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Biomedical subjects

M A Simon

Publications and source records attributed to M A Simon.

At least 37 records · Page 2Linked to original sources
PubMed1999

Neuropathogenesis of simian immunodeficiency virus in neonatal rhesus macaques.

Neonatal human immunodeficiency virus (HIV) infection usually occurs intrapartum or postpartum and results in a higher incidence of neurological dysfunction than is seen in adults. To explore the neuropathogenesis of neonatal HIV infection, we infected neonatal macaques with simian immunodeficiency virus (SIV) and followed the course of infection focusing on early time points. Infected neonates had decreased brain growth and mild histological changes in brain that resembled those seen in pediatric AIDS, including perivascular infiltrates of mononuclear cells, mineralization of vessels in the basal ganglia, and gliosis. The perivascular lesions and gliosis were associated with the presence of occasional infected cells that required in situ hybridization with radiolabeled riboprobes for detection. Using this technique, SIV-infected cells were detected in the brain parenchyma within 7 days of infection. These findings were confirmed by nested PCR for SIVgag DNA in brain and RT-PCR for viral RNA in cerebrospinal fluid. Together, these techniques revealed SIV infection of the CNS in 12 of 13 neonates infected with SIVmac239, 3 of 3 infected with SIVmac251, and 2 of 2 infected with SIVmac239/316. The prevalence of CNS infection was indistinguishable from that of older animals infected with the same dose and stock of virus, but neonates appeared to have fewer infected cells in the CNS and detecting them required more sensitive techniques. This observation was true regardless of inoculum and despite the fact that neonates had equal or greater viral loads in the periphery compared with older animals. These data suggest that maturation-dependent host factors have a major impact on the neuropathogenesis of pediatric AIDS.

Animals↗
PubMed1999

Association of simian virus 40 with a central nervous system lesion distinct from progressive multifocal leukoencephalopathy in macaques with AIDS.

The primate polyomavirus SV40 is known to cause interstitial nephritis in primary infections and progressive multifocal leukoencephalopathy (PML) upon reactivation of a latent infection in SIV-infected macaques. We now describe a second central nervous system manifestation of SV40: a meningoencephalitis affecting cerebral gray matter, without demyelination, distinct from PML. Meningoencephalitis appears also to be a primary manifestation of SV40 infection and can be seen in conjunction with SV40-induced interstitial nephritis and pneumonitis. The difference in the lesions of meningoencephalitis and PML does not appear to be due to cellular tropism, as both oligodendrocytes and astrocytes are infected in PML and meningoencephalitis, as determined by in situ hybridization or immunohistochemistry for SV40 coupled with immunohistochemistry for cellular determinants. This is further supported by examination of SV40 nucleic acid sequences from the ori-enhancer and large-T-antigen regions, which reveals no tissue-or lesion-specific variation in SV40 sequences.

Animals↗
PubMed1999

A nonhuman primate model for the selective elimination of CD8+ lymphocytes using a mouse-human chimeric monoclonal antibody.

Nonhuman primates provide valuable animal models for human diseases. However, studies assessing the role of cell-mediated immune responses have been difficult to perform in nonhuman primates. We have shown that CD8+ lymphocyte-mediated immunity in rhesus monkeys can be selectively eliminated using the mouse-human chimeric anti-CD8 monoclonal antibody cM-T807. In vitro, this antibody completely blocked antigen-specific expansion of cytotoxic T cells and decreased major histocompatibility complex class I-restricted, antigen-specific lysis of target cells but did not mediate complement-dependent cell lysis. In vivo administration of cM-T807 in rhesus monkeys resulted in near total depletion of CD8+ T cells from the blood and lymph nodes for up to 6 weeks. This depletion was not solely complement-dependent and persisted longer in adults than in juveniles. Preservation of B cell and CD4+ T cell function in monkeys depleted of CD8+ lymphocytes was demonstrated by their ability to develop humoral immune responses to the administered chimeric monoclonal antibody. Furthermore, during CD8+ lymphocyte depletion, monkeys developed delayed-type hypersensitivity reactions comprised only of CD4+ T cells but not CD8+ T cells. This CD8+ lymphocyte depletion model should prove useful in defining the role of cell-mediated immune responses in controlling infectious diseases in nonhuman primates.

