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Biomedical subjects

M H Collins

Publications and source records attributed to M H Collins.

At least 19 recordsLinked to original sources
PubMed2001

Fiber knob modifications overcome low, heterogeneous expression of the coxsackievirus-adenovirus receptor that limits adenovirus gene transfer and oncolysis for human rhabdomyosarcoma cells.

Exploiting the lytic life cycle of viruses has gained recent attention as an anticancer strategy (oncolysis). To explore the utility of adenovirus (Ad)-mediated oncolysis for rhabdomyosarcoma (RMS), we tested RMS cell lines for Ad gene transduction and infection. RMS cells were variably transduced by Ad. Compared with control cells, RMS cells were less sensitive or even resistant to oncolysis by wild-type virus. RMS cells expressed the Ad internalization receptors, alpha(v) integrins, but had low or undetectable expression of the major attachment receptor, coxsackievirus-Ad receptor (CAR). Mutant Ads with ablated CAR binding exhibited only 5-20% of transgene expression in RMS cells seen with a wild-type vector, suggesting that residual or heterogeneous CAR expression mediated the little transduction that was detectable. Immunohistochemical analysis of archived clinical specimens showed little detectable CAR expression in five embryonal and eight alveolar RMS tumors. Stable transduction of the cDNA for CAR enabled both efficient Ad gene transfer and oncolysis for otherwise resistant RMS cells, suggesting that poor CAR expression is the limiting feature. Gene transfer to RMS cells was increased >2 logs using Ads engineered with modified fiber knobs containing either an integrin-binding RGD peptide or a polylysine peptide in the exposed HI loop. The RGD modification enabled increased oncolysis for RMS cells by a conditionally replicative Ad, Ad delta24RGD, harboring a retinoblastoma-binding mutation in the E1A gene. Thus, the development of replication-competent vectors targeted to cell surface receptors other than CAR is critical to advance the use of Ad for treating RMS.

Adenoviridae↗
PubMed2001

Proliferative and apoptotic differences between alveolar rhabdomyosarcoma subtypes: a comparative study of tumors containing PAX3-FKHR or PAX7-FKHR gene fusions.

BACKGROUND: Most alveolar rhabdomyosarcomas (ARMS) have chromosome translocations and resultant gene fusion products. The more common translocation fuses the PAX3 and FKHR genes; patients who have PAX3-FKHR-positive ARMS have reduced event-free survival compared to patients with ARMS containing the less common translocation that fuses the PAX7 and FKHR genes. PROCEDURE: We examined histology, immunohistochemical markers of differentiation, and cell cycle characteristics of a panel of ARMS containing either PAX3-FKHR or PAX7-FKHR transcript to determine if these features differ between the ARMS subsets. RESULTS: Cell cycle parameters varied significantly: the number of nuclei that stained with either an immunohistochemical marker of proliferation (MIB1), or a TUNEL-based assay for apoptosis was significantly greater in tumors that expressed PAX3-FKHR compared to tumors that expressed PAX7-FKHR transcript. CONCLUSIONS: We conclude that compared to PAX7-FKHR-containing tumors, ARMS that contain PAX3-FKHR transcript have (1) increased cell proliferation, consistent with greater loss of cell cycle regulation, and (2) apoptosis that is increased but insufficient to prevent tumor formation. More marked cell cycle dysregulation may contribute to poorer prognosis for patients with ARMS that have PAX3-FKHR fusion. Med Pediatr Oncol 2001;37:83-89.

Apoptosis↗
PubMed2001

Post-transplant lymphoproliferative disease in children.

Epstein-Barr virus (EBV)-driven post-transplant lymphoproliferative disease (PTLD) is an important cause of morbidity and mortality following transplantation, and it occurs more frequently in children than in adults. Of 22 (5%) children at our institution who developed tissue-proven PTLD 1-60 months (mean 16.5 months) following organ transplant, 11 died: nine of these 22 patients developed PTLD between 1989 and 1993, and seven (78%) died; the remaining 13 developed PTLD between 1994 and 1998, and four (31%) died (p = 0.08). All nine patients who developed PTLD < 6 months after transplant died, but 11 of 13 patients who manifested disease > or = 6 months after transplant survived (p = 0.0002). Ten of 11 (91%) survivors, but only two of eight (25%) children who died, had serologic evidence of EBV infection at the time of PTLD diagnosis (p = 0.04). EBV seroconversion identified patients at risk for developing PTLD, but also characterized patients with sufficient immune function to survive EBV-related lymphoid proliferation. In situ hybridization for EBER1 mRNA was diagnostically helpful because it detected EBV in tissue sections of all 20 patients with B-cell PTLD, including those with negative serology.

