Interrelationships between Cellular Density, Mosaic Patterning, and Dendritic Coverage of VGluT3 Amacrine Cells.

Amacrine cells of the retina are conspicuously variable in their morphologies, their population demographics, and their ensuing functions. Vesicular glutamate transporter 3 (VGluT3) amacrine cells are a recently characterized type of amacrine cell exhibiting local dendritic autonomy. The present analysis has examined three features of this VGluT3 population, including their density, local distribution, and dendritic spread, to discern the extent to which these are interrelated, using male and female mice. We first demonstrate that Bax-mediated cell death transforms the mosaic of VGluT3 cells from a random distribution into a regular mosaic. We subsequently examine the relationship between cell density and mosaic regularity across recombinant inbred strains of mice, finding that, although both traits vary across the strains, they exhibit minimal covariation. Other genetic determinants must therefore contribute independently to final cell number and to mosaic order. Using a conditional KO approach, we further demonstrate that Bax acts via the bipolar cell population, rather than cell-intrinsically, to control VGluT3 cell number. Finally, we consider the relationship between the dendritic arbors of single VGluT3 cells and the distribution of their homotypic neighbors. Dendritic field area was found to be independent of Voronoi domain area, while dendritic coverage of single cells was not conserved, simply increasing with the size of the dendritic field. Bax-KO retinas exhibited a threefold increase in dendritic coverage. Each cell, however, contributed less dendrites at each depth within the plexus, intermingling their processes with those of neighboring cells to approximate a constant volumetric density, yielding a uniformity in process coverage across the population.SIGNIFICANCE STATEMENT Different types of retinal neuron spread their processes across the surface of the retina to achieve a degree of dendritic coverage that is characteristic of each type. Many of these types achieve a constant coverage by varying their dendritic field area inversely with the local density of like-type neighbors. Here we report a population of retinal amacrine cells that do not develop dendritic arbors in relation to the spatial positioning of such homotypic neighbors; rather, this cell type modulates the extent of its dendritic branching when faced with a variable number of overlapping dendritic fields to approximate a uniformity in dendritic density across the retina.

Random spatial patterning of cone bipolar cell mosaics in the mouse retina.

Retinal bipolar cells spread their dendritic arbors to tile the retinal surface, extending them to the tips of the dendritic fields of their homotypic neighbors, minimizing dendritic overlap. Such uniform nonredundant dendritic coverage of these populations would suggest a degree of spatial order in the properties of their somal distributions, yet few studies have examined the patterning in retinal bipolar cell mosaics. The present study examined the organization of two types of cone bipolar cells in the mouse retina, the Type 2 cells and the Type 4 cells, and compared their spatial statistical properties with those of the horizontal cells and the cholinergic amacrine cells, as well as to random simulations of cells matched in density and constrained by soma size. The Delauney tessellation of each field was computed, from which nearest neighbor distances and Voronoi domain areas were extracted, permitting a calculation of their respective regularity indexes (RIs). The spatial autocorrelation of the field was also computed, from which the effective radius and packing factor (PF) were determined. Both cone bipolar cell types were found to be less regular and less efficiently packed than either the horizontal cells or cholinergic amacrine cells. Furthermore, while the latter two cell types had RIs and PFs in excess of those for their matched random simulations, the two types of cone bipolar cells had spatial statistical properties comparable to random distributions. An analysis of single labeled cone bipolar cells revealed dendritic arbors frequently skewed to one side of the soma, as would be expected from a randomly distributed population of cells with dendrites that tile. Taken together, these results suggest that, unlike the horizontal cells or cholinergic amacrine cells which minimize proximity to one another, cone bipolar cell types are constrained only by their physical size.

Patterns of Acute Ischemic Stroke Treatment from 2010 to 2020: An Evolving Landscape in Stroke Management Following Thrombectomy Trials.

