Inflammation-dependent cerebrospinal fluid hypersecretion by the choroid plexus epithelium in posthemorrhagic hydrocephalus

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordThere is another record in ORE for this publication: http://hdl.handle.net/10871/33419The choroid plexus epithelium (CPE) secretes higher volumes of fluid (cerebrospinal fluid, CSF) than any other epithelium and simultaneously functions as the blood-CSF barrier to gate immune cell entry into the central nervous system. Posthemorrhagic hydrocephalus (PHH), an expansion of the cerebral ventricles due to CSF accumulation following intraventricular hemorrhage (IVH), is a common disease usually treated by suboptimal CSF shunting techniques. PHH is classically attributed to primary impairments in CSF reabsorption, but little experimental evidence supports this concept. In contrast, the potential contribution of CSF secretion to PHH has received little attention. In a rat model of PHH, we demonstrate that IVH causes a Toll-like receptor 4 (TLR4)- and NF-κB-dependent inflammatory response in the CPE that is associated with a ∼3-fold increase in bumetanide-sensitive CSF secretion. IVH-induced hypersecretion of CSF is mediated by TLR4-dependent activation of the Ste20-type stress kinase SPAK, which binds, phosphorylates, and stimulates the NKCC1 co-transporter at the CPE apical membrane. Genetic depletion of TLR4 or SPAK normalizes hyperactive CSF secretion rates and reduces PHH symptoms, as does treatment with drugs that antagonize TLR4-NF-κB signaling or the SPAK-NKCC1 co-transporter complex. These data uncover a previously unrecognized contribution of CSF hypersecretion to the pathogenesis of PHH, demonstrate a new role for TLRs in regulation of the internal brain milieu, and identify a kinase-regulated mechanism of CSF secretion that could be targeted by repurposed US Food and Drug Administration (FDA)-approved drugs to treat hydrocephalus.We thank D.R. Alessi (Dundee) and R.P. Lifton (Rockefeller) for their support. K.T.K. is supported by the March of Dimes Basil O'Connor Award, a Simons Foundation SFARI Grant, the Hydrocephalus Association Innovator Award, and the NIH (4K12NS080223-05). J.M.S. is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (NS060801; NS061808) and the US Department of Veterans Affairs (1BX002889); R.M. is supported by the Howard Hughes Medical Institute

Windborne long-distance migration of malaria mosquitoes in the Sahel

Over the past two decades efforts to control malaria have halved the number of cases globally, yet burdens remain high in much of Africa and the elimination of malaria has not been achieved even in areas where extreme reductions have been sustained, such as South Africa1,2. Studies seeking to understand the paradoxical persistence of malaria in areas in which surface water is absent for 3–8 months of the year have suggested that some species of Anopheles mosquito use long-distance migration3. Here we confirm this hypothesis through aerial sampling of mosquitoes at 40–290 m above ground level and provide—to our knowledge—the first evidence of windborne migration of African malaria vectors, and consequently of the pathogens that they transmit. Ten species, including the primary malaria vector Anopheles coluzzii, were identified among 235 anopheline mosquitoes that were captured during 617 nocturnal aerial collections in the Sahel of Mali. Notably, females accounted for more than 80% of all of the mosquitoes that we collected. Of these, 90% had taken a blood meal before their migration, which implies that pathogens are probably transported over long distances by migrating females. The likelihood of capturing Anopheles species increased with altitude (the height of the sampling panel above ground level) and during the wet seasons, but variation between years and localities was minimal. Simulated trajectories of mosquito flights indicated that there would be mean nightly displacements of up to 300 km for 9-h flight durations. Annually, the estimated numbers of mosquitoes at altitude that cross a 100-km line perpendicular to the prevailing wind direction included 81,000 Anopheles gambiae sensu stricto, 6 million A. coluzzii and 44 million Anopheles squamosus. These results provide compelling evidence that millions of malaria vectors that have previously fed on blood frequently migrate over hundreds of kilometres, and thus almost certainly spread malaria over these distances. The successful elimination of malaria may therefore depend on whether the sources of migrant vectors can be identified and controlled

Case Report: Decreased Heart Rate in a Geriatric Client Following Physical Therapy Intervention and Accommodation With the C-Leg

In this case report, a deconditioned, 82-year-old man underwent transfemoral amputation secondary to chronic infection after knee resurfacing. He was initially fit with a nonmicroprocessor knee as part of the preparatory prosthesis. Nine months after amputation, he was fit with a C-Leg as a component of the definitive prosthesis. As part of the first year of rehabilitation, the patient underwent four separate physical therapy (PT) programs that included strengthening, conditioning, and patient education interventions. Following accommodation on each of the two prostheses, the patient performed a distance-based, 75 m fastest possible walking speed test while wearing a heart rate (HR) monitor. HR, target HR, gait velocity, and physiologic cost index were measured or calculated to determine the physiologic outcomes of rehabilitation. There was a marked decrease in both resting and working HR after the fourth PT program and accommodation to the C-Leg. Target HR was also more appropriate after rehabilitation, which confirmed the decreased HR response. Because of the magnitude of HR reductions while resting and working, it is possible that the patient gave a submaximal effort in addition to experiencing a training effect. The physiologic cost index seemed to diminish the difference observed in HR because of the structure of the equation and was not found to be complementary to the HR data. As a result of PT intervention, the C-Leg knee prosthesis, and personal goals, the patient retained the ability to care for his dependent wife in the home

Comparative efficacy of transfemoral prosthetic interfaces: Analysis of gait and perceived disability

