

The metabolic syndrome, known also as the insulin resistance syndrome, refers to the clustering of several risk factors for atherosclerotic cardiovascular disease. Dyslipidaemia is a hallmark of the syndrome and is associated with a whole body reduction in the activity of lipoprotein lipase (LPL), an enzyme under the regulation of the class of nuclear receptors known as peroxisome proliferator-activated receptor (PPAR). Glycyrrhizic acid (GA), a triterpenoid saponin, is the primary bioactive constituent of the roots of the shrub Glycyrrhiza glabra. Studies have indicated that triterpenoids could act as PPAR agonists and GA is therefore postulated to restore LPL expression in the insulin resistant state.     

Permeability studies of artificial and natural cancellous bone structures

In the development of artificial cancellous bones, two major factors need to be considered: the integrity of the overall structure and its permeability. Whilst there have been many studies analysing the mechanical properties of artificial and natural cancellous bones, permeability studies, especially those using numerical simulation, are scarce. In this study, idealised cancellous bones were simulated from the morphological indices of natural cancellous bone. Three different orientations were also simulated to compare the anisotropic nature of the structure. Computational fluid dynamics methods were used to analyse fluid flow through the cancellous structures. A constant mass flow rate was used to determine the intrinsic permeability of the virtual specimens. The results showed similar permeability of the prismatic plate-and-rod model to the natural cancellous bone. The tetrakaidecahedral rod model had the highest permeability under simulated blood flow conditions, but the plate counterpart had the lowest. Analyses on the anisotropy of the virtual specimens showed the highest permeability for the horizontal orientation. Linear relationships were found between permeability and the two physical properties, porosity and bone surface area.     

Evaluation of specific humoral immune response and cross reactivity against <Emphasis Type="Italic">Mycobacterium tuberculosis</Emphasis> antigens induced in mice immunized with liposomes composed of total lipids extracted from <Emphasis Type="Italic">Mycobacterium smegmatis</Emphasis>

The development of a new tuberculosis (TB) vaccine has become one of the main objectives of the scientific community. Protein antigens have been widely explored as subunit TB vaccines, however lipid antigens could be equally important to be used or included in such a vaccine. The aim of this study was to demonstrate the potential of a liposome formulation composed of an extract of lipids from Mycobacterium smegmatis (Ms) as a TB vaccine candidate. We evaluated the immunogenicity of this formulation as well as the cross reactive response against antigens from Mycobacterium tuberculosis (MTb) in BALB/c mice. We determined the anti-liposome IgG response in sera from TB patients and from healthy subjects who displayed a positive (PPD+) or negative (PPD-) tuberculin skin test. A significant increase in anti-liposome IgG (p<0.05) was detected in animals immunized with Bacille Calmette-Guérin (BCG) compared with all groups, and in the group immunized with liposomes from Ms (LMs) compared to animals immunized with either LMs adjuvanted with aluminium (LMs-A) or the negative control group (phosphate buffered saline, PBS) respectively. With respect to the cross reactive response against a cocktail of cell wall antigens (CWA) from MTb, significantly higher IgG levels were observed in animals immunized with BCG and LMs compared to negative controls and either, aluminium-adjuvanted liposomes (LMs-A) or montanide (LMs-M) (p<0.05). Furthermore, the anti-liposome IgG response was significantly superior in sera from pulmonary TB patients compared to PPD+ and PPD- healthy subjects (p<0.001) suggesting the expression of these antigens in vivo during active MTb infection. The results obtained provide some evidence for the potential use of liposomes containing total lipid extracts of Ms as a TB vaccine candidate.     

Effects of intraoperative blood loss during liver resection on patients’ outcome: a single-center experience

Background/aim Operative bleeding is one of the major determinants of outcome in liver surgery. This study aimed to describe the impact of intraoperative blood loss on the postoperative course of liver resection (LR). Materials and methods The data of 257 patients who were treated with LR between January 2007 and October 2018 were retrospectively analyzed. LRs were performed via intermittent portal triad clamping (PTC) under low central venous pressure. Results LRs were performed for 67.7% of patients with a malignant disease and 32.3% of patients with a benign disease. Major LR was performed in 89 patients (34.6%). The mean PTC period was 20.32 min (±13.7). The median intraoperative bleeding amount was 200 mL (5–3500 mL), the 30-day mortality rate was 4.3%, and the morbidity rate was 31.9%. The hospital stay (p = 0.002), morbidity (p = 0.009), and 30-day mortality (p = 0.041) of patients with a bleeding amount of more than 500 mL significantly increased. Conclusion Surgeons should consider the adverse effects of intraoperative bleeding during liver resection on patients’ outcome. Favorable outcomes would be obtained with diligent postoperative care.     

Long-term proton pump inhibitor use is a risk factor for mortality in patients hospitalized for COVID-19

Background and aimThe aim of this study is to evaluate whether the long-term (≥4 weeks) use of proton pump inhibitors (PPIs) is a risk factor for intubation requirement and mortality in patients hospitalized for COVID-19.Materials and methods In this multicentric retrospective study, a total of 382 adult patients (≥18 years of age) with confirmed COVID-19 who were hospitalized for treatment were enrolled. The patients were divided into two groups according to the periods during which they used PPIs: the first group included patients who were not on PPI treatment, and the second group included those who have used PPIs for more than 4 weeksResultsThe study participants were grouped according to their PPI usage history over the last 6 months. In total, 291 patients did not use any type of PPI over the last 6 months, and 91 patients used PPIs for more than 4 weeks. Older age (HR: 1.047, 95% CI: 1.026–1.068), current smoking (HR: 2.590, 95% CI: 1.334–5.025), and PPI therapy for more than 4 weeks (HR: 1.83, 95% CI: 1.06–2.41) were found to be independent risk factors for mortalityConclusionThe results obtained in this study show that using PPIs for more than 4 weeks is associated with negative outcomes for patients with COVID-19. Patients receiving PPI therapy should be evaluated more carefully if they are hospitalized for COVID-19 treatment.     

