PubMed Health⌕ Search

Biomedical subjects

G Whalen

Publications and source records attributed to G Whalen.

At least 19 recordsLinked to original sources
PubMed2001

Practical experience with the Stoppa repair of ventral/incisional hernias.

BACKGROUND: Although there are several surgical techniques to repair ventral/incisional hernias, these recur as often as 50% of the time. We have reviewed our experience with a wide, preperitoneal inlay of a conforming mesh (the Stoppa repair) in the management of more difficult ventral/incisional hernias. METHODS: Retrospective chart review of all patients receiving ventral/incisional hernia repair at our institution between 29 December 1993 and 20 May 1998. Charts were analyzed for prior ventral/incisional hernia repairs, and risk factors for recurrence (morbid obesity, prior mesh infections, and asthma/chronic obstructive pulmonary disease). Follow-up was obtained through outpatient chart reviews and phone calls. RESULTS: There were 76 repairs in 67 patients. The mean length of hospital stay was 5.08 days (4.38 days primary, 5.3 days mesh, 5.5 days Stoppa). The mean length of operation time was 164 minutes (131 minutes primary, 141 minutes mesh, 231 minutes Stoppa). Forty-one percent of the patients who underwent a Stoppa repair had one or more risk factors for recurrence and 50% (mean of 1.9 prior repairs per patient) of the patients had prior repairs, compared to 26% and 36% (mean of 1.4 prior repairs per patient) for mesh patch repairs, and 33% and 21% (mean of 1 prior repair per patient) for primary repairs. The crude recurrence rates were 43.5% for primary repairs, 19.2% for mesh repairs, and 18.2% for Stoppa repairs. CONCLUSIONS: The Stoppa repair appears to be an effective technique for particularly complex ventral/incisional hernia repairs. In such repairs it achieves a recurrence rate comparable to that achieved by other mesh techniques for less complex hernias.

Comorbidity↗
PubMed2000

Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome.

Papillary thyroid carcinoma usually is sporadic, but may occur in a familial form. The complete clinical and pathological phenotype of familial papillary thyroid carcinoma (fPTC) has not been determined, and the susceptibility gene(s) is unknown. We investigated the clinical and pathological characteristics of an unusually large three-generation fPTC kindred to characterize more fully the clinical phenotype. We performed linkage analysis to determine the chromosomal location of a fPTC susceptibility gene. In addition to the known association of fPTC with nodular thyroid disease, we observed the otherwise rare entity of papillary renal neoplasia (PRN) in two kindred members, one affected with PTC and the other an obligate carrier. The multifocality of PRN in one subject adds weight to the likelihood of a true genetic predisposition to PRN. Both genetic linkage and sequence analysis excluded MET, the protooncogene of isolated familial PRN, as the cause of the fPTC/PRN phenotype. A genome-wide screening and an investigation of specific candidate genes demonstrated that the fPTC/PRN phenotype was linked to 1q21. A maximum three-point log of likelihood ratio score of 3.58 was observed for markers D1S2343 and D1S2345 and for markers D1S2343 and D1S305. Critical recombination events limited the region of linkage to approximately 20 cM. A distinct inherited tumor syndrome has been characterized as the familial association of papillary thyroid cancer, nodular thyroid disease, and papillary renal neoplasia. The predisposing gene in a large kindred with this syndrome has been mapped to 1q21.

Adult↗
PubMed1999

Familial papillary thyroid carcinoma is genetically distinct from familial adenomatous polyposis coli.

Familial papillary thyroid carcinoma (fPTC) is an inherited tumor syndrome characterized by isolated papillary thyroid carcinoma (PTC) in affected subjects. Its etiology is unknown. Large multigeneration families with PTC are very rare, and therefore, modern genetic linkage studies have not been applied extensively to this disorder. Familial adenomatous polyposis coli (FAP) is an inherited tumor syndrome enriched in PTC. FAP is caused by germline mutations of the adenomatous polyposis coli (APC) gene that is located in the 5q21 region. It is not known if fPTC is a phenotypic variant of FAP, or if it is a genetically distinct disorder. We report a large 3-generation fPTC kindred and use linkage analysis to test the hypothesis that fPTC and FAP are genetically distinct. In this kindred there are 25 living informative subjects; 5 have PTC, and 1 is an obligate carrier. Inheritance is autosomal dominant with incomplete penetrance. There is vertical transmission, multifocal disease, an average age of onset of 36 years, and 1 subject has colon cancer. The probability is approximately 1 in 2 billion against the clustering of 5 sporadic PTC cases in this kindred. To test for linkage to the APC gene we used 2 highly polymorphic markers, D5S656 and D5S421, which are located within a maximum distance of 1.7 megabase (Mb) of the APC gene and within an estimated genetic region of less than 1 centimorgan (cM) from each other. After polymerase chain reaction (PCR) amplification 18 family members were genotyped. Construction and inspection of haplotypes showed that the affected subjects do not share the same allelic composition. Using a penetrance ratio of 75%, linkage was excluded at 2 cM and 3 cM on both sides of D5S656 and D5S421, respectively. The combined haplotype of these 2 markers provided an exclusion region of 4 cM. We conclude that fPTC is genetically distinct from FAP.

