Clinical, anatomic, and electrophysiologic evaluation following intravitreal bevacizumab for macular edema in retinal vein occlusion

PURPOSE: To investigate clinical, anatomic, and electrophysiologic response after single intravitreal injection of bevacizumab for macular edema attributable to retinal vein occlusion. DESIGN: Prospective nonrandomized, interventional case series. METHODS: Twenty-one patients with macular edema attributable to vein occlusion received intravitreal injection of bevacizumab 1.25 mg. Nine patients had central retinal vein occlusion (CRVO), and 12 patients had branch retinal vein occlusion (BRVO). Complete ophthalmic examination including optical coherence tomography (OCT) was done at baseline and follow-up visits. Fifteen patients underwent fluorescein angiography at baseline. Selected patients underwent electroretinography (ERG) and visual evoked potential (VEP) at baseline and follow-up. Follow-up was for 12 weeks. RESULTS: At baseline, mean visual acuity was 20/381 (median, 20/400) and showed improvement to mean 20/135 (median, 20/60) after one month, (P = .001). At 12 weeks, mean visual acuity was 20/178 (median, 20/80) (P = .001). The mean central retinal thickness (CRT) was 647.81 microm (median, 609.00 microm) at baseline and decreased to mean 293.43 microm (median, 222.00 microm) at one month (P = .001). At 12 weeks, mean CRT was 320.90 mum (median, 280.00 microm) (P = .001). ERG and VEP showed no worsening of the waveforms. There was no significant difference in the visual outcome between the BRVO and CRVO groups. CONCLUSION: Intravitreal injection of bevacizumab appears to result in significant short-term improvement of visual acuity and macular edema secondary to vein occlusion. The present report confirms the previous studies. No ocular toxicity or adverse effects were observed. However, prospective, randomized, controlled long-term studies are required with an adequate number of patients.     

Outcomes of Donation After Circulatory Death Heart Transplantation in Australia

Background

Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice.

Treatment of gastrointestinal bleeding in left ventricular assist devices: A comprehensive review

Left ventricular assist devices(LVAD) are increasingly become common as life prolonging therapy in patients with advanced heart failure. Current devices are now used as definitive treatment in some patients given the improved durability of continuous flow pumps. Unfortunately, continuous flow LVADs are fraught with complications such as gastrointestinal(GI) bleeding that are primarily attributed to the formation of arteriovenous malformations. With frequent GI bleeding, antiplatelet and anticoagulation therapies are usually discontinued increasing the risk of life-threatening events. Small bowel bleeds account for 15%as the source and patients often undergo multiple endoscopic procedures.Treatment strategies include resuscitative measures and endoscopic therapies.Medical treatment is with octreotide. Novel treatment options include thalidomide, angiotensin converting enzyme inhibitors/angiotensin Ⅱ receptor blockers, estrogen-based hormonal therapies, doxycycline, desmopressin and bevacizumab. Current research has explored the mechanism of frequent GI bleeds in this population, including destruction of von Willebrand factor,upregulation of tissue factor, vascular endothelial growth factor, tumor necrosis factor-α, tumor growth factor-β, and angiopoetin-2, and downregulation of angiopoetin-1. In addition, healthcare resource utilization is only increasing in this patient population with higher admissions, readmissions, blood product utilization, and endoscopy. While some of the novel endoscopic and medical therapies for LVAD bleeds are still in their development stages, these tools will yet be crucial as the number of LVAD placements will likely only increase in the coming years.     

A Before and After Analysis of Health Care Utilization by Patients Enrolled in Opioid Controlled Substance Agreements for Chronic Noncancer Pain

Objective

To evaluate the impact of opioid controlled substance agreements (CSAs) enrollment on health care utilization.

