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PubMed2002

The role of genotype in determining the effects of cigarette smoking on pulmonary function.

The effect of cigarette smoking on pulmonary function is highly variable. Some heavy smokers retain normal pulmonary function and others experience profound pulmonary function loss. The role of genotype in this process is unknown. We tested for gene by environment interaction (GxE) in smoking-associated loss of forced expiratory volume in one second (FEV1) using repeated pulmonary function and smoke-exposure measures from 352 twin pairs enrolled in the NHLBI Male Veteran Twin Study. Inferences using global [Jinks and Fulker, 1970] and dichotomous [Ramakrishnan et al., 1992] procedures were supplemented with a new model for repeatedly observed twinships. The model facilitates testing of standard heritability hypotheses and families of hypotheses regarding the dependence of quantitative twin-twin phenotypic similarity on continuously varying twin-twin exposure concordance. The global and dichotomous procedures were suggestive of GxE in smoke-associated loss of FEV1 (p < 0.01, p = 0.08, respectively). With the new model, overall twin-twin correlation of FEV1 for concordant-smoking MZ and DZ twin pairs was estimated at 0.71 and 0.34, respectively. For twins with little or no difference in cigarette use, the intra-pair correlations of FEV(1) did not differ according to cigarette exposure over a wide range of exposures (0 - > or = 200 pack years). Even great twin-twin discordance in cigarette smoking (> or =10 pack years) had little effect of correlations. We conclude that a constant factor, such as genotype, appears to be interposed between the environmental toxin (cigarette smoke) and phenotype (FEV1).

Forced Expiratory Volume↗

PubMed1995

Mechanisms of nonneoplastic endocrine hyperplasia--a changing concept: a review focused on the thyroid gland.

An important part of clinical endocrinology deals with diseases caused by benign and malignant nodules growing within originally homogeneous endocrine glands. In the search for the pathogenesis of these nodules, two concepts have been advanced: either the hyperplastic tissue is considered to result from chronic intense stimulation by a trophic hormone, eventually causing the growth of polyclonal nodules (a concept known as NNEH) or else, the nodules are thought to represent true clonal tumors. It has been realized rather recently that NNEH accounts only for a small minority of rare endocrine diseases, with the exception of highly prevalent iodine deficiency goiters and, in a broader sense, for Graves' disease. Indeed, secondary hyperplasia of endocrine glands resulting from long-lasting chronic hormonal overstimulation cannot explain a large number of essential features of the diseased glands. As best documented for the thyroid gland, outstanding among the characteristics of hyperplastic glands that do not fit into the simple concept of NNEH are the inevitable nodular transformation, the frequent autonomy and irreversibility of nodular growth, the loss of function in many cells and nodules, and the tremendous regional heterogeneity of growth and function including loss of coordination between these two main features of any living cell. Hyperplasia resulting from long-lasting stimulation by a trophic hormone is not a fully reversible process, as is often thought, but definitely increases the total cell mass and leaves behind, after cessation of the stimulus, a population of newly generated cells. This process is common to NNEH and true neoplastic growth. A review of common and disparate traits between endocrine hyperplasia and neoplasia must be based on the following generally accepted facts (excluding in-depth consideration of malignancy). 1. Many endocrine tumors are clonal while others are polyclonal. For example, pituitary and sporadic parathyroid adenomas are nearly always clonal while in the thyroid, multiple clonal nodules of different origin may coexist with polyclonal nodules. 2. Clonal growth does not necessarily indicate that the autonomous expansion of a tumor is driven by presently known genetic gain-of-function or loss-of-inhibition mutations or by cytogenetic aberrations. 3. Genetic mutations and chromosomal aberration in endocrine tumors are not necessarily primary events in the tumorigenesis but may as well be a late secondary phenomenon in growing tissue. 4. Clonal nodules may overgrow from primarily polyclonal ones. The best evidence to date comes from the rare clonal parathyroid adenomas with allelic loss of chromosome 11 evolving in tertiary hyperparathyroidism.(ABSTRACT TRUNCATED AT 400 WORDS)

Goiter, Nodular↗

PubMed2000

Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?

