Why study transport of peptides and proteins at the neurovascular interface

The blood–brain barrier (BBB) is an immense neurovascular interface. In neurodegenerative, ischemic, and traumatic disorders of the central nervous system (CNS), the BBB may hinder the delivery of many therapeutic peptides and proteins to the brain and spinal cord. Fortunately, the mistaken dogma that peptides and proteins do not cross the BBB has been corrected during the past two decades by the accumulating evidence that peptides and proteins in the periphery exert potent effects in the CNS. Not only can peptides and proteins serve as carriers for selective therapeutic agents, but they themselves may directly cross the BBB after delivery into the bloodstream. Their passage may be mediated by simple diffusion or specific transport, both of which can be affected by interactions in the blood compartment (outside the BBB) and within the endothelial cells (at the BBB level). Although the majority of current delivery strategies focuses on modification of the molecule to be delivered, understanding the mechanisms of transport will eventually facilitate regulation of the BBB directly. We review the different aspects of interactions and discuss recent advances in the cell biology of peptide/protein transport across the BBB. Better understanding of the nature and regulation of the transport systems at the BBB will provide a new direction to enhance the interactions of peripheral peptides and proteins with the CNS.     

Effect of total lymphoid irradiation on IgE antibody responses in rheumatoid arthritis and systemic lupus erythematosus

Thirteen patients with rheumatoid arthritis and four patients with systemic lupus erythematosus and nephritis were treated with total lymphoid irradiation because of severe disease refractory to other forms of treatment. Serum samples before and after irradiation were tested for changes in total serum IgE and for changes in specific IgE antibodies to ryegrass pollen, dust mite, cat dander, and Alternaria. There were no statistically significant changes in total or specific IgE from lymphoid irradiation in these patients. The therapy caused a significant decrease in circulating total lymphocyte and Leu-3 (helper/inducer) T-lymphocyte counts. Therefore, reduction in circulating levels of helper/inducer T cells does not appear to influence preexisting levels of IgE antibodies.     

Enhancement of attention in man with ACTH/MSH 4–10

Normal men were infused for 4 hr with ACTH/MSH 4–10 or a control solution. Behavioral testing after the infusion indicated that subjects who received ACTH/MSH 4–10 were less anxious and had better visual memory than control subjects but the predominant effect of the heptapeptide was to increase visual attention. It was specualted that ACTH/MSH 4–10 may be uniquely coded for attentional functioning.     

Contributions to the Improvement of Living Conditions among Neglected Populations with Trachoma

Objective: Trachoma (Chlamydia-triggered blinding infection) provoked irreversible visual impairment in about 8 million people in 2011, and the prevalence among children with dirty faces is more than three fold that among children with clean faces. In 250 villages with a high prevalence of trachoma (Kolofata district, Far North Region, Cameroon), the lack of water for facial cleanliness was reported during trachoma awareness campaigns. The objective of this study was to determine if the lack of water was linked with the absence of means to dig wells.Methods: Wells, waterholes, motorcycles, irrigation pumps, electricity, goats and oxen, cell phones and distance from waterholes were recorded in January 2011 in 50 randomized villages of Kolofata’s district.Results: The number of villages with <25 goats and <5 oxen was 0 and the number of adults owning <1 goat was 0. The cost of a pail of water was 0.01 USD. Motorcycles, cell phones and televisions have been reported in more than 66% of villages. The cost for the construction of lined shaft wells ranged between 15–35 goats and 0.5–3 oxen; the cost for drinking water wells ranged between 50–200 goats and 3–30 oxen.Discussion: No link between the means for digging wells at the village level and access to water was found. Social solidarity, which refers to a social debt owed by each person to his/her group, should be added to training guides to gauge its ability to release people from the dead end of having to wait for external assistance to gain access to water.     

Responding mindfully to distressing psychosis: A grounded theory analysis

Abstract

This study investigates the psychological process involved when people with current distressing psychosis learned to respond mindfully to unpleasant psychotic sensations (voices, thoughts, and images). Sixteen participants were interviewed on completion of a mindfulness group program. Grounded theory methodology was used to generate a theory of the core psychological process using a systematically applied set of methods linking analysis with data collection. The theory inducted describes the experience of relating differently to psychosis through a three-stage process: centering in awareness of psychosis; allowing voices, thoughts, and images to come and go without reacting or struggle; and reclaiming power through acceptance of psychosis and the self. The conceptual and clinical applications of the theory and its limits are discussed.     