An immunochromatographic dipstick as an alternate for monitoring of heroin metabolites in urine samples

Heroin use and addiction pose serious risks and side effects due to overdose. Quantification of heroin in biological samples is challenging due to rapid deacetylation of heroin to its active metabolites. In this study, we report the quantification of metabolic degradation of heroin by-products in biological urine samples. The presence of the drug was monitored after oral administration of heroin at different time intervals. Various biophysical techniques, such as high performance liquid chromatography (HPLC) and mass spectrometry (MS) were used to evaluate the presence of the drug. A competitive fluorescence based immunoassay was developed with a limit of detection (LOD) up to 0.01 ng mL⁻¹ and the IC₅₀ value was 0.1 ng mL⁻¹, while the dipstick assay shows a LOD up to 5 ng mL⁻¹. Rapid detection of narcotic drugs was carried out for biological urine samples collected at various time points. Validation of the developed dipstick was carried out for the standard as well as the spiked urine samples by fluorescence based immunoassay (FIA), using anti-morphine antibodies. A strong correlation (R = 0.94) was obtained between the developed dipstick and FIA assay for biological urine samples collected at various time points. The developed immunochromatographic dipstick is highly sensitive, field applicable and cost effective, and can serve as a first choice for the monitoring of narcotic drugs in blood, urine and saliva in drug addicts and athletes.

Pathway of heroin degradation post oral administration in mice.     

Sparing of the Dystrophin-Deficient Cranial Sartorius Muscle Is Associated with Classical and Novel Hypertrophy Pathways in GRMD Dogs