BACKGROUND: Reducing the actions of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme inhibitors (ACEIs) slows nephropathy progression in patients with or without diabetes. Post hoc analyses of many ACEI-based clinical trials demonstrate the greatest slowing of renal disease progression in patients with the greatest degree of renal insufficiency at study initiation. However, many physicians fail to use ACEIs or angiotensin receptor blockers in patients with renal insufficiency for fear that either serum creatinine or potassium levels will rise. OBJECTIVE: To determine if limited initial reduction in either glomerular filtration rate (GFR) or elevation in serum creatinine levels, associated with ACEI or angiotensin receptor blocker use, results in long-term protection against decline in renal function in patients with renal insufficiency. METHODS: We reviewed 12 randomized clinical trials that evaluated renal disease progression among patients with preexisting renal insufficiency. Six of these studies were multicenter, double-blinded, and placebo controlled, with the remainder being smaller randomized studies with a minimum 2-year follow-up on renal function. These investigations evaluated patients with and without diabetes or systolic heart failure. Average duration of follow-up for all studies was 3 years. Trials were examined in the context of changes in either serum creatinine levels or GFR in the group randomized to an ACEI (N = 1,102). Sixty-four percent of these individuals (705/1,102) had renal function data at both less than 6 months and at the end of the study. RESULTS: Most trials demonstrated that patients with preexisting renal insufficiency manifested an acute fall in GFR, a rise in serum creatinine, or both. Those randomized to an ACEI with a serum creatinine level of 124 pmol/L or greater (> or =1.4 mg/dL) demonstrated a 55% to 75% risk reduction in renal disease progression compared with those with normal renal function randomized to an ACEI. An inverse correlation was observed between the amount of renal function loss at baseline and the subsequent rate of annual decline in renal function following randomization to an antihypertensive regimen that contained an ACEI. CONCLUSIONS: A strong association exists between acute increases in serum creatinine of up to 30% that stabilize within the first 2 months of ACEI therapy and long-term preservation of renal function. This relationship holds for persons with creatinine values of greater than 124 pmol/L (>1.4 mg/dL). Thus, withdrawal of an ACEI in such patients should occur only when the rise in creatinine exceeds 30% above baseline within the first 2 months of ACEI initiation, or hyperkalemia develops, ie, serum potassium level of 5.6 mmol/L or greater.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Enterocyte differentiation is compatible with SV40 large T expression and loss of p53 function in human colonic Caco-2 cells. Status of the pRb1 and pRb2 tumor suppressor gene products.

Transfer of the SV40 large-T (LT) oncogene into isolated human and murine intestinal epithelial cells induced alterations of the ultrastructural organization and polarization of the resulting immortalized cell lines. We now demonstrate that the functional expression of the SV40 LT antigen in Caco-2 cells did not alter phenotypic markers of differentiation, including expression of villin, sucrase-isomaltase, brush border and dome formation. As compared to parental cells, the transfected Caco-2 LT9 cells exhibited similar growth curves and no invasive properties in vitro. The major oncogenic function of the SV40 LT antigen in transfected Caco-2 cells is associated with reduced latency times necessary for the manifestation of tumors in athymic nude mice. The Caco-2 cell line contained deleted and mutant p53 alleles (stop codon in position 204) and has no detectable truncated p53 protein by Western blot. Molecular complexes between the SV40 LT antigen and the retinoblastoma-related proteins pRb1 and Rb2 were clearly identified at the different phases of the growth curve. When compared to normal human colonic crypts, Caco-2 cell differentiation is related to partial redistribution of pRb1 into hypophosphorylated, antiproliferative forms. The pRb2 protein is found elevated in a subset of human colorectal tumors and their corresponding liver metastases. We conclude that: (1) Caco-2 cells exert a dominant control against the oncogenic functions of the LT antigen; (2) loss of p53 function is not restrictive for the establishment of polarity and differentiation of the enterocyte lineage; (3) the levels and phosphorylation status of the Rb1 and Rb2 proteins may play important roles in the proliferation and differentiation of normal and neoplastic human colonic mucosa.

