Infectious And Hemorrhagic Hydrocephalus Share Molecular Mechanism Sensitive To Immune Modulation

Hydrocephalus, characterized by a pathologic dilation of the brain’s cerebrospinal fluid (CSF)-filled ventricles, may either be primary or acquired. Acquired hydrocephalus, most often caused by ventricular infection or hemorrhage, is currently treated by surgical CSF diversion with either a shunt or endoscopic third ventriculostomy – two procedures plagued by high failure and complication rates. The lack of pharmaceutical treatments is in part due to the obscure pathophysiology of the disease. We created novel rat models of post-infectious (PIH) and post-hemorrhagic hydrocephalus (PHH) and conducted a systems-level, multi-omics investigation of these animals to outline the cellular, molecular, and physiologic pathology of PIH and PHH, with the ultimate goal being to discover an effective pharmacological intervention. SPAK and toll like receptor 4 (TLR4) knockout (KO) rats were generated using Crispr/CAS9 genome editing. A catheter was implanted into the lateral ventricles of adult male rats; E. coli+/-LPS, LPS, autologous blood, or artificial CSF (aCSF) was administered over 48-72h. Ventricular size was determined either by volumetric analysis of serial images or MRI, and CSF secretion was measured by catheter placement into the lateral ventricle. Choroid plexus (ChP) was harvested for immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR) analysis, flow cytometry, genomic/proteomic examination, and single-cell RNA sequencing (scRNAseq). Additional proteins of interest were identified through liquid chromatography/dual mass spectroscopy (LC-MS/MS) analysis of purified protein complexes from digested ChP tissue; candidates were validated by WB/IHC. CSF cytokine analysis was performed by Eve Technologies. Intracerebroventricular (ICV) hemorrhage or infection with E. coli+LPS or LPS alone triggers a TLR4-dependent immune response at the ChP-CSF interface. The resulting CSF pro-inflammatory “cytokine storm”, elicited from peripherally-derived and border-associated ChP macrophages, caused an increase in CSF production from the ChP epithelium via phospho-activation of the tumor necrosis factor (TNF) receptor-associated kinase SPAK, which acts as regulatory scaffold for a multi-ion transporter protein complex comprised of the NKCC1, the alpha-1 subunit of the Na/K ATPase, KCNJ13, CLIC6, WNK1, and AQP1. Genetic KO of TLR4 or SPAK in rats, as well as pharmacological immunosuppression with rapamycin, prevents PIH and PHH by antagonizing the ChP inflammation that causes SPAK-dependent CSF hypersecretion. These results expand our understanding of ChP immune-epithelial cell crosstalk and reframe PIH and PHH, which are historically known as diseases of impaired CSF flow through the ventricular system, as related neuroinflammatory disorders sensitive to immunomodulation. Such findings may reduce the need for invasive, surgical CSF diversion procedures

Letter from Benjamin Reeves to George Sibley, August 25, 1831

Transcript of Letter from Benjamin Reeves to George Sibley, August 25, 1831. Reeves discusses the vouchers from the Santa Fe Trail needed to be reimbursed for their expenses

Letter from Benjamin Reeves to George Sibley, March 10, 1827

Transcript for Letter from Benjamin Reeves to George Sibley, March 10, 1827

Letter from Benjamin Reeves to Thomas Mather, November 5, 1826

Letter from Benjamin Reeves to Thomas Mather, November 5, 182

Letter from Benjamin Reeves to George Sibley, February 13, 1833

Transcript of Letter from Benjamin Reeves to George Sibley, February 13, 1833. Reeves discusses the voucher investigation in Washington

The effect of health-care privatisation on the quality of care

Over the past 40 years, many health-care systems that were once publicly owned or financed have moved towards privatising their services, primarily through outsourcing to the private sector. But what has the impact been of privatisation on the quality of care? A key aim of this transition is to improve quality of care through increased market competition along with the benefits of a more flexible and patient-centred private sector. However, concerns have been raised that these reforms could result in worse care, in part because it is easier to reduce costs than increase quality of health care. Many of these reforms took place decades ago and there have been numerous studies that have examined their effects on the quality of care received by patients. We reviewed this literature, focusing on the effects of outsourcing health-care services in high-income countries. We found that hospitals converting from public to private ownership status tended to make higher profits than public hospitals that do not convert, primarily through the selective intake of patients and reductions to staff numbers. We also found that aggregate increases in privatisation frequently corresponded with worse health outcomes for patients. Very few studies evaluated this important reform and there are many gaps in the literature. However, based on the evidence available, our Review provides evidence that challenges the justifications for health-care privatisation and concludes that the scientific support for further privatisation of health-care services is weak

Reworking the tailings: new gold histories and the cultural landscape

In addition to the superficial visual similarities between the architectural theories of the Silesian-born, seventeenth-century Dutch mathematician Nicolaus Goldmann and the early nineteenth-century French architect Jean-Nicolas-Louis Durand, there is a more profound interconnection: their use of the grid. This article evaluates the relation between the two theories and argues how Durand could have been influenced by Goldmann’s writings. It turns out to be more than likely that the two were linked by Durand´s German pupils who brought the tradition of German eighteenth-century architectural theory with them. This corpus was nourished by Leonhard Christoph Sturm´s ‘Goldmannic’ architecture

Letter from Benjamin Reeves to George Sibley, October 22, 1833

Transcript of Letter from Benjamin Reeves to George Sibley, October 22, 1833. Reeves discusses more problems with the vouchers