Both Duchenne and golden retriever muscular dystrophy (GRMD) are caused by dystrophin deficiency. The Duchenne muscular dystrophy sartorius muscle and orthologous GRMD cranial sartorius (CS) are relatively spared/hypertrophied. We completed hierarchical clustering studies to define molecular mechanisms contributing to this differential involvement and their role in the GRMD phenotype. GRMD dogs with larger CS muscles had more severe deficits, suggesting that selective hypertrophy could be detrimental. Serial biopsies from the hypertrophied CS and other atrophied muscles were studied in a subset of these dogs. Myostatin showed an age-dependent decrease and an inverse correlation with the degree of GRMD CS hypertrophy. Regulators of myostatin at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) levels were altered in GRMD CS, consistent with down-regulation of myostatin signaling, CS hypertrophy, and functional rescue of this muscle. mRNA and proteomic profiling was used to identify additional candidate genes associated with CS hypertrophy. The top-ranked network included α-dystroglycan and like-acetylglucosaminyltransferase. Proteomics demonstrated increases in myotrophin and spectrin that could promote hypertrophy and cytoskeletal stability, respectively. Our results suggest that multiple pathways, including decreased myostatin and up-regulated miRNAs, α-dystroglycan/like-acetylglucosaminyltransferase, spectrin, and myotrophin, contribute to hypertrophy and functional sparing of the CS. These data also underscore the muscle-specific responses to dystrophin deficiency and the potential deleterious effects of differential muscle involvement.Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the dystrophin gene and occurs in approximately 1 in 3500 live male births.¹ DMD boys show signs of skeletal muscle weakness, evidenced by a delay in walking until approximately 18 months and loss of ambulation by the teenage years. Necrotic muscle ultimately fails to regenerate and is replaced with fibrous connective tissue and fat. Molecular and cellular mechanisms underlying gradual muscle deterioration are poorly understood.Animal models of DMD include the mdx mouse and golden retriever muscular dystrophy (GRMD) dog.^2,3 Despite sharing the same fundamental genetic and biochemical lesions, remarkable phenotypic variation occurs among dystrophin-deficient individuals and muscles. Mdx mice have a relatively mild phenotype,⁴ whereas affected dogs have clinical and pathological features consistent with those of DMD.⁵ Even among DMD patients, who all lack dystrophin except for rare revertant fibers, symptoms can vary markedly.⁶ Dogs with GRMD also demonstrate pronounced phenotypic variation, as some dogs lose the ability to walk within the first 6 months of life, whereas others remain ambulatory to 10 years of age or older.^7–9In GRMD neonatal dogs, flexor muscles such as the sartorius are generally more severely involved than extensors, potentially due to their role in crawling.^10,11 Early dystrophic histopathological changes seen in these diseased muscles include myofiber necrosis evidenced by hyaline fibers, mineralization, edema, and inflammation, with associated regeneration.¹⁰ Presumably, as dogs subsequently begin to walk, weight-bearing extensor muscles such as the vastus lateralis (VL) are more predisposed to injury and display these same acute dystrophic changes. With regard to individual muscle variation in DMD, extensors that undergo eccentric contraction (eg, quadriceps femoris) are particularly vulnerable to early weakness and wasting.¹² On the other hand, the extraocular muscles are largely spared.¹³In DMD patients, most muscles atrophy over time, but some, such as the gastrocnemius, undergo gross enlargement.¹⁴ On the basis of early histological studies of dystrophic muscle biopsies, this calf hypertrophy was initially attributed to deposition of fat and fibrotic tissue and was termed pseudohypertrophy.¹⁵ However, in a series of 350 neuromuscular patients, including 9 with Becker muscular dystrophy, quantitative ultrasound demonstrated that calf hypertrophy was most often due to an actual increase in contractile tissue.¹⁶ Mdx mice¹⁷ and dystrophin-deficient cats¹⁸ also have muscle hypertrophy in the absence of significant fat and connective tissue infiltration. The sartorius muscle is particularly intriguing in both DMD and GRMD. Humans have a single muscle, whereas dogs have cranial and caudal bellies. Serving principally as a hip flexor, the sartorius extends from the pelvis to the proximal tibia in people. Both heads of the canine sartorius also arise from the pelvis, but they insert at different sites (caudal, proximal tibia; cranial, distal femur). The cranial sartorius (CS) muscle of neonatal GRMD dogs sustains extensive necrosis¹⁹ and then regenerates, often undergoing dramatic true hypertrophy.^9,20 In DMD patients, the sartorius muscle is relatively spared and may hypertrophy late in the disease process.^21,22Studies showing variable phenotypes among dystrophin-deficient species, individuals, and muscles suggest that factors other than dystrophin deficiency, so-called secondary effects, are involved in the disease process.²³ Determining the molecular underpinnings of the variable clinical and histopathological response to dystrophin deficiency should provide insight into disease pathogenesis and an opportunity to identify potential targets for therapy. Phenotypic–molecular correlations are inherently limited in DMD patients due to unavoidable restrictions of muscle sampling. Animal studies are potentially more powerful because multiple muscles can be sampled at different ages, thus allowing clearer distinction of factors contributing to disease progression. We chose to use the GRMD model of DMD for this study because of the availability of archived biopsy samples of multiple muscles from affected dogs at two ages and corresponding systematic functional data that could be correlated with mRNA and protein expression findings.Hierarchical clustering of several phenotypic markers, including CS muscle size, tibiotarsal joint angle,⁷ and flexor and extensor torque,⁸ was first performed in a group of GRMD and normal dogs. Consistent with our prior studies,⁹ severely affected dogs tended to have larger CS muscles. To achieve a better understanding of the molecular signals that drive muscle hypertrophy, we extended a prior, largely pathological study of differential muscle involvement in the GRMD model.¹⁹ Proteins that are well known to influence muscle size [myostatin (MSTN)]^24,25 or potentially compensate for dystrophin deficiency [utrophin (UTRN)]²⁶ were assessed in a subset of the dogs evaluated by hierarchical clustering. MSTN showed an age-dependent decrease and an inverse correlation with the degree of CS hypertrophy. Regulators of MSTN at the protein (AKT1) and miRNA (miR-539 and miR-208b targeting myostatin mRNA) level were altered, consistent with down-regulation of MSTN signaling, CS hypertrophy, and functional rescue of this muscle. The growth factor myotrophin (MTPN) was increased in the CS. These studies were augmented by analysis of mRNA, miRNA, and proteomic profiles from several GRMD muscles at two different ages to elucidate additional hypertrophic pathways. Although UTRN was also uniformly increased in GRMD muscles, there was no association with CS size. Other membrane-associated proteins, including α-dystroglycan, like-acetylglucosaminyltransferase (LARGE), and β-spectrin, were increased in the GRMD CS, consistent with a role in membrane stabilization. These results indicate that several muscle proteins may act together to stabilize myofibers and promote muscle growth. Our findings also further substantiate that differential muscle involvement can exaggerate the GRMD phenotype. This suggests that care should be taken with treatments targeting specific pathways, such as MSTN, that could selectively exaggerate muscle hypertrophy.     

Autonomic function test during the COVID-19 pandemic: the Stanford experience

Clinical Autonomic Research -