Toll‐like Receptor 4 Signaling in Neurons Enhances Calcium‐Permeable AMPA Receptor Currents and Drives Post‐Traumatic Epileptogenesis

ObjectiveTraumatic brain injury is a major risk factor for acquired epilepsies, and understanding the mechanisms underlying the early pathophysiology could yield viable therapeutic targets. Growing evidence indicates a role for inflammatory signaling in modifying neuronal excitability and promoting epileptogenesis. Here we examined the effect of innate immune receptor Toll-like receptor 4 (TLR4) on excitability of the hippocampal dentate gyrus and epileptogenesis after brain injury.MethodsSlice and in vivo electrophysiology and Western blots were conducted in rats subject to fluid percussion brain injury or sham injury.ResultsThe studies identify that TLR4 signaling in neurons augments dentate granule cell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (CP-AMPAR) currents after brain injury. Blocking TLR4 signaling in vivo shortly after brain injury reduced dentate network excitability and seizure susceptibility. When blocking of TLR4 signaling after injury was delayed, however, this treatment failed to reduce postinjury seizure susceptibility. Furthermore, TLR4 signal blocking was less efficacious in limiting seizure susceptibility when AMPAR currents, downstream targets of TLR4 signaling, were transiently enhanced. Paradoxically, blocking TLR4 signaling augmented both network excitability and seizure susceptibility in uninjured controls. Despite the differential effect on seizure susceptibility, TLR4 antagonism suppressed cellular inflammatory responses after injury without impacting sham controls.InterpretationThese findings demonstrate that independently of glia, the immune receptor TLR4 directly regulates post-traumatic neuronal excitability. Moreover, the TLR4-dependent early increase in dentate excitability is causally associated with epileptogenesis. Identification and selective targeting of the mechanisms underlying the aberrant TLR4-mediated increase in CP-AMPAR signaling after injury may prevent epileptogenesis after brain trauma. ANN NEUROL 2020;87:497-515

Increasing condom use and declining STI prevalence in high-risk MSM and TGs: evaluation of a large-scale prevention program in Tamil Nadu, India

BACKGROUND: This paper presents an evaluation of Avahan, a large scale HIV prevention program that was implemented using peer-mediated strategies, condom distribution and sexually transmitted infection (STI) clinical services among high-risk men who have sex with men (HR-MSM) and male to female transgender persons (TGs) in six high-prevalence state of Tamil Nadu, in southern India. METHODS: Two rounds of large scale cross-sectional bio-behavioural surveys among HR-MSM and TGs and routine program monitoring data were used to assess changes in program coverage, condom use and prevalence of STIs (including HIV) and their association to program exposure. RESULTS: The Avahan program for HR-MSM and TGs in Tamil Nadu was significantly scaled up and contacts by peer educators reached 77 percent of the estimated denominator by the end of the program’s fourth year. Exposure to the program increased between the two rounds of surveys for both HR-MSM (from 66 percent to 90 percent; AOR = 4.6; p < 0.001) and TGs (from 74.5 percent to 83 percent; AOR = 1.82; p < 0.06). There was an increase in consistent condom use by HR-MSM with their regular male partners (from 33 percent to 46 percent; AOR = 1.9; p < 0.01). Last time condom use with paying male partners (up from 81 percent to 94 percent; AOR = 3.6; p < 0.001) also showed an increase. Among TGs, the increase in condom use with casual male partners (18 percent to 52 percent; AOR = 1.8; p < 0.27) was not significant, and last time condom use declined significantly with paying male partners (93 percent to 80 percent; AOR = 0.32; p < 0.015). Syphilis declined significantly among both HR-MSM (14.3 percent to 6.8 percent; AOR = 0.37; p < 0.001) and TGs (16.6 percent to 4.2 percent; AOR = 0.34; p < 0.012), while change in HIV prevalence was not found to be significant for HR-MSM (9.7 percent to 10.9 percent) and TGs (12 percent to 9.8 percent). For both groups, change in condom use with commercial and non-commercial partners was found to be strongly linked with exposure to the Avahan program. CONCLUSION: The Avahan program for HR-MSM and TGs in Tamil Nadu achieved a high coverage, resulting in improved condom use by HR-MSM with their regular and commercial male partners. Declining STI prevalence and stable HIV prevalence reflect the positive effects of the prevention strategy. Outcomes from the program logic model indiacte the effectiveness of the program for HR-MSM and TGs in Tamil Nadu

Goldilocks Zone of Ictal Onset: Partially Recovered Synapses Provide the Kindling to Fuel Ictal Activity.

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Goldilocks Zone of Ictal Onset: Partially Recovered Synapses Provide the Kindling to Fuel Ictal Activity

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Goldilocks Zone of Ictal Onset: Partially Recovered Synapses Provide the Kindling to Fuel Ictal Activity.

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Recurrent tracheal tumor with a critical airway requiring ‘Y’ stent – unique presentation of tuberculosis

Tracheal tumor is a rare entity. Tracheal tumor may be a primary tracheal tumor or secondary to invasion from a mediastinal tumor (or a lymph node). These tumors are prone to cause critical airway obstruction which may require urgent care. Tuberculosis is one of the common differential diagnoses of mediastinal lymphadenopathy in TB endemic countries, though isolated tuberculous mediastinal lymphadenopathy without a lung involvement is rare. We report an extremely rare case of isolated paratracheal lymphadenitis due to tuberculosis, eroding the trachea and presented a lower tracheal tumor, which recurred again after complete debulking. Finally, the disease required a ‘Y’ stent placement, to stabilize the airway following the second recanalization. We discuss the incidence, differential diagnosis, and the bronchoscopic, interventional aspects of this entity.</jats:p