Animals↗

PubMed1999

Mitotic recombination produces the majority of recessive fibroblast variants in heterozygous mice.

Mice heterozygous at Aprt (adenine phosphoribosyltransferase) were used as a model to study in vivo loss of heterozygosity (LOH) in normal fibroblasts. Somatic cell variants that exhibited functional loss of the wild-type Aprt in vivo were recovered as APRT-deficient cell colonies after culturing in selection medium containing 2, 6-diaminopurine (DAP), an adenine analog that is toxic only to cells with APRT enzyme activity. DAP-resistant (DAP(r)) fibroblast variants were recovered at a median frequency of 12 x 10(-5) from individual ears from progeny of crosses between mouse strains 129/Sv and C3H/HeJ. The frequency of DAP(r) variants varied greatly among individual ears, suggesting that they preexisted in vivo and arose at various times during development. Polymorphic molecular markers and a cytological marker on the centromere of chromosome 8 made it possible to discriminate between each of six possible mechanistic pathways of LOH. The majority (about 80%) of the DAP(r) variants were a consequence of mitotic recombination. The prevalence of mitotic recombination in regions proximal to Aprt did not correlate with meiotic map distances. In particular, there was a higher than expected frequency of crossovers within the interval 59 cM to 67 cM. The high spontaneous frequency of Aprt LOH, mediated primarily by mitotic recombination, is fully consistent with our previous results with human peripheral T cells from individuals known to be heterozygous at APRT. Thus, this Aprt heterozygote mouse is a valid model for studying somatic mutagenesis and mitotic recombination in vivo.

Adenine Phosphoribosyltransferase↗

PubMed1997

Proteinuria and progression of renal disease: therapeutic implications.

The relationship between proteinuria and progression of renal disease has long been an issue of debate. The present review deals with some of the recent publications on this topic. New concepts are emphasized: the possible causal role of proteinuria in the pathophysiology of progressive renal function loss, and the decrease in urinary protein loss at the beginning of renoprotective therapy as a predictor of renal function outcome during this treatment.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1985

Distribution of forced expiratory volume in one second and forced vital capacity in healthy, white, adult never-smokers in six U.S. cities.

As part of a longitudinal study of the respiratory health effects of air pollution, we measured the lung function of 2,454 white adults 25 to 74 yr of age who had never smoked and who reported no respiratory symptoms. These measurements were analyzed to develop a simple model for the cross-sectional dependence of pulmonary function on height, sex, and age. Both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) can be effectively standardized for body size by dividing each pulmonary function measurement by the square of the standing height (HT2). The age-specific distribution of these standardized measurements is approximately Gaussian, with variance that is independent of age. Plots of FEV1/HT2 and FVC/HT2 against age showed a nonlinear relationship consistent with an increase in the rate of pulmonary function loss with age. On the basis of these graphic analyses, both pulmonary function measurements were fitted to a four-parameter normative model including sex and linear and quadratic terms in age as dependent variables. This model gave predictions that were very close to those from more complicated models currently in use. Predicted percentile levels were calculated for each sex and age, and shown to describe the observations well. The estimated annual change in height-standardized lung function based on the cross-sectional model was compared with the observed change between the first and second examinations of these adults 3 yr later. The observed changes were close to predicted values, except for subjects younger than 35 yr of age at their first examination. The observed change was larger for men than for women. Such simple longitudinal comparisons are subject to selection bias. In this study, subjects in the lowest quartile of FEV1/HT2 for their age and sex at the first examination had a lower probability of providing a lung function measurement 3 yr later.

Adult↗

PubMed2000

[Prevention of lactic acidosis due to metformin intoxication in contrast media nephropathy].

