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M Weil

Publications and source records attributed to M Weil.

At least 19 recordsLinked to original sources
PubMed2004

["Tingling feet," forgetfulness, and progressive personality changes in a 63-year-old patient].

A 63-year-old female was admitted to the hospital with leg and forearm paresthesias. We found progressive ataxia, dementia, and psychosocial deterioration. The clinical symptoms, the neurologic and psychiatric abnormalities together with the inflammatory cerebrospinal fluid alteration and the cerebral magnetic resonance imaging changes suggested a paraneoplastic etiology. It was confirmed by paraneoplastic antineuronal antibodies in the patient's serum and the histological diagnosis of a small cell bronchial carcinoma. The prognosis of patients with paraneoplastic symptoms is the better the earlier a diagnosis is established and antitumor therapy is initiated.

Adenomatous Polyps↗
PubMed2004

BMP controls nitric oxide-mediated regulation of cell numbers in the developing neural tube.

Balanced cell proliferation and cell death determines neural precursor cell numbers in early stages of neural tube (NT) development. We have previously shown that nitric oxide (NO) regulates cell numbers locally in the NT of eight to 12 somite embryos. Here, we demonstrate that bone morphogenetic protein-4 (BMP-4), which is expressed in the ectoderm and dorsal NT at these developmental stages, induces programmed cell death (PCD) and promotes entry into the S-phase, via nitric oxide synthase (NOS) activity. These effects can be reversed by BMP-4 antagonists, such as follistatin and noggin, or by specific NOS inhibitors, resulting in low NO levels that facilitate mitosis and reduce PCD. Ectopic BMP-4 induction of PCD is restricted to the dorsal NT, whereas promotion of the S-phase is evenly observed across the dorsal-ventral (D-V) axis. Prolonged exposure to either BMP-4 or NOS inhibitors, which results in high or low NO levels, respectively, causes NT defects. The results presented here throw new light on the BMP signaling pathway. The local presence of BMP-4 helps to regulate cell numbers in the developing NT by a NO-mediated pathway, which is essential for normal NT formation.

Animals↗
PubMed2003

Tellurium compound AS101 induces PC12 differentiation and rescues the neurons from apoptotic death.

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Studies show that anti-apoptotic and neurotrophic agents are suitable candidates to prevent delayed cell death and/or restore neural function. Here we present the nontoxic immunomodulating compound AS101, which has the ability to induce neurite outgrowth and neural differentiation in PC12 cells. The present study shows that components of the ras signaling pathway are crucial for AS101-induced PC12 differentiation. These include p21ras and its downstream effectors, c-raf-1 and MEK, as well as PI3K. Moreover, these components mediate AS101-induced upregulation of p21waf, which is obligatory for AS101-induced PC12 differentiation. Furthermore, nitric oxide plays a significant role in these AS101 activities. Finally, we show that AS101 prevents apoptosis of NGF-differentiated PC12 cells after NGF withdrawal. Taken together, these results suggest that AS101 induces PC12 cell differentiation and survival by activating the ras-ERK1/2 and ras-PI3K signal transduction pathways, as well as inducing NO production. Our findings may be important in understanding the regulation of survival/apoptosis of neurons deprived of neurotropic support. Futhermore the data propose that AS101 may have clinical potential in the treatment of neurodegenerative disorders like Parkinson's disease.

Animals↗
PubMed2002

Constitutive caspase-like machinery executes programmed cell death in plant cells.

The morphological features of programmed cell death (PCD) and the molecular machinery involved in the death program in animal cells have been intensively studied. In plants, cell death has been widely observed in predictable patterns throughout differentiation processes and in defense responses. Several lines of evidence argue that plant PCD shares some characteristic features with animal PCD. However, the molecular components of the plant PCD machinery remain obscure. We have shown that plant cells undergo PCD by constitutively expressed molecular machinery upon induction with the fungal elicitor EIX or by staurosporine in the presence of cycloheximide. The permeable peptide caspase inhibitors, zVAD-fmk and zBocD-fmk, blocked PCD induced by EIX or staurosporine. Using labeled VAD-fmk, active caspase-like proteases were detected within intact cells and in cell extracts of the PCD-induced cells. These findings suggest that caspase-like proteases are responsible for the execution of PCD in plant cells.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases.

