Neurotrophin receptor p75 mediates the uptake of the amyloid beta (Aβ) peptide,guiding it to lysosomes for degradation in basal forebrain cholinergic neurons

A fascinating yet perhaps overlooked trait of the p75 neurotrophin receptor (p75^NTR) is its ability to bind ligands with no obvious neurotrophic function. Using cultured basal forebrain (BF) neurons, this study demonstrates selective internalization of amyloid β (Aβ) 1–42 in conjunction with p75^NTR (labelled with IgG192-Cy3) by cholinergic cells. Active under resting conditions, this process was enhanced by high K⁺ stimulation and was insensitive to inhibitors of regulated synaptic activity—tetrodotoxin or botulinum neurotoxins (BoNT type/A and/B). Blockade of sarco-endoplasmic reticulum (SERCA) Ca²⁺ ATPase with thapsigargin and CPA or chelation of Ca²⁺ with EGTA-AM strongly suppressed the endocytosis of p75^NTR, implicating the role of ER released Ca²⁺. The uptake of IgG192-Cy3 was also reduced by T-type Ca²⁺ channel blocker mibefradil but not Cd²⁺, an indiscriminate blocker of high voltage-activated Ca²⁺ currents. A strong co-localization of IgG192-Cy3 with late endosome (Rab7) or lysosome (Lamp1) qualifier proteins suggest these compartments as the primary destination for internalized IgG192 and Aβ. Selective uptake and labeling of BF cholinergic cells with IgG192-Cy3 injected into the prefrontal cortex was verified also in vivo. The significance of these findings in relation to Aβ clearance in the cerebral cortex and pathophysiology of Alzheimer’s disease is discussed.     

Active immunization with recombinant V antigen from Yersinia pestis protects mice against plague.

The gene encoding V antigen from Yersinia pestis was cloned into the plasmid expression vector pGEX-5X-2. When electroporated into Escherichia coli JM109, the recombinant expressed V antigen as a stable fusion protein with glutathione S-transferase. The glutathione S-transferase-V fusion protein was isolated from recombinant E. coli and cleaved with factor Xa to yield purified V antigen as a stable product. Recombinant V antigen was inoculated intraperitoneally into mice and shown to induce a protective immune response against a subcutaneous challenge with 3.74 x 10(6) CFU of virulent Y. pestis. Protection correlated with the induction of a high titer of serum antibodies and a T-cell response specific for recombinant V antigen. These results indicate that V antigen should be a major component of an improved vaccine for plague.     

J USTIFICATION OF P ULSE O XIMETER C OSTS FOR P ARAMEDIC P REHOSPITAL P ROVIDERS

Objective. To assess the potential cost savings of decreasing prehospital oxygen utilization by using pulse oximetry to identify those patients who do not require supplemental oxygen. Methods. A prospective, controlled trial was performed comparing rates of oxygen utilization by paramedics with and without access to pulse oximetry. Consecutive patient encounters over a ten-week period were randomized by day of presentation. Pulse oximeters were made available on alternate days. On those days, patients whose oxygen saturations were less than 95% were treated with supplemental oxygen. Results. The use of pulse oximeters incurred a saving of 0.14 “D”-size oxygen cylinders per call. For the authors' service, this translates to a potential saving of $2,324 (C)/vehicle/year. Conclusion. For regions with patient demographics similar to the authors', the initial cost of providing paramedics with pulse oximeters may be offset by savings in oxygen consumption. A formula is provided to allow individual ambulance services to calculate the potential savings for their service.     

Estimating the incidence of first unprovoked seizure and newly diagnosed epilepsy in the low-income urban community of Northern Manhattan, New York City

Purpose : To estimate the incidence and mortality associated with first unprovoked seizure or newly diagnosed epilepsy in a low-income, predominantly Hispanic community in Northern Manhattan, New York City.
Methods : We performed a population-based study to determine the incidence of first unprovoked seizure or newly diagnosed epilepsy. Participants were Northern Manhattan residents seen at area hospitals and nursing homes between 2003 and 2005. Cumulative probability of mortality and standardized mortality ratios (SMRs) were also calculated.
Results : Among 209 incident cases identified, 123 (58.9%) presented with an incident single unprovoked seizure. A total of 138 (66.0%) participants were Hispanic and 94 (45.0%) had a median household income under $15,000/year. The overall age and sex-adjusted incidence of all unprovoked seizures was 41.1 (95%CI = 35.4–46.8) per 100,000 person-years. Higher incidence was observed in low-income groups. Incidence among Hispanics was similar to that of non-Hispanic whites and non-Hispanic blacks. The cumulative probability of mortality was 17% (95%CI = 12–24%) by 3 years after diagnosis and was significantly greater in females and in those with an identified etiology. SMRs were significantly increased for all groups with respect to age, Hispanic ethnicity, middle and high income, partial seizure type, and remote symptomatic etiology. Idiopathic/cryptogenic and progressive symptomatic etiologies, low income, gender, and non-Hispanic ethnicity were not associated with a significantly increased SMR.
Conclusion : Incidence of first unprovoked seizure or newly diagnosed epilepsy did not differ by race-ethnicity. Although lower income was associated with higher incidence, higher income was associated with an increased SMR. Future research should examine reasons for differential incidence by income.     