Use of the oral antidiabetic drug metformin may cause lactic acidosis, a rare but life-threatening complication, especially in patients with renal function loss. Since intravenously administered iodide-containing contrast media may cause renal function disturbances precautions should be taken in metformin-treated patients for whom a radiological study with intravenous contrast media is considered. In diabetic patients who use metformin a serum creatinine concentration should be measured prior to the radiological study. If the serum creatinine is within normal limits (< 130 mumol/l), metformin can be continued and the examination performed. If the serum creatinine concentration is increased (> or = 130 mumol/l), metformin should be discontinued and replaced by another antidiabetic drug if necessary. The radiological procedure with intravenous contrast media should be postponed for 48 hours. If such a procedure cannot be postponed, additional measures to prevent lactic acidosis (hydration, monitoring of the renal function) should be taken.

Acidosis, Lactic↗

PubMedDate not supplied

Bayesian statistics as applied to multiple sclerosis diagnosis by evoked potentials.

This study deals with the multiple sclerosis diagnosis by visual, somatosensory and brain stem auditory evoked potentials. By a statistical investigation of experimental data, four items have been selected as being both discriminative and independent: P100, N20, P40 latencies and the auditory central conduction time. The Bayesian approach was then attempted, i.e. the marginal density distributions of every item, and the joint density distribution functions have been established within both normal and multiple sclerosis population. No loss function consideration have been taken into account, as the final diagnosis is established by a neurologist who disposes of additional clinical and paraclinical information. The discrimination, as given by posterior Bayesian probability, is very satisfactory since the ratio of recognized multiple sclerosis among MS patients is over 90%, while no normal subject is diagnosed as MS.

Bayes Theorem↗

PubMed1983

Autologous cryopreserved platelets and prophylaxis of bleeding in autologous bone marrow transplantation.

Autologous platelets were harvested and cryopreserved in eight consecutive patients elected for ablative chemotherapy and autologous bone marrow transplantation (ABMT) for solid malignancy. There was a 19% loss in platelet count after the freeze thaw and wash procedure; with an in vitro functional loss of 40-60%. No correlation could be found for individual platelet transfusions between in vitro functional tests and in vivo recovery. Six consecutive patients received a total of 16 autologous platelet transfusions in the aplastic phase of ABMT. No bleeding was observed during the study period and there was no CMV infection in the recipients. While improvement in freezing and subsequent handling is desirable, autologous cryopreserved platelets can safely be used for the prophylaxis of bleeding during aplasia in patients treated with ABMT.

Adolescent↗

PubMed2005

The effect of massive weight loss on pulmonary function of morbid obese patients.

STUDY OBJECTIVES: To test if morbid obesity causes pulmonary function changes and if massive weight loss have effect on pulmonary function (especially in subjects with BMI>or=60 kg/m(2)). PARTICIPANTS: Thirty-nine morbid obese subjects before and after massive weight loss. MEASUREMENTS AND RESULTS: Patients had baseline BMI>or=40 kg/m(2), pulmonary function test (PFT) before and after surgery for gastric volume reduction and massive weight loss, and presented no complaints unrelated to obesity. Based on initial BMI, the patients were divided in groups A (BMI 40-59.9 kg/m(2)) and B (BMI>or=60 kg/m(2)). Initially, group A (n=28) had normal PFT, however group B (n=11) presented FVC and FEV(1) measurements in the lowest limit of normality (with normal FEV(1)/FVC), significantly different from group A. After massive weight loss, the group B compared to A had a significant improvement in FVC (23.7% vs. 9.7%, P=0.012) and FEV(1) (25.6% vs. 9.1%, P=0.006); thus the initial difference in FVC and FEV(1) between groups no longer existed after weight loss. CONCLUSIONS: These results point out that the severe morbid obesity (BMI>or=60 kg/m(2)) may lead to pulmonary function impairment and presents more prominent pulmonary function gain after massive weight reduction. The possible clinical implications of these results are that PFT abnormalities in subjects with BMI<60 kg/m(2) should probably be interpreted as consequence of intrinsic respiratory disease and that severe morbid obese patients may be encouraged to lose weight to improve their pulmonary function, especially those with concomitant pulmonary disorders.