Animals↗
PubMed1999

mirror controls planar polarity and equator formation through repression of fringe expression and through control of cell affinities.

The Drosophila eye is divided into dorsal and ventral mirror image fields that are separated by a sharp boundary known as the equator. We have previously demonstrated that Mirror, a homeodomain-containing putative transcription factor with a dorsal-specific expression pattern in the eye, induces the formation of the equator at the boundary between mirror-expressing and non-expressing cells. Here, we provide evidence that suggests mirror regulates equator formation by two mechanisms. First, mirror defines the location of the equator by creating a boundary of fringe expression at the mid-point of the eye. We show that mirror creates this boundary by repressing fringe expression in the dorsal half of the eye. Significantly, a boundary of mirror expression cannot induce the formation of an equator unless a boundary of fringe expression is formed simultaneously. Second, mirror acts to sharpen the equator by reducing the mixing of dorsal and ventral cells at the equator. In support of this model, we show that clones of cells lacking mirror function tend not to mix with surrounding mirror-expressing cells. The tendency of mirror-expressing and non-expressing cells to avoid mixing with each other is not determined by their differences in fringe expression. Thus mirror acts to regulate equator formation by both physically separating the dorsal cells from ventral cells, and restricting the formation of a fng expression boundary to the border where the dorsal and ventral cells meet.

Animals↗
PubMed1999

Nodular Pneumocystis carinii pneumonia in SIV-infected macaques.

Pneumocystis carinii (PC) pneumonia is a frequent manifestation of the acquired immunodeficiency syndrome (AIDS) in humans and macaques. An unusual nodular type of PC pneumonia was observed in two simian immunodeficiency virus (SIV)-inoculated rhesus macaques (Macaca mulatta). These animals developed clinical signs of simian AIDS, including anorexia, weight loss, dyspnea, and collapse. Grossly, both animals had multifocal tan-white nodules 1-10 mm in diameter scattered throughout the lungs. One animal had similar nodules involving the diaphragm and thoracic wall. The lungs were characterized by severe PC pneumonia with numerous large nodules consisting of foamy material that compressed adjacent tissue. The nodules had central areas of necrosis and lysis of alveolar septa. Varying degrees of necrotizing vasculitis were observed in areas of nodular PC pneumonia. The presence of PC in intra-alveolar spaces and nodular lesions was confirmed by immunohistochemistry. No evidence of other agents, including viral inclusions, bacteria, fungi, and lung mites, was detected. The animal with the most severe nodular PC pneumonia had vascular involvement with extrapulmonary spread to the diaphragm, thoracic wall, and regional lymph nodes. This unusual type of nodular PC pneumonia has been rarely seen in human AIDS patients.

Animals↗
PubMed1999

Fatal measles virus infection in Japanese macaques (Macaca fuscata).

An outbreak of natural measles virus infection occurred in a group of Japanese macaques (Macaca fuscata). Over a period of 4 months, 12 of 53 Japanese macaques died following a 2-23-day history of anorexia, diarrhea, and dermatitis. The monkeys were kept in outdoor exhibits but had been moved temporarily into indoor caging and then transferred to new outdoor exhibits. Ten monkeys died while they were in temporary caging, and two monkeys died after they were moved to new outdoor exhibits. The diagnoses were made based on the results of histopathology, immunohistochemistry (IHC), in situ hybridization (ISH), and electron microscopy. Measles virus antigens were detected in the lung, stomach, skin, salivary gland, spleen, and lymph nodes. Tangled, tubular nucleocapsids compatible with paramyxovirus were noted in the lung tissue. As a result of immunosuppression following measles virus infection, various secondary infections including disseminated cytomegalovirus infection, adenoviral and bacterial pneumonia, and Candida albicans-associated gingivitis and esophagitis were noted. The primary infective source or the mode of infection could not be determined in this outbreak, but measles virus may have been transmitted to the monkeys from human visitors while the monkeys were on exhibit.

