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Biomedical subjects

R Gibbons

Publications and source records attributed to R Gibbons.

At least 19 recordsLinked to original sources
PubMed2005

Understanding alpha-globin gene regulation: Aiming to improve the management of thalassemia.

Over the past 50 years, many advances in our understanding of the general principles controlling gene expression during hematopoiesis have come from studying the synthesis of hemoglobin. Discovering how the alpha- and beta-globin genes are normally regulated and documenting the effects of inherited mutations that cause thalassemia have played a major role in establishing our current understanding of how genes are switched on or off in hematopoietic cells. Previously, nearly all mutations causing thalassemia have been found in or around the globin loci, but rare inherited and acquired trans-acting mutations are being found more often. Such mutations have demonstrated new mechanisms underlying human genetic disease. Furthermore, they are revealing new pathways in the regulation of globin gene expression that, in turn, may open up new avenues for improving the management of patients with common types of thalassemia.

Chromosomes, Human, Pair 11↗
PubMed2001

V beta 6+ T cells are obligatory for vaccine-induced immunity to Histoplasma capsulatum.

We examined TCR usage to a protective fragment of heat shock protein 60 from the fungus, Histoplasma capsulatum. Nearly 90% of T cell clones from C57BL/6 mice vaccinated with this protein were Vbeta6+; the remainder were Vbeta14+. Amino acid motifs of the CDR3 region from Vbeta6+ cells were predominantly IxGGG, IGG, or SxxGG, whereas it was uniformly SFSGG for Vbeta14+ clones. Short term T cell lines from Vbeta6+-depleted mice failed to recognize Ag, and no T cell clones could be generated. To determine whether Vbeta6+ cells were functionally important, we eliminated them during vaccination. Depletion of Vbeta6+ cells abrogated protection in vivo and upon adoptive transfer of cells into TCR alphabeta(-/-) mice. Transfer of a Vbeta6+, but not a Vbeta14+, clone into TCR alphabeta(-/-) mice prolonged survival. Cytokine generation by Ag-stimulated splenocytes from immunized mice depleted of Vbeta6+ cells was similar to that of controls. The efficacy of the Vbeta6+ clone was associated with elevated production of IFN-gamma, TNF-alpha, and GM-CSF compared with that of the Vbeta14+ clone. More Vbeta6+ cells were present in lungs and spleens of TCR alphabeta(-/-) on day 3 postinfection compared with Vbeta14+ cells. Thus, a single Vbeta family was essential for vaccine-induced immunity. Moreover, the mechanism by which Vbeta6+ contributed to protective immunity differed between unfractionated splenocytes and T cell clones.

Adoptive Transfer↗
PubMed2001

Penile cancer and human papilloma virus (HPV) in a human immunodeficiency virus (HIV)-infected patient.

Only a handful of cases of penile carcinoma among human immunodeficiency virus (HIV)-infected males have been reported. This is surprising insofar as other anogenital malignancies associated with human papillomavirus (HPV) are over-represented in HIV-infected men and women. Herein we describe the case of an HIV seropositive 64-year-old Caucasian with a CD4+ T-lymphocyte count of 550 cells/mm3 and an invasive squamous cell cancer of the penis. He underwent radical penectomy to treat cancer initially confined to the penile shaft and glans penis, but ultimately succumbed to complications associated with metastatic disease. HPV type 18 was identified by in situ hybridization and polymerase chain reaction (PCR) studies in the primary tumor and in groin and lung metastasis. We also briefly review current thoughts regarding the epidemiology and pathogenesis of penile cancer, particularly in the setting of HPV and HIV co-infection.

Carcinoma, Squamous Cell↗
PubMed2001

Protective efficacy of H antigen from Histoplasma capsulatum in a murine model of pulmonary histoplasmosis.

We previously reported that immunization with H antigen from Histoplasma capsulatum did not protect mice against an intravenous challenge with yeasts. Here, we investigated the utility of H antigen to protect mice in a model of pulmonary histoplasmosis. Mice immunized with H antigen and challenged intranasally 4 weeks postvaccination were protected against sublethal and lethal challenges with H. capsulatum yeasts. If the challenge was performed 3 months after vaccination, there was a reduction in fungal burden following sublethal challenge and a modest delay in mortality in mice given a lethal inoculum. Vaccination was associated with production of gamma interferon, granulocyte-macrophage colony-stimulating factor, interleukin-4, and interleukin-10 by splenocytes. Vaccination with H antigen was not accompanied by a major expansion of CD4(+) or CD8(+) cells in spleens of mice. These results demonstrate that H antigen may be useful as a protective immunogen against pulmonary exposure to H. capsulatum.