Background and Objectives: Population-based studies on stroke can help guide the care of patients with acute ischemic stroke (AIS) by providing health care communities with information regarding the current usage of stroke treatments. It remains unclear how rapidly new techniques, particularly endovascular stroke treatment (EST), are being adopted and whether there is any disparity in their availability. Although studies using the National Inpatient Sample (NIS) have been conducted, updated studies over a longer period may provide further insights. This study aimed to understand patterns of AIS treatment, discharge disposition, in-hospital mortality, and mean length of stay (LOS) for each modality from 2010 to 2020 using the NIS database. Methods: This retrospective longitudinal study was conducted using NIS data from 2010 to 2020. Patients were categorized into groups based on whether they received intravenous recombinant tissue plasminogen activator (rt-PA), EST, both rt-PA and EST (combined therapy), or supportive care alone. Demographic, socioeconomic, regional, insurance, and hospital data were also obtained. The primary outcome was the proportion of patients receiving each modality, whereas the secondary outcomes were in-hospital mortality, mean LOS, and discharge disposition. Results: The usage rates increased (p < 0.001) in all groups between 2010 and 2020 (rt-PA: 5.09% to 8.39%, EST: 0.31% to 4.40%, and rt-PA+EST: 0.46% to 1.09%). The highest increase in usage was observed for EST, with a thirteen-fold increase. Mortality decreased from 2010 to 2020 in all groups (rt-PA: 8.45% to 3.54%, EST: 25.22% to 12.50%, and rt-PA+EST: 21.12% in 2010 to 9.30%) (p < 0.001). Combination therapy demonstrated the greatest improvement, with an 11.2% reduction in absolute mortality. Mean LOS was reduced for patients who received rt-PA (6.8 to 4.8 days), EST (9.3 to 8.9 days), and combined therapy (10.0 to 8.3 days) (p < 0.001) over the study period. The proportion of patients discharged to home increased for rt-PA (29.01% to 41.85%), EST (14.13% to 17.70%), and combined therapy (12.89% to 24.29%) (p < 0.001). Overall, stroke treatment usage was higher among the higher income groups, regardless of race. Higher usage was also observed for Whites in the West and Hispanic ethnicities in the South and West. Regardless of income or treatment method, utilization rates were lower for Black patients. Utilization rates were lower for Black patients with Medicare, Medicaid, or self-pay than for White patients. Discussion: Our study demonstrated that endovascular stroke treatment continues to expand, leading to better outcomes for mortality, LOS, and home discharge. Despite these positive patterns, there are visible inequities across regions, income status, and races.

Peroneal Nerve Repair with Cross-Bridge Ladder Technique: Parallel End-to-Side Neurorrhaphies.

Background Multiple nerve transfer techniques are used to treat patients with nerve injuries when a primary repair is not possible. These techniques are categorized to end-to-end, end-to-side, and side-to-side neurorrhaphy. Our study aims to explore the utility of the cross-bridge ladder technique (H-shaped), which has shown promising results in animal models and probably underutilized clinically. Methods Four patients with significant loss of ankle dorsiflexion were seen in the clinic and underwent evaluation, including electrodiagnostic studies. A cross-bridge ladder repair technique was used between the tibial nerve as the donor and the common peroneal nerve as the recipient via one or two nerve grafts coapted in parallel with end-to-side neurorrhaphies. Dorsiflexion strength was measured preoperatively using the Medical Research Council (MRC) grading system and at each postoperative follow-up appointment. Results All four patients had suffered persistent and severe foot drop (MRC of 0) following trauma that had occurred between 6 and 15 months preoperatively. Three of the four patients improved to an MRC of 2 several months postoperatively. The last patient had an immediate improvement to an MRC of 2 by his first month and had a complete recovery of ankle dorsiflexion within 4 months from surgery. Conclusion We demonstrate the utility and clinical outcomes of the cross-bridge ladder technique in patients with persistent and prolonged foot drop following trauma. Both early and late recovery were seen while all patients regained motor function, with some patients continuing to improve up to the most recent follow-up. IRB Approval: Obtained 2013-1411-CP005.

Candida Shunt Infection Causing Arachnoiditis and Hydrocephalus: A Case Report.

Arachnoiditis is a relatively rare condition and can result in long-term chronic and debilitating complications if not diagnosed early and treated properly. However, diagnosis of arachnoiditis is rare and knowledge of potential causes of this condition is still sparse. Current known causes of arachnoiditis include infections, trauma, spinal tumors, and iatrogenic causes induced via neurological interventions. Here, we present a case of a 65-year-old female who presented with arachnoiditis caused by Candida albicans infection from a contaminated ventriculoperitoneal (VP) shunt, placed following the development of hydrocephalus from subarachnoid hemorrhage. During her initial assessment, the possibility of arachnoiditis was raised after spinal magnetic resonance imaging (MRI) due to leg weakness and spasms with bladder dysfunction. However, further workup was not pursued after a normal spinal angiogram and lack of constitutional symptoms. She presented six months later with symptoms of fever and lower abdominal pain. She was diagnosed with fungal arachnoiditis after a computerized tomography (CT) of the abdomen showed thickening of the fascia around the shunt catheter and fluid collections near the tip of the shunt in the abdominal cavity after hospitalization. The diagnosis was made after an ultrasound-guided tap of the same area revealed budding yeast and cerebrospinal fluid (CSF) showed growths of Candida albicans. Her shunt was removed, and she received intravenous (IV) antifungals and recovered. MRI should be considered with clinical presentations that are characteristic of arachnoiditis. Symptoms from fungal infections are usually dramatic; however, in some instances as in this case, they may follow a more progressive course. The patient should be extensively evaluated for infection, especially fungal, in interventions involving device placement even when minimally, but persistently, symptomatic.

