A systematic review of late-onset and very-late-onset multiple acyl-coenzyme A dehydrogenase deficiency: Cohort analysis and patient report from Taiwan

Multiple acyl-coenzyme A dehydrogenase deficiency (MADD) is a rare metabolic disorder with a dramatic clinical presentation. It was recently discovered that MADD may present at an advanced age.The clinical and laboratory data of an index patient and patients previously diagnosed at our institution were collected. A systematic review of previous studies retrieved from the PubMed, MEDLINE, and Embase databases published by February 1, 2020 was performed to collect patients with very-late-onset MADD (VLO-MADD, onset age > 60 years) globally and patients with late-onset MADD (LO-MADD, onset age < 60 years) in Taiwan. The clinical characteristics of the VLO-MADD patients were compared to those of LO-MADD patients.We report a patient with VLO-MADD who developed the first symptom at the age of 61 years. The patient presented with a Reye-like syndrome after taking aspirin for coronary artery disease. Repeated bouts of weakness were noted. Two variants of c.250 G > A (;) 419C > T were observed in the ETFDH gene. Another four patients with VLO-MADD were identified globally. Eighteen patients with LO-MADD were collected from our department and previously reported patients in Taiwan. There was no difference in the clinical symptoms (except for the onset age) or laboratory data between these two groups. Homozygous variants were not observed in any patients in the VLO-MADD group but were detected in 12 patients (66.6%) in the LO-MADD group (p = 0.014).Patients with MADD may first show symptoms in their 6th decade or beyond. The disease course may lead to erroneous diagnoses in this age group.     

Glycogen synthase kinase-3β inactivation is an intracellular marker and regulator for endotoxemic neutrophilia

Neutrophilia, defined as a large number of neutrophils in the circulating blood, is caused by increased differentiation and survival from activation-induced apoptosis. Regulation of apoptosis is essential for neutrophil homeostasis; however, the molecular signaling that regulates this process needs further investigation. Unlike TLR4 wild-type C3H/HeN mice, TLR4 mutated C3H/HeJ mice were insusceptible to LPS-induced blood neutrophilia. LPS prevented constitutive apoptosis in neutrophils and partly involved a blockade of the mitochondrial pathway including mitochondria transmembrane potential loss, myeloid cell leukemia sequence (Mcl) 1 degradation, and caspase-3 activation. In apoptotic neutrophils, glycogen synthase kinase (GSK)-3β was activated, and inhibiting GSK-3β decreased Mcl-1 degradation and apoptosis. LPS caused p38 MAPK-, JNK-, and PI3K/AKT-mediated Mcl-1 stabilization and prevented apoptosis, and LPS induced GSK-3β inactivation mainly through p38 MAPK and PI3K/AKT. Neutrophils in the neutrophilia showed increased GSK-3β inactivation and Mcl-1 stabilization accompanied by activation of p38 MAPK, JNK, and AKT. Notably, LPS-induced ROS generation can partly facilitate p38 MAPK/JNK/AKT activation to regulate GSK-3β-mediated Mcl-1 stability, apoptosis, and neutrophilia. These results demonstrate that the molecular basis of endotoxemic neutrophilia is through a direct action on neutrophils involving GSK-3β inactivation to prevent constitutive apoptosis.     

In vivo three-dimensional mandibular kinematics and functional point trajectories during temporomandibular activities using 3d fluoroscopy