Animals↗
PubMed2001

A longitudinal subspecialty experience for internal medicine residents.

OBJECTIVE: Market and technology innovations have greatly changed the teaching and practice of medicine in the past 10 years. This report describes an innovation in the ambulatory education of internal medicine residents: a subspecialty continuity clinic. METHODS: A subspecialty continuity clinic was developed to improve the training of internal medicine residents in caring for complex ambulatory patients. The clinic structure is discussed from the perspective of patients, residents, and subspecialists. Logistical challenges and solutions are described. RESULTS: Two and one-half years into the program, feedback from residents and subspecialists has been positive. In-training examination scores are relatively higher in the involved specialties, and residents are managing illnesses they rarely saw in an outpatient setting before this program. CONCLUSION: This experience suggests that a subspecialty continuity clinic is worthwhile and practical in educating primary care residents.

Ambulatory Care↗
PubMed2000

Recombinant murine granulocyte-macrophage colony-stimulating factor modulates the course of pulmonary histoplasmosis in immunocompetent and immunodeficient mice.

Several endogenous cytokines, including granulocyte-macrophage colony-stimulating factor (GM-CSF), are necessary for eliminating Histoplasma capsulatum from tissues. In this study, we explored the efficacy of recombinant murine GM-CSF in the treatment of pulmonary histoplasmosis. This cytokine significantly reduced fungal burden in a dose-dependent manner. Pretreatment did not consistently produce a better result than treatment started after infection. The biological effectiveness of GM-CSF was not associated with modulation of lung cytokine production or alteration in lung inflammation, but it directly activated a nonadherent lung cell population to exert anti-Histoplasma activity. GM-CSF improved survival of T-cell-depleted mice exposed to H. capsulatum. When combined with a suboptimal amount of amphotericin B, GM-CSF enhanced survival of normal or T-cell-depleted mice given a lethal challenge. These results suggest that this cytokine may be useful as an adjunctive treatment for histoplasmosis.

Amphotericin B↗
PubMed1999

Neutralization of endogenous granulocyte-macrophage colony-stimulating factor subverts the protective immune response to Histoplasma capsulatum.

We examined the influence of endogenous GM-CSF on the course of primary and secondary pulmonary histoplasmosis. A high proportion (>/=75%) of C57BL/6 mice given mAb to GM-CSF did not survive primary infection, whereas 88-94% of infected controls survived. Analysis of leukocytes revealed significantly fewer CD4+ and CD8+ cells in lungs, but not airways, of anti-GM-CSF-treated mice as compared with infected controls. However, the histopathology was similar between the two groups. Lungs of mice given mAb to GM-CSF manifested depressed levels of TNF-alpha, IFN-gamma, and reactive nitrogen intermediates and elevated levels of IL-4 and IL-10. Administration of mAb to IL-4, to IL-10, or both restored protective immunity in GM-CSF-neutralized mice. In secondary infection, administration of mAb to GM-CSF exacerbated infection but did not alter survival over 30 days. The character of the inflammatory response was similar, and no differences were detected in Th1 or Th2 cytokine production between the two groups. Thus, endogenous GM-CSF is essential for survival in primary but not secondary infection, and blockade perturbs protective immunity. These findings reveal a new mechanism whereby GM-CSF contributes to host protection and demonstrate differences in control of primary and secondary histoplasmosis.

Administration, Intranasal↗
PubMed1999

The URA5 gene is necessary for histoplasma capsulatum growth during infection of mouse and human cells.

The Histoplasma capsulatum URA5 gene, which has recently been cloned and disrupted by allelic replacement, encodes orotidine-5'-monophosphate pyrophosphorylase. Inactivation of URA5 by either targeted or UV mutagenesis results in disruption of the pyrimidine biosynthetic pathway and uracil auxotrophy. We examined the effect of uracil auxotrophy due to a ura5 mutation on H. capsulatum virulence in both cell culture and whole-animal models. Uracil auxotrophs of two H. capsulatum restriction fragment length polymorphism classes were found to be avirulent in cultured murine and human cells, as well as in mice. Moreover, virulence could be restored either by supplying a functional URA5 gene in trans or by supplying exogenous uracil during infection in vitro. These experiments demonstrate that the pyrimidine biosynthetic pathway is essential for H. capsulatum growth and virulence.

Animals↗
PubMed1999

Treatment outcomes for female octogenarians with breast cancer.