Animals↗
PubMed1999

Delay in the diagnosis and treatment of primary bone sarcoma of the pelvis.

BACKGROUND: Symptoms arising from primary bone sarcoma of the pelvic girdle are often insidious in onset and nonspecific in nature. To make the subtle initial signs and symptoms of these tumors more apparent to clinicians, we studied a cohort of patients who had a primary bone sarcoma of the pelvic girdle. Our purpose was to describe the initial clinical findings and to evaluate the duration, frequency, and implications of delays in the treatment of these tumors. METHODS: We retrospectively analyzed the data on sixty-eight patients who had a primary bone sarcoma of the pelvic girdle. The data that we reviewed included demographic characteristics; histological diagnosis; anatomical location, size, and stage of the tumor; characteristics of the biopsy specimen; duration and description of symptoms before an accurate diagnosis was made; delay before recognition of the tumor on radiographs; results of diagnostic imaging; inaccurate diagnoses; type of intervention based on these inaccurate diagnoses; and outcome with regard to survival. There were forty high-grade sarcomas and twenty-eight low-grade sarcomas. RESULTS: Excluding two asymptomatic patients in whom the sarcoma was noted incidentally, the average duration of symptoms before an accurate diagnosis was made was ten months (median, six months; range, one month to four years). Common symptoms and findings on physical examination included pain in the buttock (twenty-three patients; 35 percent), a mass (twenty patients; 30 percent), sciatica (nineteen patients; 29 percent), pain in the hip (seventeen patients; 26 percent), pain in the groin (thirteen patients; 20 percent), and low-back pain (fourteen patients; 21 percent). In thirty (44 percent) of the sixty-eight patients, the pelvic sarcoma was not recognized initially and an inaccurate diagnosis was made. The misdiagnoses included a herniated lumbar disc, spinal stenosis, spondylolisthesis, tendinitis, bursitis, an inguinal hernia, a stress fracture, a pilonidal cyst, a recurrent urinary-tract infection, and degenerative arthritis of the spine, hip, and knee. Inappropriate treatment for these misdiagnoses included seven operative procedures (two laminectomies, two debridements, one hip arthrotomy, one total knee replacement, and one inguinal herniorrhaphy), six courses of nonsteroidal anti-inflammatory medications, five chiropractic adjustments, four trials of physical therapy, and three local injections of steroids. It took an average of seven months for the clinicians to arrive at the diagnosis of primary pelvic sarcoma. With the numbers available, no significant association between the duration of symptoms before an accurate diagnosis was made and the grade or the stage of the tumor could be detected. In addition, no association between the duration of symptoms and the survival of the patient (p = 0.54) could be determined, with univariate analysis. The grade and the stage of the tumor were strongly associated with the outcome, with a low tumor grade proving to be a favorable prognostic indicator for survival (p = 0.006). CONCLUSIONS: Patients who have a primary bone sarcoma of the pelvis often have had symptoms for a long duration that mimic those of more commonly encountered non-neoplastic musculoskeletal conditions. When a patient has symptoms that appear to be out of the ordinary, particularly refractory pain or pain at rest, physicians should include the pelvic girdle in the evaluation and should carefully examine a high-quality radiograph of the entire pelvis.

Adolescent↗
PubMed1999

Aneurysmal bone cyst of the extremities. Factors related to local recurrence after curettage with a high-speed burr.

