Duchenne muscular dystrophy (DMD) is an incurable X-linked muscle-wasting disease caused by mutations in the dystrophin gene. Gene therapy using highly functional microdystrophin genes and ...recombinant adeno-associated virus (rAAV) vectors is an attractive strategy to treat DMD. Here we show that locoregional and systemic delivery of a rAAV2/8 vector expressing a canine microdystrophin (cMD1) is effective in restoring dystrophin expression and stabilizing clinical symptoms in studies performed on a total of 12 treated golden retriever muscular dystrophy (GRMD) dogs. Locoregional delivery induces high levels of microdystrophin expression in limb musculature and significant amelioration of histological and functional parameters. Systemic intravenous administration without immunosuppression results in significant and sustained levels of microdystrophin in skeletal muscles and reduces dystrophic symptoms for over 2 years. No toxicity or adverse immune consequences of vector administration are observed. These studies indicate safety and efficacy of systemic rAAV-cMD1 delivery in a large animal model of DMD, and pave the way towards clinical trials of rAAV-microdystrophin gene therapy in DMD patients.
Background
The imaging and electrodiagnostic (EDX) characteristics of traumatic brachial plexus injury (TBPI) are incompletely reported.
Objectives
To describe the epidemiological, clinical, and EDX ...characteristics of TBPIs in a series of cases in dogs and cats; to determine the association between clinical data, EDX findings, and clinical outcomes; and to assess the sensitivity and specificity of EDX studies to classify nerve lesions.
Animals
One hundred and seventy‐five dogs and 51 cats with TBPI and EDX exploration of radial nerve, ulnar nerve, or both nerves.
Methods
Retrospective case series. All medical records were searched for dogs and cats presenting with TBPIs that underwent EDX exploration. Epidemiological, clinical, EDX, and follow‐up data were extracted. Association between clinical data, EDX findings, and clinical outcomes was explored.
Results
Forty‐six percent of affected animals were injured before 2 years of age and 57% of dogs weighed more than 20 kg. The radial compound muscle action potential (CMAP) amplitude for dogs and cats that had clinical improvement was higher than in animals without improvement (4.3 mV 0‐23.6 vs 0 mV 0‐2.4, respectively, P = .02). A discriminating radial CMAP amplitude threshold value of 5 mV had a specificity of 93% (95% CI 80‐100) to predict recovery.
Conclusions and Clinical Importance
Electrodiagnostic studies, particularly measurement of radial CMAP amplitude, are valuable diagnostic tests to refine the prognosis of these animals.
A 3‐year‐old female German Shepherd dog was presented with generalized tonic‐clonic epileptic seizures, right‐sided central vestibular syndrome, and right trigeminal nerve dysfunction. Acute lacunar ...ischemic strokes within both thalami, right side of the mesencephalon, left side of the myelencephalon, both sides of the cervical spinal cord, and acute hemorrhagic strokes within the rostral part of the right cerebellar hemisphere and right rostral colliculus were identified on magnetic resonance imaging. Additional evaluation identified multiple renal infarcts and complete splenic torsion, with entrapment of the left pancreatic lobe. Medical management, splenectomy, partial pancreatectomy, and intensive physical rehabilitation led to clinical improvement. The histology of the spleen was consistent with hemorrhagic infarction. Three months after onset, neurological examination identified only mild vestibular sequelae. The final diagnosis was multiple ischemic strokes secondary to primary splenic torsion. Spontaneous early hemorrhagic transformation, a well‐known condition in human medicine, also was found in this case.
Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disorder caused by mutations in the dystrophin gene, without curative treatment yet available. Our study provides, for the first time, the ...overall safety profile and therapeutic dose of a recombinant adeno-associated virus vector, serotype 8 (rAAV8) carrying a modified U7snRNA sequence promoting exon skipping to restore a functional in-frame dystrophin transcript, and injected by locoregional transvenous perfusion of the forelimb. Eighteen Golden Retriever Muscular Dystrophy (GRMD) dogs were exposed to increasing doses of GMP-manufactured vector. Treatment was well tolerated in all, and no acute nor delayed adverse effect, including systemic and immune toxicity was detected. There was a dose relationship for the amount of exon skipping with up to 80% of myofibers expressing dystrophin at the highest dose. Similarly, histological, nuclear magnetic resonance pathological indices and strength improvement responded in a dose-dependent manner. The systematic comparison of effects using different independent methods, allowed to define a minimum threshold of dystrophin expressing fibers (>33% for structural measures and >40% for strength) under which there was no clear-cut therapeutic effect. Altogether, these results support the concept of a phase 1/2 trial of locoregional delivery into upper limbs of nonambulatory DMD patients.