Adolescent↗
PubMed2001

Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study.

Inflammatory myofibroblastic tumor (IMT) is an uncommon mesenchymal neoplasm with a variable histologic appearance that may mimic other spindle cell processes, particularly nodular fasciitis, desmoid tumor, and in intra-abdominal locations, gastrointestinal stromal tumor. Recently, gene fusions involving ALK at chromosome 2p23 have been described in IMTs. The resultant ALK protein overexpression in the myofibroblastic component of these tumors is detectable by immunohistochemistry. We examined 73 IMTs, 20 cases of nodular fasciitis, 15 desmoid fibromatoses, and 15 gastrointestinal stromal tumors by immunohistochemistry using ALK-11, a rabbit polyclonal antibody that recognizes the C-terminus of the protein. ALK positivity was detected in 44 of 73 (60%) IMTs. All cases of nodular fasciitis, desmoid fibromatosis, and gastrointestinal stromal tumors were ALK negative (p < 0.001). These findings demonstrate that ALK positivity is common in IMTs, and immunohistochemistry using anti-ALK antibodies can be helpful in the differential diagnosis of these neoplasms. In addition, anti-ALK staining seems to correlate with those IMTs that have the typical tri-patterned histologic appearance and clinical presentation, providing additional support to the premise that IMT is a distinctive clinicopathologic entity within the broad category of inflammatory pseudotumors.

Adolescent↗
PubMed2001

Autopsy pathology of pediatric posttransplant lymphoproliferative disorder.

OBJECTIVES: Posttransplant lymphoproliferative disorder (PTLD) causes significant morbidity and mortality, is related to Epstein-Barr virus (EBV) infection, and is more common in children than in adults. We reviewed autopsies of children who died with PTLD to compare postmortem with antemortem PTLD histology, to assess the extent of PTLD, to document associated pathology, and to identify cause of death. METHODS: Postmortem examinations were performed on 7 patients after bone marrow (n = 3) or liver (n = 4) transplant. PTLD was classified histologically as hyperplasia or lymphoma. In situ hybridization for EBER1 messenger RNA was performed on tissue samples from all cases. EBV serologies were used to categorize infections as negative, primary, or reactive. RESULTS: PTLD was diagnosed in 5 children 12 to 35 (mean: 22) days before death, and 1.5 to 4 (mean: 3) months after transplant; PTLD was diagnosed in 2 cases at autopsy 2.5 and 4 months after transplant. Postmortem PTLD histology resembled antemortem histology; 5 PTLDs were lymphoma, 1 was hyperplasia, and 1 contained both lymphoma and hyperplasia. EBER1 messenger RNA was detected in 6 B-cell PTLDs, including lesions from patients who did not have EBV serology that indicated active infection. Complete autopsy of 4 patients who died with biopsy-proven PTLD revealed widely disseminated disease, and lymph node, brain, gastrointestinal tract, and kidney were involved in all 4 patients. Cases diagnosed at autopsy were 1 widely disseminated PTLD that had been suspected but not proven antemortem, and 1 PTLD confined to abdominal lymph nodes that was not suspected antemortem. Severe organ dysfunction (renal failure, gastrointestinal hemorrhage) was caused by massive PTLD infiltration in 2 patients. The conditions other than PTLD that contributed to morbidity and death were organ infection (5 cases), infarcts (4 cases), and diffuse alveolar damage (3 cases). CONCLUSIONS: PTLD may occur within weeks after transplant in children. The distribution of PTLD comprises a spectrum from localized and subclinical to widely disseminated and symptomatic. PTLD may cause demise quickly after the onset of signs and symptoms, through massive organ infiltration or associated conditions, such as diffuse alveolar damage. EBV serology may not accurately reflect the presence or extent of PTLD. Autopsy studies of transplant patients are necessary to identify the true incidence, natural history, and response to treatment of PTLD.

Autopsy↗
PubMed2001

Venlafaxine in the treatment of postpartum depression.