Adenomatous Polyposis Coli↗
PubMed1994

Differential expression of a novel protein kinase in human B lymphocytes. Preferential localization in the germinal center.

B lymphocytes which reside in the germinal center region of lymphoid follicles are functionally and phenotypically distinct from the surrounding mantle zone B cells. We have isolated cDNA clones for several genes that are differentially expressed between these two populations of B lymphocytes. One such gene, BL44, is preferentially expressed in germinal center B cells. The nucleotide sequence of a 2,874-base pair BL44 cDNA was determined and a 2,451-bp open reading frame found that encodes for a 97-kDa serine/threonine protein kinase referred to as GC kinase. It has an NH2-terminal catalytic domain most similar to that of the Drosophila NinaC protein and the yeast STE20 protein. GC kinase mRNA transcripts are not unique to germinal center B cells and are found in several other tissues, including brain, lung, and placenta. The GC kinase protein was immunoprecipitated from transfected COS cells and from the Burkitt cell line RAMOS. GC kinase immunoprecipitated from transfected COS cells phosphorylated the substrates casein and myelin basic protein. In addition, a 97-kDa phosphoprotein likely to be GC kinase itself was detected. GC kinase may participate in an important signal transduction pathway in germinal center B cells.

3T3 Cells↗
PubMed1990

Natural killer cell-mediated lysis of Mycobacterium-avium complex-infected monocytes.

Since the precise mechanism of host responses to infection with Mycobacterium-avium complex (MAC) is unclear and since cytotoxic lymphocytes may be involved in the destruction of cells infected with intracellular pathogens, we investigated the ability of normal peripheral blood lymphocytes to kill MAC-infected monocytes in a short-term isotope release assay. Nylon wool-passed lymphocytes lysed MAC-infected but not uninfected monocytes during a 4-hr assay. Infected monocytes were less sensitive to cell-mediated killing than the standard natural killer (NK) cell-sensitive cell line K562, although the kinetics of lysis were similar. The release of lymphocyte-derived mediators such as tumor necrosis factor, interleukin-2 (IL-2), and interferon-alpha and -gamma could not be implicated as a cause of monocyte death. Through the use of cell-specific monoclonal antibodies plus complement, the phenotype of the effector cell was that of an NK cell (CD3 negative, partially CD8 negative, and CD16 positive). The use of highly purified, negatively selected NK cells confirmed these results. NK cell-mediated lysis of infected monocytes decreased MAC viability, indicating that this cytotoxic activity would not favor dissemination of the organism. The killing of MAC-infected monocytes was reduced by K562 cells, suggesting that these targets shared common recognition/binding structures. These results suggest that NK-cell function may be important in the prevention of or response to MAC infection and may help explain the predilection of AIDS patients to develop widespread disease.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Modulation of suppression of mitogen-induced T cell-dependent B cell responses by natural killer cells.

We examined the ability of human natural killer (NK) cells to modualte pokeweed mitogen (PWM)-induced polyclonal antibody production. Highly purified NK cells inhibited plaque-forming cell (PFC) responses and this suppression could be substantially increased by preincubation of NK cells with the known enhancers of NK cell lytic activity, interferon (IFN)-alpha, IFN-gamma, and interleukin-2. Additionally, costimulation of NK cells with two anti-CD2 antibodies (9-1 and 9.6), which recognize different epitopes on the CD2 molecule, also augmented the inhibitory effect. When subpopulations of NK cells were assayed for suppressor cell activity, this activity was primarily mediated by NK cells bearing Leu-7 but not Leu-2 (CD8) antigens. Thus, alteration of NK cell lytic activity may have significant effects on the immunoregulatory functions of these cells, which may have important implications for the in vivo manipulation of cytotoxic responses.

Antibodies, Monoclonal↗
PubMed1989

Natural killer cells can enhance the proliferative responses of B lymphocytes.