Background
Auto-antibodies (auto-Abs) neutralizing type I interferons (IFN) have been found in about 15% of critical cases COVID-19 pneumonia and less than 1% of mild or asymptomatic cases. ...Determining whether auto-Abs influence presentation and outcome of critically ill COVID-19 patients could lead to specific therapeutic interventions. Our objectives were to compare the severity at admission and the mortality of patients hospitalized for critical COVID-19 in ICU with
versus
without auto-Abs.
Results
We conducted a prospective multicentre cohort study including patients admitted in 11 intensive care units (ICUs) from Great Paris area hospitals with proven SARS-CoV-2 infection and acute respiratory failure. 925 critically ill COVID-19 patients were included. Auto-Abs neutralizing type I IFN-α2,
β
and/or ω were found in 96 patients (10.3%). Demographics and comorbidities did not differ between patients with
versus
without auto-Abs. At ICU admission, Auto-Abs positive patients required a higher FiO
2
(100% (70–100) vs. 90% (60–100),
p
= 0.01), but were not different in other characteristics. Mortality at day 28 was not different between patients with and without auto-Abs (18.7 vs. 23.7%,
p
= 0.279). In multivariable analysis, 28-day mortality was associated with age (adjusted odds ratio (aOR) = 1.06 1.04–1.08,
p
< 0.001), SOFA score (aOR = 1.18 1.12–1.23,
p
< 0.001) and immunosuppression (aOR = 1.82 1.1–3.0,
p
= 0.02), but not with the presence of auto-Abs (aOR = 0.69 0.38–1.26,
p
= 0.23).
Conclusions
In ICU patients, auto-Abs against type I IFNs were found in at least 10% of patients with critical COVID-19 pneumonia. They were not associated with day 28 mortality.
Objective
To evaluate the cervical nerve 8 cross‐transfer technique (C8CT) as a part of surgical treatment of caudal brachial plexus avulsion (BPA) in the dog.
Study Design
Case series.
Animals
...Client‐owned dogs suspected to have caudal BPA based on neurological examination and electrophysiological testing (n = 3).
Methods
The distal stump of the surgically transected contralateral C8 ventral branch (donor) was bridged to the proximal stump of the avulsed C8 ventral branch (recipient) and secured with 9‐0 polypropylene suture under an operating microscope. A carpal panarthrodesis was performed on the injured limb after C8CT.
Results
Surgical exploration confirmed avulsion of nerve roots C7, C8, and T1 in all cases. There was no evidence of an iatrogenic effect on the donor forelimb. Gradual improvement in function of the affected forelimb occurred in all dogs, with eventual recovery of voluntary elbow extension. Reinnervation was evident in EMG recordings 6 months postoperatively in all three dogs. Stimulation of the donor C8 ventral branch led to motor evoked potentials in the avulsed side triceps brachialis and radial carpus extensor muscles. Variable functional outcome was observed in the 3 dogs during clinical evaluation 3‐4 years after surgery. Digital abrasion wounds, distal interphalangeal infectious arthritis, and self‐mutilation necessitated distal phalanx amputation of digits 3 and 4 in 2 dogs.
Conclusion
C8CT provided partial reconnection of the donor C8 ventral branch to the avulsed brachial plexus in the 3 dogs of this series. Reinnervation resulted in active elbow extension and promoted functional recovery in the affected limb.
Nitrogen deficit affects both crop production and composition, particularly in crops requiring an optimal fruit N content for aroma development. The adaptation of cultural practices to improve N use ...efficiency (NUE) (i.e. N uptake, assimilation and partitioning) is a priority for the sustainable production of high-quality crops. A trial was set on potted grapevines (Vitis vinifera L. cv. Chasselas) to investigate the potential of crop limitation (via bunch thinning) to control plant NUE and ultimately fruit N composition at harvest. A large crop load gradient was imposed by bunch thinning (0.5-2.5 kg m-2) and N traceability in the plant was realised with an isotope-labelling method (10 atom % 15N foliar urea). The results indicate that the mobilisation of root reserves plays a major role in the balance of fruit N content. Fertiliser N uptake and assimilation appeared to be strongly stimulated by high-yielding conditions. Fertilisation largely contributed to fulfilling the high fruit N demand while limiting the mobilisation of root reserves under high yield conditions. Plants were able to modulate root N reserve mobilisation and fertiliser N uptake in function of the crop load, thus maintaining a uniform N concentration in fruits. However, the fruit free amino N profile was modified, which potentially altered the fruit aromas. These findings highlight the great capacity of plants to adapt their N metabolism to constraints, crop thinning in this case. This confirms the possibility of monitoring NUE by adapting cultural practices.
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