The selective degeneration of an axon, without the death of the parent neuron, can occur in response to injury, in a variety of metabolic, toxic, and inflammatory disorders, and during normal development. Recent evidence suggests that some forms of axon degeneration involve an active and regulated program of self-destruction rather than a passive "wasting away" and in this respect and others resemble apoptosis. Here we investigate whether selective axon degeneration depends on some of the molecular machinery that mediates apoptosis, namely, the caspase family of cysteine proteases. We focus on two models of selective axon degeneration: Wallerian degeneration of transected axons and localized axon degeneration induced by local deprivation of neurotrophin. We show that caspase-3 is not activated in the axon during either form of degeneration, although it is activated in the dying cell body of the same neurons. Moreover, caspase inhibitors do not inhibit or retard either form of axon degeneration, although they inhibit apoptosis of the same neurons. Finally, we cannot detect cleaved substrates of caspase-3 and its close relatives immunocytochemically or caspase activity biochemically in axons undergoing Wallerian degeneration. Our results suggest that a neuron contains at least two molecularly distinct self-destruction programs, one for caspase-dependent apoptosis and another for selective axon degeneration.

Animals↗
PubMed2000

Effects of bone marrow transplantation on the cardiovascular abnormalities in canine mucopolysaccharidosis VII.

The genetic mucopolysaccharidoses (MPS) are a family of lysosomal storage diseases resulting from defective catabolism of glycosaminoglycans (GAGs). Echocardiographic abnormalities in dogs with MPS type VII (Sly syndrome, beta-glucuronidase deficiency) included mitral valve thickening and insufficiency, large aortic dimensions in both the long and short axes, and thickened aortic valves. Grossly, at post mortem examination, there was nodular thickening of the mitral valve, a prominent ductus diverticulum, and a dilated aorta with thickened walls. Histologically, cytoplasmic vacuolation was seen in cells of the mitral valves, coronary arteries, and aorta. By electron microscopy, the cells of the mitral valve were packed with electron-lucent cytoplasmic vacuoles. The mean residual activity of beta-glucuronidase in the aorta and myocardium was <1% of normal, the mean hexosaminidase A activity >2. 5 times normal, and the mean GAG concentrations more than twice normal. In three MPS VII dogs that received heterologous BMT at 6 weeks of age, the echocardiographic abnormalities were improved, and the histopathologic and ultrastructural pathology was reduced. In the aorta and myocardium, the mean beta-glucuronidase activity of the BMT group was 4.5% and 11% of normal, respectively, and the hexosaminidase A activity and GAG concentrations were normalized. Bone Marrow Transplantation (2000) 25, 1289-1297.

Animals↗
PubMed1999

Caspase activation in the terminal differentiation of human epidermal keratinocytes.

The epidermis is a multilayered squamous epithelium in which dividing basal cells withdraw from the cell cycle and progressively differentiate as they are displaced toward the skin surface. Eventually, the cells lose their nucleus and other organelles to become flattened squames, which are finally shed from the surface as bags of cross-linked keratin filaments enclosed in a cornified envelope [1]. Although keratinocytes can undergo apoptosis when stimulated by a variety of agents [2], it is not known whether their normal differentiation programme uses any components of the apoptotic biochemical machinery to produce the cornified cell. Differentiating keratinocytes have been reported to share some features with apoptotic cells, such as DNA fragmentation, but these features have not been seen consistently [3]. Apoptosis involves an intracellular proteolytic cascade, mainly mediated by members of the caspase family of cysteine proteases, which cleave one another and various key intracellular target proteins to kill the cell neatly and quickly [4]. Here, we show for the first time that caspases are activated during normal human keratinocyte differentiation and that this activation is apparently required for the normal loss of the nucleus.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Lack of correlation between mitotic arrest or apoptosis and antitumor effect of docetaxel.