Scant information is available comparing the treatment outcomes of minor surgery (lumpectomy) versus extensive treatment (radical and simple mastectomy or lumpectomy and radiation) in octogenarians with breast cancer. Medical records of women (ages 80-89) who received treatment for breast cancer from 1984 through 1994 were reviewed. All patients were stage T1 or T2, and none had palpable lymph nodes. The recurrence rate, disease-free interval, and death rate for both groups were compared. Of the 41 patients representing 43 minor surgeries, 12 per cent (5 of 41) of patients developed recurrence, all of which were related to the primary breast tumor. The mean disease-free interval was 28.6 +/- 24.7 months (range, 6-65). Forty-six per cent (18 of 39) of patients died, 10 per cent (4 of 39) from recurrence and metastatic disease from breast cancer and 36 per cent (14 of 39) from other causes. Of those who underwent extensive treatment, 14.6 per cent (7 of 48) of patients experienced recurrence, all related to the primary breast tumor. The mean disease-free interval was 24.0 +/- 21.9 months (range, 2-71). Forty-eight per cent (23 of 48) of patients died, 10 per cent (5 of 48) from recurrence and metastatic disease from breast cancer and 37 per cent (18 of 48) from other causes. None of the differences between the minor surgery versus extensive treatment groups were statistically significant. The recurrence rate, disease-free interval, and death rate from recurrent disease are similar for patients undergoing minor surgery compared with those undergoing extensive treatment.

Aged↗
PubMed1998

Vbeta4(+) T cells promote clearance of infection in murine pulmonary histoplasmosis.

T cells are essential for controlling infection with Histoplasma capsulatum. Because the T cell receptor is vital for transducing the biological activities of these cells, we sought to determine if exposure to this fungus induced an alteration in the Vbeta repertoire in lungs of C57BL/6 mice infected intranasally. Vbeta2(+) cells were elevated on day 3 after infection; Vbeta4(+) cells were higher than controls on days 7, 10, and 14 after infection. Vbeta10(+) cells were increased on days 14 and 21, and Vbeta11(+) exceeded controls only on day 14. We investigated the clonality and function of Vbeta4(+) cells because their expansion transpired during the critical time of infection, that is, when cellular immunity is activated. Sequence analysis demonstrated preferential use of a restricted set of sequences in the complementarity-determining region 3. Elimination of Vbeta4(+) cells from mice impaired their ability to resolve infection. In contrast, depletion of Vbeta7(+) cells, the abundance of which was similar to that of Vbeta4(+), did not alter elimination of the fungus. The identification of clonotypes of Vbeta4(+) cells suggests that a few antigenic determinants may drive proliferation of this subset, which is necessary for optimal clearance.

Amino Acid Sequence↗
PubMed1998

Testimony psychotherapy in Bosnian refugees: a pilot study.

OBJECTIVE: The authors sought to describe the use of the testimony method of psychotherapy in a group of traumatized adult refugees from genocide in Bosnia-Herzegovina. METHOD: The subjects were 20 Bosnian refugees in Chicago who gave written informed consent to participate in a case series study of testimony psychotherapy. All subjects received testimony psychotherapy, averaging six sessions, approximately 90 minutes, weekly or biweekly. Subjects received standardized instruments for posttraumatic stress disorder (PTSD), depression, traumatic events, global functioning, and prior psychiatric history. The instruments were administered before treatment, at the conclusion of the treatment, and at the 2- and 6-month follow-ups. RESULTS: The posttreatment assessments demonstrated significant decreases in the rate of PTSD diagnosis, PTSD symptom severity, and the severity of reexperiencing, avoidance, and hyperarousal symptom clusters. Depressive symptoms demonstrated a significant decrease, and there was a significant increase in scores on the Global Assessment of Functioning Scale. Two-month and 6-month follow-up assessments demonstrated further significant decreases in all symptoms and an increase in scores on the Global Assessment of Functioning Scale. CONCLUSIONS: This pilot study provides preliminary evidence that testimony psychotherapy may lead to improvements in PTSD and depressive symptoms, as well as to improvement of functioning, in survivors of state-sponsored violence.

Adult↗
PubMed1997

The effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia. A meta-analysis.