BACKGROUND: Although postpartum depression is a highly prevalent illness, antidepressant treatment studies of postpartum depression are sparse. Incomplete recognition and treatment of puerperal illness place women at risk for chronic depression and may have adverse effects on child development. METHOD: An 8-week, flexible-dose, open study of venlafaxine (immediate release; mean dose = 162.5 mg/day) was performed in a group of 15 women who met DSM-III-R criteria for major depressive disorder with onset within the first 3 months postpartum. Patients were assessed at baseline and every 2 weeks across the study. Measurements of outcome included the 17-item Hamilton Rating Scale for Depression (HAM-D), the Kellner Symptom Questionnaire, and the Clinical Global Impressions scale (CGI). RESULTS: Despite baseline scores of depression that were particularly high, response to treatment was robust. Twelve of 15 patients experienced remission of major depression (HAM-D score < or = 7 or CGI score < or = 2). Dramatic decrease in anxiety paralleled the decrease in depression across the sample. CONCLUSION: Venlafaxine is effective in the treatment of postpartum major depression. Early identification of women who suffer from postpartum mood disturbance is critical to minimize the morbidity associated with untreated mood disturbance and the effect of depression on children and families.

Adult↗
PubMed2000

Acute effects of intense interval training on running mechanics.

The aims of this study were to determine if there are significant kinematic changes in running pattern after intense interval workouts, whether duration of recovery affects running kinematics, and whether changes in running economy are related to changes in running kinematics. Seven highly trained male endurance runners (VO2max = 72.3+/-3.3 ml x kg(-1) x min(-1); mean +/- s) performed three interval running workouts of 10 x 400 m at a speed of 5.94+/-0.19 m x s(-1) (356+/-11.2 m x min(-1)) with a minimum of 4 days recovery between runs. Recovery of 60, 120 or 180 s between each 400 m repetition was assigned at random. Before and after each workout, running economy and several kinematic variables were measured at speeds of 3.33 and 4.47 m x s(-1) (200 and 268 m x min(-1)). Speed was found to have a significant effect on shank angle, knee velocity and stride length (P < 0.05). Correlations between changes pre- and post-test for VO2 (ml x kg(-1) x min(-1)) and several kinematic variables were not significant (P > 0.05) at both speeds. In general, duration of recovery was not found to adversely affect running economy or the kinematic variables assessed, possibly because of intra-individual adaptations to fatigue.

Adaptation, Physiological↗
PubMed2000

Forehead lipoblastoma mimicking a hemangioma.

A case of forehead lipoblastoma simulating a hemangioma in a male infant is reported, to alert pediatricians to this rare tumor and to increase the index of suspicion in atypical hemangiomas. A 2-month-old male infant developed a protruding forehead mass with increased vascularity. It demonstrated progressive and accelerated growth over the subsequent 6 months, unresponsive to steroid therapy. A magnetic resonance imaging scan supported the diagnosis of hemangioma because of the hypervascular nature of the lesion. Surgical excision was performed because of visual obstruction. Pathologic examination of the specimen was consistent with a very primitive lipoblastoma. This tumor is a rare, benign lesion of immature fat cells that is found almost exclusively in the pediatric population. Lipoblastomas are more common in males than females and frequently present as asymptomatic, rapidly enlarging, soft lobular masses on the extremities. Complete surgical excision is the definitive treatment. In the vast majority of reported cases, however, the preoperative diagnosis was incorrect, underscoring the diagnostic dilemma presented by these rare tumors.

Diagnosis, Differential↗
PubMed1999

Long-term outcome of infants with single ventricle and total anomalous pulmonary venous connection.

BACKGROUND AND METHODS: Between January 1, 1984, and December 1, 1997, 73 infants with functional single ventricle and total anomalous pulmonary venous connection were admitted to our institution. A retrospective review was undertaken to determine factors influencing survival. RESULTS: Heterotaxy syndrome was present in 52 patients and hypoplastic left heart syndrome in 14. Obstructed total anomalous pulmonary venous connection was present in 21 patients. The pulmonary venous connection was supracardiac in 32 patients, cardiac in 21 patients, infracardiac in 13, and mixed in 7. Twelve patients died before the operation. The remaining 61 patients underwent surgery at a median age of 5 days (range 1 day-2. 5 years). Overall survival was 45% at 6 months of age, 37% at 1 year, and 19% at 5 years. Survival for patients undergoing surgery was 54% at 6 months of age, 44% at 1 year, and 23% at 5 years. By univariate analysis with the Cox proportional hazards model, younger age at the time of the initial operation and repair of total anomalous pulmonary venous connection were predictors of mortality. Lung tissue from 14 patients was available for histologic examination. The pulmonary veins were dilated and wall thickness was increased. Increased muscularization of the arteries was seen in 11 patients. CONCLUSIONS: The long-term prognosis for children undergoing staged reconstructive operations for single ventricle and total anomalous pulmonary venous connection is poor. Early mortality is high and late death is a continuing risk. Development of the pulmonary vasculature, especially the pulmonary veins, is abnormal, even in children without clinical evidence of pulmonary venous obstruction.