In addition to lytic activity against malignant and virally transformed target cells, recent evidence has suggested that natural killer (NK) cells can modulate immune activities such as the suppression of B cell responses through noncytotoxic means. Using human B cells and highly purified autologous NK cells, we have demonstrated that NK cells can substantially augment the proliferative responses of B cells stimulated with the surface immunoglobulin crosslinking agents anti-IgM or Staphylococcus aureus Cowan strain I (SAC). This "enhancer" activity of NK cells was quite potent and was observed at an NK:B cell ratio as low as 0.05. Peak blastogenic responses of B cells cocultured with NK cells in the presence of B cell activators were observed at 2-3 days, similar to the responses of B cells in the absence of NK cells. Using the inhibitor of DNA synthesis mitomycin C, we determined that B cells and not NK cells were proliferating in cocultures of these lymphocytes stimulated with SAC. Activated B cells neither prevented the lysis of the isotope-labeled NK-sensitive target cell line K562 nor formed conjugates with NK cells, suggesting that cell contact was not a prerequisite for the effect. These studies have further expanded the functional repertoire of NK cells to include enhancer as well as suppressor and lytic activities.

Antibodies, Anti-Idiotypic↗
PubMed1989

Suppression of B cell responses by natural killer cells is mediated through direct effects on T cells.

We examined the ability of human natural killer (NK) cells to modulate T cell-dependent mitogen-induced B cell responses. Highly purified NK cells inhibited the polyclonal antibody responses of autologous pokeweed mitogen (PWM)-stimulated unfractionated mononuclear cells in a reverse hemolytic plaque-forming cell (PFC) assay. Investigation of the possible mechanism(s) of the suppressor activity of NK cells revealed that lysis of mitogen-stimulated cells was unlikely. Chromium-51 release cytotoxicity assays of PWM-stimulated mononuclear cells did not demonstrate lysis by NK cells. Additionally, the monoclonal antibody 13.3, which abrogates NK cell cytolysis, did not reverse NK cell-dependent suppression of PFC formation. The putative lytic molecule elaborated by NK cells, NK cytotoxic factor, did not suppress B cell responses, further supporting a nonlytic inhibitory mechanism. That NK cell-derived lymphokines such as IFN-alpha, IFN-gamma, or IL-2 were uninvolved in the down-regulation of B cells was corroborated by the failure of antibodies to these mediators to reverse the suppression. NK cells did not suppress PFC formation when T cells were replaced by supernatants from PWM-stimulated T cells; additionally, NK cells had no effect on the generation of these necessary T cell factors. However, the coculture of T cells with NK cells resulted in the induction of suppressor activity within the T cell population suggesting that this was the mechanism of NK cell-mediated suppression of B cell responses.

Antibody Formation↗
PubMed1989

The selective management of penetrating wounds of the back.

Fifty patients with penetrating wounds of the back were prospectively evaluated and managed selectively on the basis of physical examination. Despite the theoretic problems of evaluating the retroperitoneum, physical examination was found to be a reliable method of determining the need for laparotomy. Every patient who had a significant injury had evidence for this on initial physical examination and no patient judged to have a normal examination required laparotomy. The negative laparotomy rate was 4% and no patients died as a result of delayed surgical intervention. Careful physical examination and surgical judgment allow for safe management of penetrating back wounds.

Adolescent↗
PubMed1988

Novel interleukin 2 (IL-2) receptor appears to mediate IL-2-induced activation of natural killer cells.

A novel IL-2 receptor, distinct from the Tac protein, has been identified on the surface of purified human natural killer (NK) cells by chemical cross-linking of 125I-IL-2. This protein is approximately 70,000 D in size (p70) and appears to be identical to the recently recognized second subunit of the human high affinity IL-2 receptor complex. Scatchard analysis of 125I-IL-2 binding to purified NK cells revealed approximately 2,300 p70 binding sites per cell with an apparent dissociation constant of 200 pM, a value intermediate between the previously recognized high and low affinity forms of the human IL-2 receptor. The monoclonal anti-Tac antibody did not inhibit the cross-linking of 125I-IL-2 to the p70 binding sites present on NK cells. Functionally, the addition of high concentrations of recombinant IL-2 to the enriched NK cells promoted a rapid augmentation of cytolytic activity and a more delayed increase in cellular proliferation. Anti-Tac effectively blocked the IL-2-induced proliferative response in these cells, but failed to alter the enhancement of cytotoxicity. Analysis of NK cytoplasmic RNA isolated at various time points after IL-2 stimulation revealed the rapid induction of c-myb and Tac gene expression that was also not inhibited by the anti-Tac antibody. These findings suggest that IL-2 binding to the p70 receptor constitutively expressed on the surface of NK cells may mediate both the development of increased cytolytic activity and rapid changes in gene expression. The activation of the Tac gene may in turn permit the formation of the high affinity IL-2 receptor complex (comprised of at least the Tac and p70 proteins) that appears to transduce the requisite signals involved in NK cell proliferation.