The effect of renal artery-only or renal artery–vein clamping during partial nephrectomy on short and long-term functional results: Is clamping technique important?

Purpose

To evaluate the effect of artery-only (AO) and artery–vein (AV) clamping during partial nephrectomy (PN) on short- and long-term renal function outcome.

Methods

Medical records of 154 patients in the AO group and 192 patients in the AV group who underwent open and minimally invasive (laparoscopic/robotic) PN between January 2011 and January 2018 were retrospectively assessed. Preoperative patient and tumor-specific characteristics in addition to perioperative factors and renal function outcomes were compared. The change in the estimated glomerular filtration rate (eGFR) from postoperative 1–3 days, 12 and 24 months after surgery was calculated. Acute kidney injury (AKI) was defined a as a?>?25% reduction in eGFR.

Results

There were no statistically significant differences between the clamping techniques in terms of postoperative 1–3 days, 12 and 24 months eGFR change percentage and risk of progression to chronic kidney disease (CKD). No significant difference in short- and long-term renal functions was found between the minimally invasive or open AO and AV clamping subgroups at any time point. In multivariate analysis, the R.E.N.A.L score (AO group p?=?0.026, AV group p?<?0.001) and preoperative eGFR (AO group p?<?0.001, AV group p?=?0.010) were strong predictors of the acute kidney injury in both groups. Older age (AO group p?=?0.045, AV group p?=?0.010) and preoperative eGFR (AO group p?=?0.008, AV group p?=?0.002) were significantly associated with CKD progression at 2-year follow-up in both groups.

Conclusion

AV clamping does not adversely affect postoperative renal function compared to AO clamping. Preoperative patient- and tumor-related factors are more important for renal function regardless of the clamping technique.

     

Craniovertebral junction Pott's disease

Pott's disease of the craniovertebral junction is extremely rare. The authors studied the immediate and long-term outcome after transoral decompression, occipitocervical stabilization with fusion and antitubercular therapy (ATT) in patients who had neurological deficits due to craniovertebral junction (CVJ) tuberculosis. This is a retrospective study of the management and outcome in 10 consecutive patients in whom features of spinal cord (with or without) compression were observed, and CVJ tuberculosis was diagnosed in two different neurological departments between 1990 and 2002. They ranged in age from 15 to 72 years. The onset of symptoms was either acute or subacute. Patients presented with neck and occipital pain (90%), progressive tetraparesia (40%), sensory symptoms (40%), neck stiffness (30%) and urinary dysfunction (20%). The disease caused spinal cord compression in six patients, atlantoaxial dislocation in five patients, basilar impression in one and upper vertebral column destruction without dislocation in three. Two patients presented with multiple spinal tuberculosis. Antitubercular therapy was used in all cases for 15 months. Surgical treatment performed in all patients. Four patients underwent transoral drainage of retropharyngeal abscess with granulation tissue and one odontoidectomy. Six patients then underwent occipitocervical (occiput -C3 or -C4) fusion with insertion of titanium plate and screw. Postoperatively, ATT was prescribed for 15 months. At long-term follow-up (median 50.2 months), functional status considerably improved. Two patients died 2 months later due to myocardial infarction. Patients with CVJ with features of cervical myelopathy are ideally treated with transoral decompressive procedures followed by occipitocervical fusion, because this therapy provides immediate neurological improvement, stability and allows early mobilization. The long-term prognosis in patients with this disease is excellent, provided it is treated with appropriate surgical intervention and with adequate duration of ATT. This approach provides excellent access to this region, with a low operative morbidity and no mortality.     

Automatic detection of bubbles in the subclavian vein using Doppler ultrasound signals

INTRODUCTION: It is possible to detect venous gas bubbles by listening to the Doppler audio signals. However, a serious disadvantage of the audio evaluation is the inability of continuous monitoring and the inter-rater agreement. Several researchers have worked on the automated detection of emboli, but no current system has the required sensitivity and specificity for clinical use. METHOD: We developed software that integrated frequency filtering, processing, and detection phases of microemboli into a graphical user interface. The detection algorithm consists of a rule-based criterion with a user-defined threshold sliding in-time axis that estimates the duration of the embolic event. Subclavian Doppler audio recordings obtained from a high altitude diving expedition were analyzed using digital filtering and non-linear operator combinations of the software. The data set includes 43 embolic events in 9 recordings from 4 different subjects. RESULTS: It was determined that embolic signals are best differentiated from the background signal at the 4500-8000-Hz frequency band. By using the non-linear "Teager Energy Operator", embolic signals were amplified against their background and a high level of sensitivity and specificity was obtained (83.7% and 97.3%, respectively). The duration of the detected emboli was estimated as 12.17 +/- 4.36 ms (mean +/- SD). DISCUSSION: The optimal frequency band for the detection of subclavian emboli is significantly higher than previous findings for the transcranial site. The duration output of the software can be used to estimate the size and the composition of emboli. Successful integration of the software into an ambulatory detection system may provide important site-specific bubble size distribution data for decompression modeling.