Role of Microglia and Astrocytes in Spinal Cord Injury Induced Neuropathic Pain.

Background: Spinal cord injuries incite varying degrees of symptoms in patients, ranging from weakness and incoordination to paralysis. Common amongst spinal cord injury (SCI) patients, neuropathic pain (NP) is a debilitating medical condition. Unfortunately, there remain many clinical impediments in treating NP because there is a lack of understanding regarding the mechanisms behind SCI-induced NP (SCINP). Given that more than 450,000 people in the United States alone suffer from SCI, it is unsatisfactory that current treatments yield poor results in alleviating and treating NP. Summary: In this review, we briefly discussed the models of SCINP along with the mechanisms of NP progression. Further, current treatment modalities are herein explored for SCINP involving pharmacological interventions targeting glia cells and astrocytes. Key message: The studies presented in this review provide insight for new directions regarding SCINP alleviation. Given the severity and incapacitating effects of SCINP, it is imperative to study the pathways involved and find new therapeutic targets in coordination with stem cell research, and to develop a new gold-standard in SCINP treatment.

Can normal inflammatory markers rule out acute appendicitis? The reliability of biochemical investigations in diagnosis.

BACKGROUND: Acute appendicitis is a common general surgical condition where diagnosis is predominantly clinical, with the aid of adjunct investigations. This study reviews the relationship between normal and elevated biochemical inflammatory markers, duration of symptoms and proven appendicitis. METHODS: A multicentre prospective observational study was performed across 27 centres and included a total of 949 patients with clinical suspicion of appendicitis, who had both white cell count (WCC) and C-reactive protein (CRP) recorded and underwent appendicectomy. RESULTS: A total of 90.4% of patients with raised WCC and CRP had appendicitis with a positive predictive value (PPV) of 0.9 and negative predictive value (NPV) of 0.4. Sensitivity and specificity of elevated WCC (sensitivity 66.5%, specificity 66.0%) and elevated CRP (sensitivity 77.3%, specificity 52.0%) lie within ranges identified by previous studies. A total of 39.8% of patients with normal CRP and WCC had appendicitis. Sensitivity and PPV for patients with elevated inflammatory markers were high until 48 h of symptoms (sensitivity 94%, PPV 0.87). NPV was elevated after 24 h (NPV 0.65 in patients with 24-48 h of symptoms, and 0.61 after 48 h), whilst those with symptoms less than 24 h had a lower NPV of 0.52. CONCLUSION: Whilst elevated inflammatory markers are a helpful aid in the diagnosis of appendicitis, they should not be relied on by themselves. Nor can normal inflammatory markers be used to exclude appendicitis, even in those with prolonged duration of symptoms. The diagnosis of appendicitis should be guided by a combination of clinical judgement with the assistance of inflammatory markers.

Consecutive organ transplantation in inbred rats: long-term results--Are organs recyclable?

Using 9-12-month-old Lewis rats, our laboratory performed consecutive organ transplantations to assess the technical feasibility and observe the histopathologies of prolonged transplants and implants over a rat's life span. This study includes a total of 688 cases of consecutive syngeneic organ transplantation, including pancreaticoduodenum (PD), en-bloc liver-pancreaticoduodenum-spleen-stomach (LPdSpSt), and spleen bearing ovary or testicle. A 52-month-old consecutively transplanted pancreas showed normal acini and islet cells. Consecutively transplanted LPdSpSt cases at 25-28 months preserved normal histology. After 26.5 months of ovarian follicle implantation into the spleen, the pathology of the organ exhibited typical dysgerminoma. However, 29.5-month-old infantile testicle implants in the spleen showed seminoma. Our studies suggest that transplanted organs can be reusable and retransplanted, and we hope this could be one of the clues to solve donor-organ shortages in the future.