Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy.
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Biomedical subjects
Publications and source records attributed to B Goldberg.
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Despite extensive and costly efforts, attempts to develop a vaccine against human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), have been unsuccessful. Using the Maginot Line as a metaphor, we discuss the reasons why an antibody-based vaccine strategy against HIV has failed. The concept of a vaccine that exclusively promotes cell-mediated immunity against the virus is outlined, and important factors in the formulation of this novel vaccine are delineated. In particular, vaccine adjuvants and HIV peptides that elicit a cell-mediated immune response are crucial components of this immunization strategy. Examination of primate immune systems that resist retroviral pathogenicity will also play an important role in the development of a successful AIDS vaccine.
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African trypanosomes are pathogens of humans and livestock in equatorial Africa. There is a great deal of resistance to present front line drugs for treating African trypanosomiasis such as melarsoprol (Arsobal) and pentamidine. In the search for new and novel drugs against this disease, we have found a unique transporter of S-adenosylmethionine (AdoMet), a metabolite used in transmethylation reactions and polyamine synthesis. This transporter is distinct from those for methionine and adenosine, since AdoMet uptake was not inhibited by trypanocidal drugs, which compete with adenosine for transport. AdoMet analogs competing with [methyl-3H]AdoMet for uptake required a positively charged sulfonium group on the 5' position of the ribose. Since transport of AdoMet does not normally occur to a significant extent in mammalian cells, the parasite transporter provides a selective and novel route to deliver new chemotherapeutic agents against these organisms.
5'-Deoxy-5'-(methylthio)adenosine (MTA), a key by-product of polyamine biosynthesis, is cleaved by MTA phosphorylase and is salvaged as adenine and, through conversion of the ribose moiety, methionine. An analog of MTA, 5'-deoxy-5'-(hydroxyethylthio)adenosine (HETA), is a substrate for trypanosome MTA phosphorylase and is active in vitro and in vivo against Trypanosoma brucei brucei, an agent of bovine trypanosomiasis. In this study, HETA and three O-acylated HETA derivatives were examined for their activities against model infections of T. b. brucei and Trypanosoma brucei rhodesiense, the agent of East African sleeping sickness. HETA was curative (>60%) for infections caused by 5 of 11 clinical isolates of T. b. rhodesiense when it was given to mice at 200 mg/kg of body weight for 7 days as a continuous infusion in osmotic pumps. HETA at 150 to 200 mg/kg also extended the life spans of the mice infected with four additional isolates two- to fivefold. Di- and tri-O-acetylated derivatives of HETA also proved curative for the infections, while a tri-O-propionyl derivative, although also curative, was not as effective. This study indicates that substrate analogs of MTA should be given important consideration for development as novel chemotherapies against African trypanosomiasis.
Anterior knee pain represents one of the most common musculoskeletal complaints of adolescents. It is a disorder in which there is broad clinical experience and yet it represents a difficult and frustrating entity for the athlete to endure and for the physician to treat. An appropriate clinical examination and selected diagnostic studies can define the diagnosis and the introduction of conservative therapy usually will correct the problem. Occasionally, surgical intervention is required, and debate remains as to the optimal techniques that should be used.
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Recombinant human granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in patients with cancer and HIV disease. Since lymphocyte counts have been reported to increase with G-CSF therapy, we studied the effect of G-CSF on lymphocyte subsets in HIV-infected patients. Six patients with HIV-associated neutropenia were treated with G-CSF and had significant increases in white blood cell counts. G-CSF induced a significant rise in total lymphocytes, total T-cells, CD8 T-cells, and natural killer cells. A smaller but statistically significant increase in CD4 T-cells and cytotoxic CD8 T-cells was also noted. We conclude that G-CSF has the ability to raise lymphocyte subset levels in patients with HIV disease. The potential immunologic benefit of G-CSF therapy merits further investigation.
Endoluminal ultrasound imaging of the ureter can demonstrate the periureteral anatomy. Ultrasound probes are available as catheters from 3.5F to 6.2F. The transducer is available as a 12.5 or 20 MHz design and gives a cross-sectional image with penetration of 1.5 to 2 cm. Endoureteral ultrasonography has demonstrated blood vessels associated with the obstructed ureteropelvic junction (UPJ) in more than 50% of patients. These vessels have been located at all sites adjacent to the UPJ. The anteromedial location is the most common site. In comparison, only 8 significant crossing vessels were found in 44 patients with a normal UPJ. Inspection of the UPJ with a high insertion of the ureter demonstrates a characteristic sonographic image with a septum between the ureteral and renal pelvic lumen. Endoluminal ultrasonography of the obstructed UPJ can be used to guide the site of endopyelotomy to avoid damage to adjacent vessels. The presence of such vessels may also be related to the success of the procedure. An ultrasound-guided cutting device has been developed for preclinical studies.
To determine the acute and chronic ultrasonographic and histologic characteristics of injected glutaraldehyde cross-linked collagen in an animal model in order to enhance the therapeutic efficacy of the delivery of collagen for the treatment of urinary incontinence, three different depths of endoluminal ultrasound-guided injection (submucosal, intramuscular, periadventitial) of collagen into the urethral and bladder walls in two Yucatan mini pigs were investigated. The ultrasonographic characteristics of the injected material were examined 1, 4, 8, and 12 weeks later. A separate set of collagen injections, into the dermis and intramuscular layer of the lateral thigh of the animals, was undertaken with small-parts ultrasound guidance and follow-up. The injected tissues of the bladder, urethra, and thigh were ultrasonographically and histologically examined 3 months post-injection. Acutely injected collagen appeared hypoechoic on ultrasonography, although echogenicity increased over time. Submucosally injected collagen remained contained, forming a discrete collection of the material, whereas periadventitially injected collagen dispersed immediately. The ultrasonographic appearance and size of collagen collections correlated directly with their histologic identification and measurement. Injected collagen generated little inflammatory reaction, although infiltration by histiofibroblasts and neovascularization of the injected collagen occurred. Submucosal collagen injection resulted in superior longevity compared with intramuscular injection. From the results of our study, we hypothesize that durable success with collagen injection for the treatment of urinary incontinence is attributable to histiofibroblast infiltration of the injected collagen. When injected collagen is replaced with a hypertrophic scar, long-lasting clinical success is likely. If the injected collagen is replaced with a contracted scar, however, urethral coaptation may not persist. Endoluminal ultrasonography is helpful in ensuring the accurate submucosal location of collagen injection and in avoiding dispersion of the material and should enhance therapeutic efficacy in the treatment of urinary incontinence.
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