Introduction: The High-Fidelity (HiFi) interface is an emerging transfemoral interface technology. However, no comparison of this interface to traditional transfemoral interface designs is currently available. The purpose of this study is to measure the effects of the HiFi system on gait and perceived disability compared with a traditional socket design in a subject with transfemoral amputation. Methods: The subject was first tested with a traditional ischial containment socket, then fit with the HiFi system, and tested again after a 30-day accommodation period. Three-dimensionalmotion analysis was performed using an 8-camera Vicon Motion Capture system. The Oswestry Low Back Pain Disability Questionnaire v2.0 and Western Ontario and McMaster University Osteoarthritis index were administered at initial and secondary testing to evaluate perceived disability. A one-way analysis of variance and Fischer\u27s least significant difference were used to determine statistical difference between conditions. The level of significance for all tests was set at P ≤ 0.05. Results: Notable results included an increase in self-selected gait velocity, prosthetic hip adduction, and hip extension. Reductions in lateral center of mass deviation during gait and in perceived disability was also shown with use of the HiFi condition. Discussion: This study analyzed the effects of the HiFi Interface System on biomechanical parameters of gait and perceived disability compared with a baseline IRC condition in this elderly subject with history of TF amputation. Several improvements and markers of increased stability with use of the HiFi were noted. Perceived disability was also greatly improved comparatively. Conclusions: TheHiFi Interface Systempresented some biomechanical advantages to traditional IRC socket designs in this case, which may allow for increased stability in patients utilizing a TF prosthesis. Further research with larger samples is warranted

Radiographic assessment of extremity osseointegration for the amputee

Osseointegration (OI) is a bone-anchoring procedure that allows the direct skeletal attachment of a prosthesis through the use of an implant. Transcutaneous OI implants are similar to subcutaneous intramedullary joint implants with some exceptions. Particularly, OI implants are inserted at the distal aspect of the femur, while intramedullary implants are inserted at the proximal aspect of the femur. In this report, an additional adaptation of the radiographic zonal analysis used for intramedullary implants, known as Gruen zones, is introduced to include OI implants of extremity prosthetics. Radiographic zonal analyses and interpretations are proposed. Gruen zones are used for intramedullary implants, which are generally inserted from the proximal aspect of the bone. OI extremity implants are inserted from the distal end of the bone. Therefore, the zonal analysis is inverted. A radiographic zonal analysis has been introduced by the Osseointegration Group of Australia (OGA). This analysis is needed specifically for the clinical evaluation of extremity OI, as significant changes to the bone and OI implant have been reported and need to be clinically described. A classification technique is necessary for establishing treatment guidelines for the extremity osseointegrated implant. The OGA Zonal analysis addresses this need by adapting a common reference standard to osseointegration of the extremity amputee.6 page(s

Malignant Cerebellar Edema Subsequent to Accidental Prescription Opioid Intoxication in Children

We present two recent cases of toddlers who developed malignant cerebellar edema subsequent to accidental ingestion of prescription opioids. Both children presented acute neurological decline, hydrocephalus, and tonsillar herniation requiring emergent ventricular drain placement, suboccipital craniectomy, and partial cerebellectomy. Together with several other reports, these cases suggest the existence of an uncommon yet severe syndrome of acute opioid-induced malignant cerebellar edema. We hypothesize that the condition results from a combination of primary opioid receptor-mediated changes in neuronal metabolism that are exacerbated by secondary hypoxic insult. If recognized promptly, this syndrome can be treated with emergent neurosurgical intervention with good clinical outcomes. These cases also illustrate the unintended consequences and innocent victims of the spiraling prescription opioid epidemic, which will likely increase in prevalence. Recognition of this syndrome by clinicians is thus critical

Glymphatic System Impairment in Alzheimer's Disease and Idiopathic Normal Pressure Hydrocephalus

Approximately 10% of dementia patients have idiopathic normal pressure hydrocephalus (iNPH), an expansion of the cerebrospinal fluid (CSF)-filled brain ventricles. iNPH and Alzheimer's disease (AD) both exhibit sleep disturbances, build-up of brain metabolic wastes and amyloid-β (Aβ) plaques, perivascular reactive astrogliosis, and mislocalization of astrocyte aquaporin-4 (AQP4). The glia–lymphatic (glymphatic) system facilitates brain fluid clearance and waste removal during sleep via glia-supported perivascular channels. Human studies have implicated impaired glymphatic function in both AD and iNPH. Continued investigation into the role of glymphatic system biology in AD and iNPH models could lead to new strategies to improve brain health by restoring homeostatic brain metabolism and CSF dynamics

Functional Performance Differences between the Genium and C-Leg Prosthetic Knees and Intact Knees

Microprocessor prosthetic knees (MPKs) have advanced technologically, offering new features to decrease impairment and activity limitations for persons with transfemoral amputation (TFA). The Genium knee is functionally untested, and functional differences between it and intact knees are unknown. This study sought to determine whether Genium use improves functional performance compared with the C-Leg. A randomized experimental crossover design was used, with a cross-section of five nonamputee controls for comparison to nor­mal. Twenty community-ambulating persons with TFA were trained and tested for accommodation with study components. All subjects (n = 25) were assessed using the Continuous-Scale Physical Functional Performance-10 (CS-PFP10) assessment. Subjects with TFA used both MPK systems. Genium use improved upper-body flexibility, balance, and endurance domain scores (7.0%–8.4%, p \u3c / = 0.05) compared with the C-Leg. Only in the endurance domain did Genium users score sig­nificantly lower than nonamputees (22.4%, p = 0.05). Comparing the C-Leg with nonamputees, CS-PFP10 total (2.0%–24.4%, p = 0.03) and all domains except upper-body strength were lower than nonamputees (–13.4% to –28.9%, p \u3c / = 0.05). Nonetheless, regardless of knee condition, subjects with TFAs did not equal or surpass nonamputees in any functional domain, suggesting room for improvements in TFA functional performance