Cardiac Surgical Procedures↗
PubMed1999

The hypoplastic left heart syndrome with intact atrial septum: atrial morphology, pulmonary vascular histopathology and outcome.

OBJECTIVES: The purpose of this study was to investigate the outcome in infants with hypoplastic left heart syndrome and intact atrial septum and to evaluate the relationship of atrial morphology, left atrial decompression pathway and lung histopathology to outcome. BACKGROUND: In the hypoplastic left heart syndrome, severe restriction at the atrial level results in marked systemic hypoxemia after birth. Infants with intact atrial septum may be at high risk for mortality after Norwood operation. METHODS: Of 316 infants with hypoplastic left heart syndrome seen at our center over a 6.5-year period, 18 (5.7%) had intact atrial septum. Medical records and echocardiograms were reviewed. RESULTS: On echocardiography, three types of intact atrial septal morphology were identified: 1) large left atrium, thick prominent septum secondary with thin septum primary adherent (type A, n = 12); 2) small left atrium with thick, muscular atrial septum (type B, n = 4), and 3) giant left atrium, thin atrial septum with severe mitral regurgitation (type C, n = 2). Seven infants had left atrial decompression pathways that were severely obstructed (3/12 type A, 4/4 type B). Norwood operation was performed in 17 infants; one underwent emergency balloon atrial septostomy and died. Of six early survivors, all with type A atrial morphology and unobstructed decompression pathway, three died after subsequent cavopulmonary surgery. Lung histopathology revealed severely dilated lymphatics and "arterialization" of the pulmonary veins in those with the severest degree of obstruction to left atrial egress (type B atrial morphology). CONCLUSIONS: Despite aggressive intervention, outcome for infants born with hypoplastic left heart syndrome and intact atrial septum is poor. Maldevelopment of the pulmonary vasculature contributes to the high mortality seen. Atrial morphology can be used as a marker for the severity of pulmonary vascular disease.

Heart Atria↗
PubMed1999

Absence of SYT-SSX fusion products in soft tissue tumors other than synovial sarcoma.

The chromosomal translocation t(X;18), which generates SYT-SSX1 and SYT-SSX2 fusion products, is a sensitive marker for synovial sarcoma; most synovial sarcomas test positive for this marker. However, few studies have addressed the presence of t(X;18) or its fusion products in spindle cell sarcomas in the differential diagnosis of synovial sarcoma. We studied the presence of the SYT-SSX fusion products with reverse transcriptase polymerase chain reaction on frozen tissue samples of 24 synovial sarcomas and 24 other spindle cell sarcomas, including 12 malignant peripheral nerve sheath tumors. In cases histopathologically diagnosed as synovial sarcoma, SYT-SSX fusion products were detected in 21 of 24 (87%) lesions. No evidence of these fusions was found in 12 malignant peripheral nerve sheath tumors, 2 hemangiopericytomas, 3 leiomyosarcomas, 2 fibrosarcomas, 1 poorly differentiated sarcoma (malignant fibrous histiocytoma), 1 sarcoma with rhabdoid features, and 2 sarcomas not otherwise specified. One lesion with histologic, immunohistologic, and ultrastructural features indeterminate for a diagnosis of synovial sarcoma or malignant peripheral nerve sheath tumor was studied and was positive for SYT-SSX1. The SYT-SSX fusion products appear specific for synovial sarcoma and are not seen in other spindle cell lesions in its differential diagnosis.

Adult↗
PubMed1999

Elevated levels of the IGF-binding protein protease MMP-1 in asthmatic airway smooth muscle.

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is co-mitogenic with insulin-like growth factors (IGFs) in airway smooth-muscle (ASM) cells in vitro. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced IGF binding proteins (IGFBPs), which are cell growth-inhibitory proteins. We also identified this IGFBP protease to be the matrix metalloproteinase-1 (MMP-1), and showed that this enzyme had a significant role in modulating IGF action in ASM cells. In the present study, we tested the hypothesis that ASM hyperplasia in vivo involves induction of MMP-1 leading to IGFBP proteolysis. We detected the presence of MMP-1 and measured its levels in human airway tissue sections prepared from nonasthmatic and asthmatic subjects. Six nonasthmatic and six asthmatic airway tissue samples were analyzed for immunoreactive MMP-1 through an immunohistochemical detection method. Both the bronchial and tracheal smooth-muscle cells from different regions of the same sample were examined and documented. The immunostaining for MMP-1 was significantly elevated in both the bronchial and tracheal smooth-muscle cells of the airway sections from asthmatic samples relative to that of the nonasthmatic samples. The differences in levels of MMP-1, IGFBP-2, IGFBP-3, and IGFBP proteolytic activity were quantified using densitometric analyses of the ASM tissue extracts that were separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The MMP-1 levels in the asthmatic airway tissue extracts were 12-fold higher than those found in control samples. In addition, IGFBP-2 and IGFBP-3, which we have previously demonstrated to be proteolytic substrates of MMP-1, were found to be cleaved in asthmatic airway tissue extracts. Furthermore, the asthmatic airway extracts contained IGFBP proteolytic activity that was shown by immunodepletion studies to be due to MMP-1. These observations demonstrate that MMP-1 may play a significant role in inducing ASM hyperplasia and airway obstruction in asthma by modulating the IGF axis.

