Conscious neurosensory mapping of the internal structures of the human knee without intraarticular anesthesia

The conscious neurosensory characteristics of the internal components of the human knee were documented by instrumented arthroscopic palpation without intraarticular anesthesia. With only local anesthesia injected at the portal sites, the first author (SFD) had both knees inspected arthroscopically. Subjectively, he graded the sensation from no sensation (0) to severe pain (4), with a modifier of either accurate spatial localization (A) or poor spatial localization (B). The nature of the intraarticular sensation was variable, ranging from 0 on the patellar articular cartilage to 4A on the anterior synovium, fat pad, and joint capsule. The sensation arising from the cruciate ligaments ranged from 1 to 2B in the midportion, and from 3 to 4B at the insertion sites. The sensation from the meniscal cartilages ranged from 1B on the inner rim to 3B near the capsular margin. Innervation of most intraarticular components of the knee is probably crucial for tissue homeostasis. Failure of current intraarticular soft tissue reconstructions of the knee may be due, in part, to the lack of neurosensory restoration. Research studies of the knee designed to delineate factors that restore neurosensory characteristics of the musculoskeletal system may lead to techniques that result in true restoration of joint homeostasis and function.     

CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS)

BACKGROUND: The rate of progression to AIDS varies among individuals infected with HIV-1. Factors responsible include two inherited human alleles, CCR5 delta32 and CCR2-641, which alter the protein-coding regions for the HIV-1 coreceptors/chemokine receptors CCR5 and CCR2b. We tested the hypothesis that polymorphisms of the CCR5 promoter might affect the rate of progression of HIV-1 infected people to AIDS. METHODS: We used directed heteroduplex analysis to identify polymorphism in the CCR5 promoter. Promoter-variants were compared in vitro with a chloramphenicol acetyltransferase reporter gene, and in vivo by genotyping HIV-1 seroconvertors discordant at polymorphous loci. FINDINGS: An A/G polymorphism was identified at basepair 59029 (Genbank U95626) in the CCR5 promoter. Both promoter alleles were common (43-68% allelic frequency for 59029-A depending on race). When in-vitro promoter activity was measured, 59029-G had 45% lower activity than 59029-A (p=0.05). In a cohort of HIV-1 seroconvertors lacking both CCR5 delta32 and CCR2-641, 59029-G/G individuals progressed to AIDS on average 3.8 years more slowly than 59029-A/A individuals (p=0.004). 59029-G/A discordance did not correlate with discordant rates of infection. INTERPRETATION: Our results are consistent with the hypothesis that CCR5 is important in HIV-1 pathogenesis. CCR5 59029-G/G appears to be protective relative to CCR5 59029-A/A, and about twice as protective relative to CCR5 delta32 or CCR2-641. This effect may be the result of reduced CCR5 mRNA production. These results identify the first site in the CCR5 promoter that may be a useful target for treatment of HIV-1 infection.     

Local GABA circuit control of experience-dependent plasticity in developing visual cortex

Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.