Objectives:To measure in vivo three-dimensional kinematics of the mandible and associated end-point trajectories and to quantify their relationships during temporomandibular joint activities using 3D fluoroscopy.Methods:A novel fluoroscopy-based 3D measurement method was used to measure motions of the mandible and the associated end points (i.e. incisors and lateral poles of both condyles) during open close, lateral gliding and protrusion-retraction movements in healthy young individuals. The contributions of each of the rotational and translational components of the mandible to the end-point trajectories were quantified through experiment-based computer simulations.Results:The mandibular rotation was found to account for 91% of the maximal mouth-opening-capacity and 73% of the maximal lateral incisor movement, while the condylar translation contributed to 99% of the anterior protrusion distance. Incisor trajectories were nearly vertical within the first 60% of the maximal opening during the open-close movement.Conclusions:Similar condylar downward rotation paths but with bilaterally asymmetrical ranges were used to perform basic mandibular movements of different targeted TI trajectories in three dimensions, that is, open-close, lateral-gliding and protrusion-retraction. Mandibular rotations contributed to the majority of the principal displacement components of the incisor, that is, vertical during open-close and towards the working-side-during lateral-gliding, while mandibular translation contributed mainly to the forward movement of the incisor during protrusion-retraction. Owing to the anatomical constraints, the freedom of mandibular translation is limited and mainly in the anteroposterior direction, which is considered helpful for the control and stability of the TMJ during oral activities.     

Three-dimensional assessment of facial morphology in children and adolescents with juvenile idiopathic arthritis and moderate to severe TMJ involvement using 3D surface scans

Objective

This study aims to (1) assess the facial morphology in juvenile idiopathic arthritis (JIA) subjects with moderate to severe temporomandibular joint (TMJ) involvement using 3D surface scans and (2) compare the facial morphology in these subjects to that in JIA subjects without TMJ involvement.

Methods

Sixty JIA subjects were included and grouped as follows: group 1 (no involvement group), JIA without TMJ involvement; Group 2 (unilateral group), JIA with moderate to severe unilateral TMJ involvement; and group 3 (bilateral group), JIA with bilateral TMJ involvement. Standard orientation of all surfaces was accomplished. The means and variabilities of facial morphology in groups 2 and 3 were assessed and compared with those of group 1 in three dimensions, respectively.

Results

Group 2 (unilateral group) exhibited a more retruded and wider chin, shorter mandibular height, and more prominent cheek (2, 2, 5, and 2 mm, on average, respectively) on the affected side and a more retruded and narrower chin and more prominent malar region (4, 3, and 2 mm, on average, respectively) on the unaffected side compared with group 1 (no involvement group) (p < 0.05). Group 3 (bilateral group) exhibited a more retruded chin, shorter mandibular height, more prominent upper cheeks, and narrower perioral region (5, 5, 3, and 2 mm, respectively) compared with group 1 (no involvement group) (p < 0.05).

Conclusions

In JIA subjects with moderate to severe unilateral or bilateral TMJ involvement, the affected side(s) revealed similar facial dysmorphology with reduced mandibular height, chin retrusion, and prominent upper cheek.

Clinical relevance

Three-dimensional surface scans can be a non-ionizing indicator of signs of TMJ involvement in JIA subjects.

     

Andrographolide mitigates cardiac apoptosis to provide cardio‐protection in high‐fat‐diet‐induced obese mice

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD‐induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac‐damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro‐apoptotic proteins and decrease in the proteins of IGF‐1R‐survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.     

What are Journals for?