Adult↗

PubMed1981

Transepidermal water loss as a function of skin surface temperature.

Transepidermal water loss (TEWL) was measured as a function of skin temperature, using human cadaver skin in modified skin diffusion chambers. A formula was derived to allow conversion of TEWL at any skin temperature to a standard reference temperature. This formula permits more accurate comparison of TEWL within and between subjects.

Adult↗

PubMed1986

Identification and treatment of cyclosporine-associated allograft thrombosis.

Endothelial injury associated with cyclosporine (CSA) therapy in the absence of rejection has resulted in irreversible intrarenal allograft thrombosis and transplant loss. Indium 111 (111In)-labeled platelet scanning is an effective way to identify those transplants that are at risk for acute loss. Two hundred prospective 111In scans were obtained (100 on allografts with normal function and 100 with transplant dysfunction of all causes). 111In scans in patients with dose-dependent CSA nephrotoxicity (N = 58) and biopsy proved acute rejection (N = 22) were negative. Grossly abnormal scans (three to eight times greater than hepatic uptake) were noted in nine recipients identified as having a hemolytic uremic-like syndrome associated with CSA use. Accelerated allograft functional loss was irreversible in six patients despite stopping CSA, systemic anticoagulation, increased steroids and antilymphocyte globulin, and infusion of fresh-frozen plasma. Three patients with grossly positive 111In scans and clinical and laboratory parameters consistent with this syndrome were treated with cessation of CSA and intra-arterial infusion of streptokinase into the renal allograft followed by systemic heparinization. Normal transplant function was regained and continues at 1, 7, and 8 months after transplant. 111In-labeled platelet scanning can noninvasively identify this syndrome of CSA-associated arteriopathy and allow for early therapy to reverse it. Intrarenal arterial streptokinase therapy is a successful way to treat acute CSA-associated arteriopathy.

Blood Platelets↗

PubMed1998

Clinical classification of glaucomatous visual field loss by frequency doubling perimetry.

PURPOSE: To determine whether the frequency doubling perimeter (FDP) can grade glaucomatous visual function loss in a clinically relevant manner. Sinusoidal gratings < 1 cpd that undergo counterphase flicker > 15 Hz appear to have twice as many bands of light, a phenomenon referred to as the "frequency doubling illusion." Evidence suggests that this psychophysical effect is mediated in part by large-diameter ganglion cells, which are reported to be lost early in the glaucomatous disease process. A portable, commercially available FDP has already demonstrated high diagnostic potential for glaucoma screening. METHODS: Sixty-four eyes of 42 glaucomatous patients and 22 eyes of 14 normal subjects were evaluated by means of both frequency doubling perimetry and Humphrey perimetry. A clinical scoring algorithm modeled after the Hodapp-Parrish-Anderson criteria for scoring Humphrey visual field defects was derived for the FDP at the halfway point of the study, and all participants were reassessed with this algorithm upon its completion. RESULTS: FDP mean and pattern deviation showed strong linear correlations with Humphrey 30-2 mean deviation (R = 0.75; P < .0001) and corrected pattern standard deviation values (R = 0.64; P < .0001). Despite this, neither global index could consistently categorize the graded glaucomatous visual fields in a manner consistent with the Hodapp-Parrish-Anderson criteria. The new FDP scoring algorithm did provide good segregation (73% precise parity, 93% parity within one Humphrey grade). CONCLUSIONS: Sixteen-zone frequency doubling perimetry can segregate glaucomatous visual field loss into pathologic categories approximating those obtained with Humphrey 30-2 perimetry by means of a formula modeled after the Hodapp-Parrish-Anderson criteria.