Antigens, Surface↗
PubMed1987

Selective effects of cyclophosphamide therapy on activation, proliferation, and differentiation of human B cells.

The immune function of B lymphocytes from 12 patients with nonneoplastic immune-mediated diseases receiving chronic low-dose (2 mg/kg per d) cyclophosphamide (CY) was evaluated. There was a selective and differential suppressive effect of CY therapy on the various stages of the B cell cycle including activation, proliferation, and differentiation. The proliferative responses to Staphylococcus aureus Cowan strain I (SAC) and mitogenic concentrations of anti-mu were suppressed. In contrast, B cells that have been presumably activated in vivo proliferated with a normal pattern when exposed to B cell growth factor in vitro. Chronic low-dose CY therapy also suppressed B cell differentiation. Secretion of immunoglobulin by B cells following in vitro triggering with SAC and a T cell supernatant was suppressed in CY-treated patients. Moreover, differentiation of the large in vivo-activated B cells (which do not require an in vitro activation signal) in the presence of appropriate T lymphocyte supernatant was also suppressed. This selective suppression of B cell function at multiple points in the B cell cycle may be responsible for the efficacy of CY therapy in certain antibody and immune complex-mediated diseases.

Adolescent↗
PubMed1985

Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition.

We studied purified subpopulations of lymphocytes from patients with the acquired immunodeficiency syndrome (AIDS) in order to determine whether intrinsic defects in lymphocyte function, aside from those due to alterations in lymphocyte numbers, were present. Mitogen-stimulated DNA synthesis, production of gamma interferon, production of interleukin-2, and expression of interleukin-2 receptors, although variably decreased in unseparated cell populations, were normal in populations of purified T-cell subsets. In contrast, DNA synthesis in response to the soluble protein antigen tetanus toxoid was decreased in both unseparated and purified T-cell subpopulations. Cell-mixing experiments demonstrated that the hyporesponsiveness of the unfractionated lymphocytes from patients with AIDS was not due to active suppression. We conclude that the lymphocytes of patients with AIDS, although capable of undergoing a normal degree of blast transformation and lymphokine production after mitogenic stimulation, have an intrinsic defect in their ability to recognize and respond to soluble antigen.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Correlation between immunologic function and clinical subpopulations of patients with the acquired immune deficiency syndrome.

The present study was designed to determine whether there was a significant correlation between the clinical presentation of patients with AIDS or AIDS-related illnesses and the degree of their underlying immunologic abnormalities. In 17 patients who presented with opportunistic infections, the mean number of T4 lymphocytes was 34/mm3 and the mean proliferative response to phytohemagglutinin 26,000 cpm; in 12 patients who presented with Kaposi's sarcoma alone, the mean number of T4 cells was 231/mm3 and the mean proliferative response to phytohemagglutinin, 32,809 cpm; and in nine patients with the lymphadenopathy syndrome, the mean number of T4 cells was 703/mm3 and the mean proliferative response to phytohemagglutinin, 49,317 cpm. These findings suggest that those patients who present with opportunistic infections as their initial clinical manifestation of AIDS may represent a subgroup with a more severe immunologic derangement prior to clinical diagnosis. Thus, in those who have a predisposition to Kaposi's sarcoma, this disease will often develop, prior to the development of T cell dysfunction, to the degree of that in those who present with opportunistic infections. This finding is of importance in attempts to understand the pathogenesis of this syndrome and in the design of therapeutic trials.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation.

The present study demonstrates the graded effect of in vitro corticosteroids (CSs) on the different phases of B cell activation, proliferation, and differentiation. Early events such as activation and proliferation of high-dose anti-mu or Staphylococcus aureus-stimulated B cells are profoundly suppressed by the presence of in vitro CSs. The suppressed proliferative response may be mediated by a direct effect on B cells and/or modulation of accessory cell function. Later events in the B cell cycle such as the proliferative response to B cell growth factor after either in vivo or in vitro activation are less sensitive to the suppressive effects of in vitro CSs. The final events in the B cell cycle; namely, the differentiation to the immunoglobulin-producing state, is not suppressed by in vitro CSs. Indeed, depending on the systems employed, there is either no effect or enhancement of immunoglobulin secretion by the presence of in vitro CSs. The graded effect of in vitro CSs on the discrete phases of the B cell activation, proliferation, and differentiation cycle provide new insights into the complex nature of CS-induced modulation of human B cell responses.

Adult↗