‘The secret is comprised in three words – work, finish, publish.’Michael FaradayThere are many reasons doctors want to publish their work. For most at an early stage in their career, this may be to add a line to their curriculum vitae and advance their careers but for academics, publishing is an expectation. Many will believe they have something important to say, and wish to provoke debate and discussion; others wish to share knowledge and experiences, which in medicine can lead to a satisfying change in clinical practice. All serve to register one’s idea and educate others. However, for some, the reason is as basic as money. As we celebrate the 350th anniversary of the first academic publication, perhaps we have come full circle when it comes to why people publish?Publishing is a flourishing business. There were approximately 28,100 active scholarly peer-reviewed journals in mid-2012, collectively publishing about 1.8–1.9 million articles per year. The number of articles published each year and the number of journals have both grown steadily for more than two centuries, by about 3% and 3.5% per year respectively.¹ Journals have a responsibility to refine and define information and act as a scientific filter. Many of us will receive daily invitations in our email inbox from eclectic and new journals that are likely to take anything – is the filter now too porous? But this industry is like any other commercial activity and the supply still far outstrips the demand. Perhaps the internet revolution has merely fuelled our hunger to publish more?The launch of this exciting and innovative series about publishing coincides with the 350th celebration of the publication of the first academic journal. In the age of social media, the first question is ‘What are journals for?’, which Simon Rallison sets out to answer. Simon is Director of Publications at the Physiological Society, and was previously a journal publisher with Earthscan, Springer and Blackwell.Writing is hard work and, through this series, I hope the reader will get some useful insight into this service industry for academia.Jyoti ShahCommissioning EditorIn an age of the internet and social media, why are we still using (admittedly with refinements and improvements) a form of publication dating from 1665? What exactly is a journal in the 21st century and what role does it have to perform? Surprisingly, the academic journal has not evolved since it was invented 350 years ago.¹ The first issue of the Philosophical Transactions of the Royal Society was published in 1665, the brainchild of Henry Oldenburg and Robert Hooke. Since then, journals have digitised and now offer greater opportunity for research communication – but are authors taking advantage of what journals can offer? The academic and research community is generally very conservative about what it reads and how it views journals. There are, however, also frequent misunderstandings about the operation of journals.     

Persistent reversed end diastolic flow in the fetal middle cerebral artery: an ominous finding

Fetal persistent middle cerebral artery reversed end diastolic flow is a rare and ominous finding. Previous cases have been associated with intracranial hemorrhage, growth restriction, anaemia, and hepatic anomaly. Intrauterine demise or early neonatal death is a common outcome. We report the case of persistent middle cerebral artery reversed end diastolic flow in a well-grown fetus at 32 weeks’ gestation resulting from acute, severe anaemia due to a large feto-maternal hemorrhage. An emergency cesarean section was performed and the neonate required advanced resuscitation and immediate blood transfusion. Postnatal magnetic resonance imaging confirmed a hemorrhagic parietal infarct and bilateral ischaemic changes in the basal ganglia. This provides further evidence that persistent middle cerebral artery reversed end diastolic flow in any fetus is an ominous finding warranting urgent diagnostic evaluation and/or delivery.     

The efficacy of immediate versus delayed antibiotic administration on bacterial growth and biofilm production of selected strains of uropathogenic Escherichia coli and Pseudomonas aeruginosa

Purpose

The treatment of urinary tract infections (UTI) with antibiotics is commonly used, but recurrence and antibiotic resistance have been growing and concerning clinicians. We studied whether the rapid onset of a protective biofilm may be responsible for the lack of effectiveness of antibiotics against selected bacteria.

Materials and Methods

Two established uropathogenic Escherichia coli strains, UTI89 and CFT073, and two Pseudomonas aeruginosa strains, PA01 and Boston-41501, were studied to establish a reliable biofilm formation process. Bacterial growth (BG) was determined by optical density at 600 nm (OD 600) using a spectrophotometer, while biofilm formation (BF) using crystal violet staining was measured at OD 550. Next, these bacterial strains were treated with clinically relevant antibiotics, ciprofloxacin HCl (200 ng/mL and 2 μg/mL), nitrofurantoin (20 μg/mL and 40 μg/mL) and ampicillin (50 μg/mL) at time points of 0 (T0) or after 6 hours of culture (T6). All measurements, including controls (bacteria -1% DMSO), were done in triplicates and repeated three times for consistency.

Results

The tested antibiotics effectively inhibited both BG and BF when administered at T0 for UPEC strains, but not when the antibiotic administration started 6 hours later. For Pseudomonas strains, only Ciprofloxacin was able to significantly inhibit bacterial growth at T0 but only at the higher concentration of 2 μg/mL for T6.

Conclusion

When established UPEC and Pseudomonas bacteria were allowed to culture for 6 hours before initialization of treatment, the therapeutic effect of selected antibiotics was greatly suppressed when compared to immediate treatment, probably as a result of the protective nature of the biofilm.