Algorithms↗

PubMed2001

Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines.

Neuroblastomas can acquire a sustained high-level drug resistance during chemotherapy and especially myeloablative chemoradiotherapy. p53 mutations are rare in primary neuroblastomas, but a loss of p53 function could play a role in multidrug resistance. We determined p53 function by measuring induction of p21 and/or MDM2 proteins in response to melphalan (L-PAM) in seven L-PAM-sensitive and 11 L-PAM-resistant neuroblastoma cell lines. p53 was functional in seven/seven drug-sensitive but in only 4/11 drug-resistant cell lines (P = 0.01). In four of the seven cell lines lacking p53 function, mutations of p53 were detected by the microarray GeneChip p53 Assay and automated sequencing, whereas six cell lines with functional p53 had no evidence of p53 mutations. All of the cell lines with wild-type (wt) p53 showed a strong transactivation of the p53-HBS/CAT reporter gene, whereas the four cell lines with mutant p53 failed to transactivate p53 HBS/CAT. Overexpression of MDM2 protein (relative to p53 functional lines) was seen in two p53-nonfunctional cell lines with wt p53; one showed genomic amplification of MDM2. Nonfunctional and mutated p53 was detected in a resistant cell line, whereas a sensitive cell line derived from the same patient before treatment had functional and wt p53. Loss of p53 function was selectively achieved by transduction of human papillomavirus 16 E6 (which degrades p53) into two drug-sensitive neuroblastoma cell lines with intact p53, causing high-level drug resistance to L-PAM, carboplatin, and etoposide. These data obtained with neuroblastoma cell lines suggest that the high-level drug resistance observed in some recurrent neuroblastomas is attributable to p53 mutations and/or a loss of p53 function acquired during chemotherapy. If confirmed in patient tumor samples, these data support development of p53-independent therapies for consolidation and/or salvage of recurrent neuroblastomas.

Antineoplastic Agents↗

PubMed2003

The last 2 years of life: functional trajectories of frail older people.

OBJECTIVES: To characterize the functional trajectories during the last 2 years of life of patients with progressive frailty, with and without cognitive impairment, and to assess whether it was possible to identify discrete functional indicators that signal the end of life. DESIGN: A retrospective analysis of functional trajectories during the last 24 months of life. SETTING: Twelve demonstration sites of the Program of All-inclusive Care for the Elderly (PACE). PACE cares for frail older people who meet criteria for nursing home placement, with the goal of keeping the patient at home. PARTICIPANTS: Nine hundred seventeen patients who died while enrolled in PACE. MEASURES: At PACE entry and every 3 months thereafter, data were collected about the degree of dependence (none, partial, or full) in bathing, eating, and walking and the degree of incontinence (none, bladder, or bowel). Cognitive impairment was defined as six or more errors on the Short Portable Mental Status Questionnaire. To describe the end-of-life trajectories of patients, data were analyzed from observational windows of time, beginning with the patients' dates of death and extending backward in time to 24 months before death. Each analytical window was 3 months in duration. For each of the functional measures, the probability of functional deterioration in the last 2 years of life in patients with (64%) and without (36%) cognitive impairment was also compared. RESULTS: The mean age at death was 84; 69% of patients were women. For patients with and without cognitive impairment, a prolonged, steady increase in the rates of functional dependence that were evident at least 1 year before death, rather than sudden increases in functional dependence shortly before death, characterized the functional trajectories. It was not possible for any of the four measures to detect a time point before death at which there was an abrupt decline in function likely to signal impending death. For each measure, patients with cognitive impairment declined earlier, were more likely than patients without cognitive impairment to have the maximal level of dependence in the 0- to 3-month window before death (e.g., 56% vs 30% for mobility, P <.001), and were more likely to decline in the 2 years before death (e.g., 56% vs 36% for mobility, P <.001). CONCLUSION: Patients with advanced frailty, with or without cognitive impairment, have an end-of-life functional course marked by slowly progressive functional deterioration, with only a slight acceleration in the trajectory of functional loss as death approaches. Patients with cognitive impairment have particularly high rates of functional impairment at the time of death. These results suggest that end-of-life care systems that are targeted toward patients with functional trajectories clearly suggesting impending death (such as the Medicare hospice benefit) are poorly suited to older people dying with progressive frailty.