Adolescent↗
PubMed1998

Hodgkin disease?

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Adolescent↗
PubMed1998

Matrix metalloproteinase-9 (MMP-9) expression in childhood osseous osteosarcoma.

BACKGROUND: Over 80% of patients with osteosarcoma treated with excision alone develop pulmonary metastases, suggesting that the majority of patients with this disease harbor "micrometastases" at diagnosis. There are no histologic or molecular variables which can predict the presence or absence of micrometastasis. Matrix metalloproteinases (MMPs) are a class of matrix- and basement membrane-degrading enzymes whose expression is associated with tumor cell invasive and metastatic behavior. One of these enzymes, MMP-9 or gelatinase B, is expressed in developing and remodeling bone and in osteosarcoma cell lines. We speculated that MMP-9 expression might be associated with the micrometastatic behavior of osteosarcoma. PROCEDURE: We examined a series of pediatric primary osseous osteosarcomas and metastases for the expression of MMP-9, using a monoclonal antibody. RESULTS: We found intense MMP-9 immunostaining in most tumor cells in all samples of pretreatment osteosarcomas. In all postchemotherapy resection samples, tumor cells stained similarly, but there were fewer positively staining cells overall. In 4 of 5 metastastic lesions examined, intense immunostaining for MMP-9 was detected. CONCLUSIONS: These results suggest that MMP-9 expression is common in osteosarcoma, and that further study of the role of MMP-9 in pediatric osteosarcoma behavior is warranted.

Bone Neoplasms↗
PubMed1998

Increased pulmonary blood flow produces endothelial cell dysfunction in neonatal swine.

BACKGROUND: The mechanisms by which increased pulmonary blood flow results in pulmonary hypertension have not been determined. METHODS: To determine if increased pulmonary blood flow produces endothelial dysfunction that precedes vascular remodeling and smooth muscle proliferation, neonatal swine (n = 12) (age, 6.1+/-0.5 days) underwent ligation of the left pulmonary artery (LPA) to increase blood flow to the right lung. At 12 weeks of age, endothelium-dependent vasodilatation was assessed by acetylcholine infusion and endothelium-independent vasodilatation by inhaled nitric oxide (NO) in the LPA group and age-matched controls (CON) (n = 11). RESULTS: Mean pulmonary artery pressure was 24.1+/-3.0 mm Hg in the LPA group and 20.8+/-1.9 mm Hg in the CON group (p < 0.1). Pulmonary vascular resistance was 13.2+/-2.2 Wood units in the LPA group and 5.8+/-0.8 Wood units in the CON group (p = 0.001). Acute occlusion of the left pulmonary artery in the CON group increased pulmonary vascular resistance to 6.9+/-3.9 Wood units (p = 0.04). Administration of acetylcholine in the CON group after preconstriction with the thromboxane A2 analogue U46619 resulted in a 30.6%+/-5.4% decrease in pulmonary vascular resistance. In the LPA group, acetylcholine produced paradoxical vasoconstriction and a 15.4%+/-4.1% increase in pulmonary vascular resistance (p < 0.001 versus CON) indicating loss of endothelium-dependent vasodilatation. Nitric oxide decreased pulmonary vascular resistance by 41.9%+/-3.3% in the CON group and 30.8%+/-2.7% in the LPA group (p = 0.04 versus CON), indicating preserved endothelium-independent vasodilatation in both groups. Morphometric analysis was performed in 4 animals from each group. Medial wall thickness as percent of external diameter of small arteries (<100 microm) was the same in both groups (6.4%+/-0.4% in the LPA group versus 6.6% +/-0.4% in the CON animals; p > 0.1). CONCLUSIONS: Increased pulmonary blood flow in immature animals produces endothelial cell dysfunction with loss of endothelium-dependent vasodilatation before the onset of pulmonary vascular remodeling. Subsequent smooth muscle proliferation may be mediated by endothelium-derived factors.

Animals↗