Saturable Leptin Transport Across the BBB Persists in EAE Mice

We have shown that mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, have upregulated leptin receptor expression in reactive astrocytes of the hippocampus, a region involved in sickness behavior. Leptin can exacerbate EAE when its serum concentration is high. Although leptin receptors in astrocytes modulate leptin transport across cultured endothelial cell monolayers, it is not known how leptin transport in EAE mice is regulated. Here, we determined brain and cervical spinal cord uptake of leptin in early and recovery stages of EAE, after either intravenous delivery or in situ brain perfusion of ¹²⁵I-leptin and the vascular marker ¹³¹I-albumin. While increased vascular space and general blood–brain barrier (BBB) permeability after EAE were expected, the specific saturable transport system for leptin crossing the BBB also persisted. Moreover, there was upregulation of leptin transport in hippocampus and cervical spinal cord in the early stage of EAE, shown by higher leptin uptake in these regions and by competitive inhibition with coadministered excess unlabeled leptin. We conclude that EAE induced a time- and region-specific increase of leptin transport. The results provide a link between circulating leptin and enhanced leptin signaling that may play a crucial role in disease progression.     

Hypersomnolence and Reduced Activity in Pan-Leptin Receptor Knockout Mice

Excessive obesity correlates with hypersomnolence and impaired cognitive function, presumably induced by metabolic factors and cytokines. Production of the adipokine leptin correlates with the amount of adiposity, and leptin has been shown to promote sleep. To determine whether leptin plays a major role in the hypersomnolence of obesity, we measured sleep architecture in pan-leptin receptor knockout (POKO) mice that do not respond to leptin because of the production of a mutant, non-signaling receptor. The obese POKO mice had more non-rapid eye movement (NREM) sleep and less waking time than their littermate controls. This was mainly seen during the light span, although increased bouts of rapid eye movement sleep were also seen in the dark span. The increase of NREM sleep correlated with the extent of obesity. The POKO mice also had decreased locomotor activity and more immobility in the open field test, but there was no increase of forced immobility nor reduction of sucrose intake as would be seen in depression. The increased NREM sleep and reduced locomotor activity in the POKO mice suggest that it was obesity, rather than leptin signaling, that played a predominant role in altering sleep architecture and activity.     

Mobilizing political support proved critical to a successful switch from tOPV to bOPV in Kano,Nigeria 2016

Background

Kano is one of the high-risk states for polio transmission in Northern Nigeria. The state reported more cases of wild polioviruses (WPVs) than any other state in the country. The Nigeria Demographic and Health Survey of 2013 indicated that OPV3 coverage in the routine immunization (RI) programmewas 57.9%. Additionally, serial polio seroprevalence studies conducted from 2011 to 2015 in the eightmetropolitan LGAs indicated low immunity levels against all three polio serotypes in children below one year. Areas with sub-optimal RI coverage such as Kanothat fail to remove all tOPV during the tOPV-bOPV switchwill be at increased risk of VDPV2 circulation.

Methods

We assessed the impact of political leadership engagement in mobilizing other stakeholders on the outcomes of the bOPV-tOPV switch in Kano State from February to May 2016 using nationally-selected planning and outcome indicators.

Results

A total of 670 health facilities that provide RI services were assessed during the pre-switch activities. Health workers were aware of the switch exercise in 520 (95.1%) of the public health facilities assessed. It was found that health workers knew what to do should tOPV be found in any of the 521 (95.2%)public health facilities assessed. However, there was a wide disparity between the public and private health practitioners’ knowledge on basic concepts of the switch.There was 100% withdrawal of tOPV from the state and the seven zonal cold stores. Unmarked tOPVwas found in the cold chain system in 2 (4.5%) LGAs. Only one health facility (0.8%) had tOPV in the cold chain. No tOPVwas identified outside the cold chain without the “Do not use” sticker in any of the health facilities.

Conclusion

The engagement of the political leadership to mobilize other key stakeholders facilitated successful implementation of the tOPV-bOPVswitch exercise and provided opportunity to strengthen partnerships with the private health sector in Kano State.

     

Effects of cholinergic stimulation on pituitary hormone release

Physostigmine was infused into human volunteers to assess the effect of central cholinergic stimulation on memory and on neuroendocrine function. Methscopolamine bromide, a peripheral anticholinergic agent, was given simultaneously. The lower dose of physostigmine (1.0 mg) produced no change in AVP, cortisol, melatonin, GH or LH in those subjects without unpleasant cholinergic side effects. Larger doses of physostigmine usually produced nausea, and were associated with marked elevations of AVP, cortisol and prolactin, but no change in GH, LH or melatonin. Thus, cholinergic agents easily induce a stress response, but the GH component of this response can be suppressed by peripheral cholinergic blockade.