BACKGROUND: Herpes zoster is a common affliction in older patients, with up to 15% experiencing some residual pain in the distribution of the rash several months after healing. Despite numerous randomized clinical trials, the effect of treating herpes zoster with oral acyclovir in preventing postherpetic neuralgia remains uncertain because of conflicting results. METHODS: Meta-analysis of published randomized clinical trials on the use of acyclovir to prevent postherpetic neuralgia using the fixed-effects model of Peto. RESULTS: Thirty clinical trials of treatment with oral acyclovir in immunocompetent adults were identified. After excluding studies with duplicate data, suboptimal and topical dosing, non-placebo-controlled or nonrandomized designs, and those using intravenous acyclovir, 5 trials were found to be homogeneous and were combined for analysis. From these trials, the summary odds ratio for the incidence of "any pain" in the distribution of rash at 6 months in adults treated with acyclovir was 0.54 (95% confidence interval, 0.36-0.81). CONCLUSION: Treatment of herpes zoster with 800 mg/d of oral acyclovir within 72 hours of rash onset may reduce the incidence of residual pain at 6 months by 46% in immunocompetent adults.

Acyclovir↗
PubMed1996

A protective domain of heat-shock protein 60 from Histoplasma capsulatum.

Vaccination with recombinant (r) hsp60 protects mice against Histoplasma capsulatum. To map the domain of rhsp60 that confers protection, four gene segments were cloned into pET19b and expressed in Escherichia coli. rhsp60 fragments were tested for their capacity to induce proliferation by sensitized splenocytes and to protect BALB/c and C57BL/6 mice. All polypeptides stimulated cells from BALB/c mice immunized with yeasts or with rhsp60. Fragment 3 caused the most vigorous response by cells from mice immunized yeasts, and fragment 1 caused the most vigorous response by cells from mice immunized with rhsp60. Splenocytes from yeast-immunized C57BL/6 mice did not recognize any polypeptide. In contrast, cells from C57BL/6 mice inoculated with rhsp60 responded to all fragments but most intensely to fragment 2. In both strains, fragment 3 conferred protection against sublethal and lethal challenges. Thus, a common protective domain of hsp60 has been identified.

Animals↗
PubMed1996

Human recombinant transforming growth factor-beta 1 in healing of calvarial bone defects.

Bone healing plays an important role in orthognathic and craniofacial surgery. Bone tissue repair and regeneration are regulated by an array of growth and morphogenetic factors. Osteogenesis proceeds through a cascade of molecular and cellular events sequentially coordinated by members of both the bone morphogenetic protein and transforming growth factor-beta (TGF-beta) families. The efficacy of a single application of 2, 5, or 10 micrograms of recombinant human (rh) TGF-beta 1 to promote bone regeneration in 5-mm experimental calvarial defects of adult male rats was assessed histologically and histomorphometrically. The histomorphometric results of the experimental site were compared with those of the contralateral control side. Dosegroup comparisons were also performed. None of the control and experimental bone defects demonstrated complete bone closure. Limited bone regeneration was found close to the margins of the defects. A statistically significant difference in volume fraction composition (bone, osteoid, and soft tissue) was found between the 5- and 10-microgram rhTGF-beta 1-implanted and control defects. No difference was found in the 2-microgram rhTGF-beta 1-implanted group. The percentage of bone closure was statistically significantly higher in the 5-microgram rhTGF-beta 1-implanted group than in the control group. The present findings indicate that a single application of different doses of rhTGF-beta 1 does not promote clinically relevant osteogenesis in membranous calvarial bone defects in adult rats.

Animals↗
PubMed1995

Age-related bone loss. A hypothesis and initial assessment in mice.

The osteopenia associated with advanced age appears to be a universal phenomenon in humans and animals, but the mechanisms by which it occurs are understood incompletely. However, the explanation must lie in an absolute or relative diminution in the level of osteoblastic bone-forming activity when compared with osteoclastic bone-resorbing activity. The authors postulated that with old age there would be a reduction in the number or function or both of osteoblastic stem cells that could account for part of the diminution in bone formation. They further postulated that there would be either no change or an increase in osteoclastic potential and bone resorption. To test these concepts, bone marrow cells were isolated from 4- to 6-month-old or 24-month-old mice and cultured in vitro under a variety of circumstances that permitted an assessment of the stromal osteogenic cells and marrow hemopoietic progenitor cells belonging to the monocyte and osteoclast series. These data show a marked reduction in the number and in vitro activity of stromal osteogenic cells from old animals. There is an increase in old mice in the number of marrow cells capable of forming osteoclasts in coculture and responsive to the growth factors believed operational in the monocyte and osteoclast series. The authors now are exploring the hypothesis that an age-related diminution in transforming growth factor-beta levels is responsible for these changes in progenitor cell levels in marrow and their functional status as expressed in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