PURPOSE: To determine, as we did for paclit-axel, whether mitotic arrest and apoptosis induced in murine tumors in vivo by docetaxel correlate with the drug's antitumor effect and whether the antitumor efficacy of docetaxel depends on p53 mutational status of tumors. METHODS: C3Hf/Kam mice were implanted with one of the following 15 syngeneic tumors: seven adenocarcinomas (MCa-4, MCa-29, MCa-35, MCa-K, OCa-I, ACa-SG, and HCa-I), two squamous cell carcinomas (SCC-IV and SCC-VII), five sarcomas (FSa, FSa-II, Sa-NH, NFSa, and Sa-4020) and one lymphoma (Ly-TH). When the tumors had grown to 8 mm in diameter, the mice were treated with 31.3 mg/kg docetaxel i.v. Tumor growth delay was the endpoint of docetaxel's antitumor effect. In separate groups of mice, mitotic arrest and apoptosis were determined micromorphometrically 1 to 72 h after docetaxel treatment. Tumors were assayed for their p53 status by sequence analysis of RNA prepared from freshly excised tumors. RESULTS: Docetaxel caused statistically significant growth delay in six of seven adenocarcinomas, three of five sarcomas, and the lymphoma, but not in either of the squamous cell carcinomas. The drug induced mitotic arrest in all tumor types, but to various degrees ranging from 6.4+/-0.4% to 25.1+/-0.1%. In contrast, docetaxel induced appreciable apoptosis in only 5 of 15 tumors, with 10.3+/-1.6% being the highest apoptotic value. Neither mitotic arrest nor apoptosis were significantly correlated with tumor growth delay. However, tumors that responded to docetaxel by significant tumor growth delay histologically displayed massive cell destruction by cell lysis, and four of these tumors also showed marked infiltration with mononuclear lymphoid cells. Of the 15 tumors only 3 had mutant p53. CONCLUSIONS: Docetaxel exhibited a strong antitumor effect in two-thirds of murine tumors, and on a milligram per kilogram basis was more effective than paclitaxel against the same tumors. The drug was a potent inducer of mitotic arrest but a weak inducer of apoptosis, neither of which correlated with its antitumor effect. Tumor cell lysis appeared to be a major mode of tumor cell destruction and can be regarded as the main mechanism underlying antitumor efficacy of docetaxel. In contrast, paclitaxel's antitumor efficacy is related to its ability to induce apoptosis. At the molecular level, there was no dependency of antitumor efficacy of docetaxel on p53 mutational status of tumors.

Animals↗
PubMed1999

Short-term impact of safer choices: a multicomponent, school-based HIV, other STD, and pregnancy prevention program.

This study evaluated the effectiveness of the first year of Safer Choices, a theoretically based, multicomponent HIV, STD, and pregnancy prevention program for high school youth. The study featured a randomized trial involving 20 schools in California and Texas, with a cohort of 3,869 ninth-grade students. Students who completed both the baseline and the first follow-up survey approximately seven months later were included in the analysis (n = 3,677). Safer Choices enhanced 9 of 13 psychosocial variables including knowledge, self efficacy for condom use, normative beliefs and attitudes regarding condom use, perceived barriers to condom use, risk perceptions, and parent-child communication. Safer Choices also reduced selected risk behaviors. Specifically, Safer Choices reduced the frequency of intercourse without a condom in the three months prior to the survey, increased use of condoms at last intercourse, and increased use of selected contraceptives at last intercourse.

Adolescent↗
PubMed1998

The importance of timing differentiation during limb muscle development.

BACKGROUND: Skeletal muscle of trunk, limbs and tongue develops from a small population of cells that originates from somites. Although promoters and inhibitors of muscle differentiation have been isolated, nothing is known about how the amplification of the muscle precursor pool is regulated; this amplification provides muscle mass during development. Furthermore, little is known about how cells accumulate in the pre-muscle masses in the limbs. We investigated the role of bone morphogenetic protein (BMPs) and Sonic hedgehog (Shh) during proliferation, differentiation and positioning of muscle. RESULTS: The proliferation of muscle precursors in limbs was linked to Pax-3 expression. Ectoderm removal downregulated Pax-3 expression, arrested proliferation and prematurely initiated muscle differentiation which exhausted the muscle precursor pool and prevented further muscle growth. BMP-2, BMP-4 and BMP-7 had a dose-dependent effect on pre-myogenic cells: low concentrations maintained a Pax-3-expressing proliferative population, substituting for ectoderm-derived proliferative signals and delaying differentiation, whereas high concentrations prevented muscle development, probably by inducing apoptosis. In the limb, Shh upregulated Bmp-2 and Bmp-7 expression which delayed muscle differentiation, upregulated Pax-3, amplified the muscle precursor population and stimulated excessive muscle growth. CONCLUSIONS: These data indicate that embryonic muscle growth requires muscle differentiation to be delayed. Muscle differentiation may occur through a default pathway after cells escape proliferative signals. Positioning of muscle is regulated by high concentrations of BMPs, thus a single type of signalling molecule can determine crucial steps in muscle development: when and where to proliferate, and when and where to differentiate.