BACKGROUND: Aneurysmal bone cyst is a benign, locally destructive lesion of bone. The rates of local recurrence after curettage have varied widely. Therefore, we performed a retrospective study of patients who had had an aneurysmal bone cyst in order to identify the rate of local recurrence and the prognostic factors related to local recurrence after use of contemporary methods of curettage with a high-speed burr. METHODS: We reviewed the cases of forty patients who had been managed by the same surgeon for an aneurysmal bone cyst, as diagnosed on the basis of the latest pathological review, between January 1, 1976, and December 31, 1993. The patients were evaluated with regard to age, gender, the duration and type of symptoms, the presence or absence of pathological fracture, the status of the growth plate, the bone and part of the bone that were involved, the type of operative procedure, the outcome, the radiographic stage, the findings on magnetic resonance imaging and computerized tomography (when it became available) and on bone scintigraphy, and histological parameters. The median duration of follow-up was eighty-seven months (range, fifteen to 267 months). According to the criteria of Enneking, no patient had a stage-1 lesion (one with a surrounding rim of cortical bone), twenty-four had a stage-2 lesion (one with a clearly defined border but no cortical bone), and sixteen had a stage-3 lesion (one with no clearly defined border). RESULTS: Of the forty patients, thirty-four had curettage with use of a high-speed burr. Of these thirty-four, twenty-two had filling of the defect with a cancellous autogenous graft; four, with a cancellous allograft; and three, with polymethylmethacrylate. In five patients, no material was put into the defect. The remaining six patients had resection through the margin of the lesion. Four (12 percent) of the thirty-four patients who had curettage had a local recurrence. No patient who had an excision through the margin of the lesion had a local recurrence. All local recurrences were in skeletally immature girls who were three, four, ten, and eleven years old. Univariate analysis with use of the chi-square, Fisher exact, and Wilcoxon log-rank tests showed that local recurrence was associated only with a young age (p = 0.0036) and open growth plates (p = 0.039). All local recurrences occurred within two years postoperatively, at two, seven, nine, and twenty-four months, and all were treated successfully with a second operation. CONCLUSIONS: Rates of local control of almost 90 percent can be achieved with thorough curettage with use of a mechanical burr and without use of liquid nitrogen, phenol, or other adjuvants in patients who have an aneurysmal bone cyst of an extremity. A young age and open growth plates are associated with an increased risk of local recurrence.

Adolescent↗
PubMed1999

Botanical medicines with gynecological anticancer activity: a literature review.

This article reviews the existing scientific literature reporting effects of botanical substances on the prevention and treatment of gynecological cancers. Anticancer effects were reported for 14 of 27 herbal substances searched for, 8 of which had reported effects specifically in gynecological cancer models. Research reviewed included in vitro studies in gynecological cancer cell lines, animal studies, an ex vivo study, and an epidemiological study. No clinical trials on gynecological cancer prevention or treatment were found for any of the 8 identified agents. Despite the increasing use of botanical medicines in the prevention and treatment of cancer in general, there is a paucity of studies describing their efficacy or safety in gynecological cancer. Given the prevalent use of botanical medicine in complementary and alternative cancer therapy, the need for research to evaluate safety and efficacy using both in vitro and in vivo methods is pressing.

Animals↗
PubMed1999

Similar motor block effects with different disposition kinetics between lidocaine and (+ or -) articaine in patients undergoing axillary brachial plexus block during day case surgery.

AIM: The aim of this investigation was to compare the clinical effects and pharmacokinetics of lidocaine and articaine in two groups of 15 patients undergoing axillary brachial plexus anesthesia. METHOD: The study had a randomized design. Thirty patients were allocated to one of the two groups. Each patient received either lidocaine (600 mg = 2.561 mMol + 5 microg/ml adrenaline) or articaine (600 mg = 2.113 mMol + 5 microg/ml adrenaline), injected via the axilla of the brachial plexus over a period of 30 seconds. Onset of surgical analgesia was defined as the period from the end of the injection of the local anesthetic to the loss of pinprick sensation in the distribution of all three nerves. RESULTS: The mean onset time of sensory block of the median nerve of both lidocaine and articaine were approximately 10 min. Lidocaine is biexponentially eliminated with a t1/2alpha of 9.95 +/- 14.3 min and a t1/2beta of 2.86 +/- 1.55 h. Lidocaine is metabolized into MEGX (mono-ethyl-glycyl-xilidide) (t(max) 2.31 +/- 0.84 h; C(max) 0.32 +/- 0.13 mg/l; t1/2beta 2.36 +/- 2.35 h). Lidocaine total body clearance was 67.9 +/- 28.9 l/h. Articaine is rapidly and monoexponentially eliminated with a t1/2beta of 0.95 +/- 0.39 h. The total body clearance of articaine is higher than that of lidocaine, 1,133 +/- 582 l/h vs 67.9 +/- 28.9 l/h, respectively (p < 0.0001). The volume of distribution (V(d)), of articaine is a factor 16 higher times than that of lidocaine (p < 0.0001). CONCLUSION: For the axillary administration, lidocaine and articaine show similar pharmacodynamics with a different pharmacokinetic behavior and can therefore be used to the clinical preference for this regional anesthetic technique.