Activities of Daily Living↗

PubMed1996

Free tissue transfer in pediatric patients.

The majority of reports on free tissue transfer involve adults; few have specifically addressed children. During the past 5 years, 20 free tissue transfers were performed in 19 pediatric patients. Patients ranged in age from 3 to 17 years, with a mean age of 10 years. Eight patients were 6 years and younger; 11 patients were 13 to 17 years old. Soft-tissue defects requiring reconstruction resulted from acute trauma in 12 patients, tumor ablation in 5 patients, infection in 1 patient, and hemifacial atrophy in 1 patient. Soft-tissue defects occurred in the lower extremity in 16 patients, the head and neck in 2 patients, and the upper extremity in 1 patient. The donor tissues included the latissimus dorsi muscle in 7 patients, the radial forearm flap in 7 patients, the rectus abdominis muscle in 4 patients, and the scapular fasciocutaneous flap in 2 patients. All patients received aspirin preoperatively. Mean operative time was 6.5 hours, with a range of 4 to 8 hours. Postoperative heparin infusion was used for 5 days in 7 of the 8 patients age 6 years and younger. All free tissue transfers were successful. One flap to a traumatic foot wound (patient age, 4 years) had a venous thrombosis on the second postoperative day, and was successfully treated with urokinase and heparin infusions and repeat venous anastomosis. There were no other significant morbidities and no mortalities. Hospitalization following free tissue transfer averaged 13 days, with a range of 6 to 37 days. Follow-up has averaged 31 months, with a range of 8 to 59 months. Late complications included a progressive equinus deformity 3 years after a heel reconstruction following a lawn mower injury and a contour deformity following a scapula flap to a gunshot wound of the foot. Sixteen of the 17 lower extremity reconstructions have shown normal growth. No growth disturbances or significant functional losses have occurred at the donor sites. Most patients have maintained normal extremity function including participation in athletics. Special considerations in this group of patients have included subtherapeutic heparin infusion during the postoperative period in young children, minimizing the aesthetic defect at the donor site and providing composite reconstructions whenever possible.

Adolescent↗

PubMed1997

Multiple extracellular domains of CCR-5 contribute to human immunodeficiency virus type 1 entry and fusion.

Human immunodeficiency virus type 1 (HIV-1) entry is governed by the interaction of the viral envelope glycoprotein (Env) with its receptor. The HIV-1 receptor is composed of two molecules, the CD4 binding receptor and a coreceptor. The seven-membrane-spanning chemokine receptor CCR-5 is one of the coreceptors used by primary isolates of HIV-1. We demonstrate that the mouse homolog of CCR-5 (mCCR-5) does not function as an HIV-1 coreceptor. A set of chimeras of human CCR-5 and mCCR-5 was studied for Env-induced cell fusion and HIV-1 infection. Using the HIV-1ADA envelope glycoprotein in a syncytium formation assay, we show that replacement of any fragment containing extracellular domains of mCCR-5 by its human counterparts is sufficient to allow Env-induced fusion. Conversely, replacement of any fragment containing human extracellular domains by its murine counterpart did not lead to coreceptor function loss. These results show that several domains of CCR-5 participate in coreceptor function. In addition, using a panel of primary nonsyncytium-inducing and syncytium-inducing isolates that use CCR-5 or both CXCR-4 and CCR-5 as coreceptors, we show that the latter dual-tropic isolates are less tolerant to changes in CCR-5 than strains with a more restricted coreceptor use. Thus, different strains are likely to have different ways of interacting with the CCR-5 coreceptor.

Amino Acid Sequence↗