Animals↗
PubMed1998

High affinity ligands from in vitro selection: complex targets.

Human red blood cell membranes were used as a model system to determine if the systematic evolution of ligands by exponential enrichment (SELEX) methodology, an in vitro protocol for isolating high-affinity oligonucleotides that bind specifically to virtually any single protein, could be used with a complex mixture of potential targets. Ligands to multiple targets were generated simultaneously during the selection process, and the binding affinities of these ligands for their targets are comparable to those found in similar experiments against pure targets. A secondary selection scheme, deconvolution-SELEX, facilitates rapid isolation of the ligands to targets of special interest within the mixture. SELEX provides high-affinity compounds for multiple targets in a mixture and might allow a means for dissecting complex biological systems.

Blood Proteins↗
PubMed1998

Locoregional approaches to therapy with gliomas as the paradigm.

Most malignant gliomas recur locally, despite the fact that these tumors are usually found to be diffusely infiltrating on pathologic studies. Thus, efforts have concentrated on local disease control as an initial step to improve the prognosis of these patients. This review discusses the most recent studies on locoregional approaches in therapy for this poor-prognosis neoplasm. Emphasis is placed on the radiotherapeutic and combined modality (radiotherapy and chemotherapy) approaches reported during the past year.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Are caspases involved in the death of cells with a transcriptionally inactive nucleus? Sperm and chicken erythrocytes.

We show that mouse sperm die spontaneously within 1-2 days in culture and that treatment with either staurosporine (STS) and cycloheximide (CHX) or a peptide caspase inhibitor does not accelerate or delay the cell death. Chicken erythrocytes, by contrast, are induced to die by either serum deprivation or treatment with STS and CHX, and embryonic erythrocytes are more sensitive than adult erythrocytes to both treatments. Although these erythrocyte deaths display a number of features that are characteristic of apoptosis, they are not blocked, or even delayed, by peptide caspase inhibitors, and most of the cells die without apparently activating caspases. A small proportion of the dying erythrocytes do activate caspase-3, but even these cells, which seem to be the least mature erythrocytes, die just as quickly in the presence of caspase inhibitors. Our findings raise the possibility that both mouse sperm and chicken erythrocytes have a death programme that may not depend on caspases and that chicken erythrocytes lose caspases as they mature. Chicken erythrocytes may provide a useful 'stripped down' cell system to try to identify the protein components of such a death programme, which may serve to back-up the conventional caspase-dependent suicide mechanism in many cell types.

Animals↗
PubMed1998

[Diagnostic validity of thermography of lameness in horses].

Thirty-six lameness free horses and 119 horses with lameness of the distal forelimb including the carpus were evaluated through thermography. Examination was done with an infrared thermography camera "Thermovision 470" and a specially developed analyzing software program. Temperature differences between corresponding regions of the left and right forelimb were determined and scrutinized statistically between various lameness groups. By creating temperature differences between both limbs a parameter for skin temperature was found which is independent of surrounding temperature. In lameness free horses skin temperature was contralaterally symmetric and there was no significant temperature difference between left and right limb. A significant (p < 0.01) temperature difference of all regions in comparison to lameness free horses was demonstrated in diseases like navicular disease, pododermatitis and tendopathia. Horses with a diagnosis of coffin bone fracture and arthropathia showed a significant (p < 0.05) temperature difference in almost all regions compared to controls, whereas horses with laminitis and periostitis did not show a significant difference. Loss of symmetric distribution of skin temperature could be demonstrated between affected and non-affected regions. Thermography can show and quantitatively prove very well changes in skin temperature in forelimb lameness. It must be emphasized that thermography in lameness diagnosis of horses is only useful in combination with a thorough clinical examination including additional examination procedures.

Animals↗