Ambulatory Surgical Procedures↗
PubMed1998

Early regeneration of thymic progenitors in rhesus macaques infected with simian immunodeficiency virus.

The thymus plays a critical role in the maturation and production of T lymphocytes and is a target of infection by human immunodeficiency virus (HIV) and the related simian immunodeficiency virus (SIV). Using the SIV/macaque model of AIDS, we examined the early effects of SIV on the thymus. We found that thymic infection by SIV resulted in increased apoptosis 7-14 d after infection, followed by depletion of thymocyte progenitors by day 21. A marked rebound in thymocyte progenitors occurred by day 50 and was accompanied by increased levels of cell proliferation in the thymus. Our results demonstrate a marked increase in thymic progenitor activity very early in the course of SIV infection, long before marked declines in peripheral CD4(+) T cell counts.

Animals↗
PubMed1998

Mutational analysis of the SRC homology 2 domain protein-tyrosine phosphatase Corkscrew.

The SRC homology 2 (SH2) domain protein-tyrosine phosphatase, Corkscrew (CSW) is required for signaling by receptor tyrosine kinases, including the Sevenless receptor tyrosine kinase (SEV), which directs Drosophila R7 photoreceptor cell development. To investigate the role of the different domains of CSW, we constructed domain-specific csw mutations and assayed their effects on CSW function. Our results indicate that CSW SH2 domain function is essential, but either CSW SH2 domain can fulfill this requirement. We also found that CSW and activated SEV are associated in vivo in a manner that does not require either CSW SH2 domain function or tyrosine phosphorylation of SEV. In contrast, the interaction between CSW and Daughter of Sevenless, a CSW substrate, is dependent on SH2 domain function. These results suggest that the role of the CSW SH2 domains during SEV signaling is to bind Daughter of Sevenless rather than activated SEV. We also found that although CSW protein-tyrosine phosphatase activity is required for full CSW function, a catalytically inactive CSW is capable of providing partial function. In addition, we found that deletion of either the CSW protein- tyrosine phosphatase insert or the entire CSW carboxyl terminus, which includes a conserved DRK/GRB2 SH2 domain binding sequence, does not abolish CSW function.

Adaptor Proteins, Signal Transducing↗
PubMed1998

SRC64 regulates the localization of a Tec-family kinase required for Drosophila ring canal growth.

Mutation of the Src64 gene of Drosophila results in ovarian ring canal defects and reduced female fertility. We used a dosage-sensitive modifier screen to search for downstream components of the SRC64 signaling pathway. We show that mutations affecting Tec29, an essential gene encoding a member of the Tec family of protein tyrosine kinases, dominantly enhance the Src64 ring canal phenotype. Loss of Tec29 function in the female germline results in a phenotype strikingly similar to that caused by the loss of Src64 function. In each case, the ring canals are reduced in size and phosphotyrosine content. We further demonstrate that TEC29 localizes to the ring canal, and this subcellular localization requires Src64 function. These data suggest that TEC29 is a downstream target of SRC64, and that regulating TEC29 localization during ring canal growth may be a crucial SRC64 function.

Animal Structures↗