The liver in infectious mononucleosis

Summary 1. Twenty-two patients with infectious mononucleosis were studied by liver biopsy and paper electrophoresis of the serum proteins. The findings were compared with a similar group of 30 patients with infectious hepatitis.2. The essential histologic features of infectious mononucleosis were the presence in the hepatic sinusoids and portal tracts of chronic inflammatory cells resembling small lymphocytes, with essentially no parenchymal cell damage. Admixed with this lymphocytic infiltrate, but in relatively minimal numbers, were a few plasma cells and polymorphonuclear leukocytes. In addition, in infectious mononucleosis there were, with rare exceptions, no lipochrome-containing Kupffer cells. Thus, in the majority of cases, the histologic picture was distinct from that seen in infectious hepatitis. Only in comparing a few of the more severe infectious mononucleosis cases with subsiding infectious hepatitis cases was there any tendency for the two pictures to merge, and the distinction on histologic grounds between the two entities could be made in the great majority of cases.3. The most commonly seen abnormalities in the paper electrophoretic patterns of sera obtained from patients with infectious mononucleosis were decreased albumin, increased gamma globulin, not infrequent but variable changes in alpha₂ globulin, and the presence of abnormal proteins migrating with mobilities intermediate to alpha₂ and beta, and beta and gamma globulins. The abnormalities observed in infectious hepatitis were similar to those of infectious mononucleosis, except that in hepatitis alpha₂ globulin was decreased more consistently, gamma globulin increased less frequently, and beta globulin, which was normal in practically all the cases of infectious mononucleosis, was increased in a considerable number of cases.4. Treatment of patients with infectious mononucleosis need not include prolonged bed rest and restriction of activity in an effort to avoid the development of chronic liver disease.     

Common sense in the treatment of pilonidal disease

Summary The management of pilonidal cyst disease in a large military hospital is described. Of special interest to the military practice is the “buddy” system, in which patients help one another to keep their wounds clean and dry. The specific objectives of our technic are: 1) obtaining excellent hemostasis by the use of zinc peroxide paste; 2) avoiding recurrences by an open-wound method of treatment; 3) preservation of a pad of subcutaneous tissue over the postsacral fascia, thus reducing long-term morbidity by insuring a mobile scar; 4) decreasing the duration of hospitalization, achieved by frequently drying the wounds with warm air. Read at the meeting of the American Proctologic Society, Hollywood, Florida, April 12 to 16, 1970. The opinions or assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Navy Department.     

Profiling penciclovir susceptibility and prevalence of resistance of herpes simplex virus isolates across eleven clinical trials

Summary. A susceptibility testing program was established to determine the prevalence of resistance to penciclovir among herpes simplex virus isolates collected from patients participating in 11 world-wide clinical trials involving penciclovir (topical or intravenous formulations) or famciclovir, the oral prodrug of penciclovir. These trials represented nine randomised double blind, placebo or aciclovir-controlled studies and two open-label studies. Groups surveyed included immunocompetent or immunocompromised patients receiving 2 to 12 months chronic suppressive therapy for genital herpes, immunocompetent patients with recurrent herpes labialis treated for four days, and immunocompromised patients with mucocutaneous herpes simplex virus (HSV). Another subset of patients had been identified as non-responders to aciclovir or to valaciclovir. This program assessed the susceptibility profile for a total of 2145 herpes simplex virus isolates from 913 immunocompetent and 288 immunocompromised patients treated with penciclovir, famciclovir, aciclovir or placebo (depending on trial design). HSV isolates were tested for susceptibility to penciclovir using the plaque reduction assay (PRA) in MRC-5 cells. Resistance was defined as an IC₅₀2.0µg/ml or an IC₅₀>10-fold above the wild type control virus IC₅₀ within that particular assay. Penciclovir-resistant HSV was isolated from 0.22% immunocompetent patients, and 2.1% of immunocompromised patients overall and therefore the frequency of penciclovir-resistant herpes simplex virus in the immunocompetent population approximates that of aciclovir-resistant herpesvirus reported previously. Penciclovir-resistant HSV isolates were more common in isolates from immunocompromised patients, consistent with aciclovir clinical experience. Treatment with penciclovir (intravenous formulation) was associated with the development of resistant HSV in only one severely immunocompromised patient (day 7 isolate IC₅₀=2.01µg/ml), although treatment was effective and resulted in the complete clearance of the lesion by day 8. No patients receiving topical penciclovir developed treatment-associated penciclovir-resistant HSV, and a single immunocompromised patient developed resistant HSV upon treatment with oral famiciclovir.Received October 28, 2002; accepted March 26, 2003 Published online June 5, 2003