Biomedical subjects

M A Klein

Publications and source records attributed to M A Klein.

At least 55 records · Page 3Linked to original sources

PubMed1998

[Significance of prion protein in transmission of prions and in pathogenesis of spongiform encephalopathies].

Prion disease or transmissible spongiform encephalopathies are caused by novel pathogens termed prions. Unlike classical infectious agents such as viruses or bacteria, prions lack an independent genome and consist largely if not entirely of an abnormal form of the host-encoded prion protein. How prions multiply is not known. A wealth of experimental evidence supports an essential role for the host-encoded prion protein in susceptibility and pathogenesis of prion diseases and in the propagation and spread of prions. In addition, B lymphocytes have been found to play a crucial role in the neuroinvasiveness of prions.

Animals↗

PubMed1997

PrP-expressing tissue required for transfer of scrapie infectivity from spleen to brain.

Much available evidence points to a pathological isoform of the prion protein PrP being the infectious agent that causes transmissible spongiform encephalopathies, but the mechanisms controlling the neurotropism of prions are still unclear. We have previously shown that mice that do not express PrP (Prnp[o/o] mice) are resistant to infection by prions, and that if a Prnp(+/+) neurograft is introduced into such animals and these are infected intracerebrally with scrapie, the graft but not the surrounding tissue shows scrapie pathology. Here we show that PrP-expressing neurografts in Prnp(o/o) mice do not develop scrapie histopathology after intraperitoneal or intravenous inoculation with scrapie prions. Prion titres were undetectable in spleens of inoculated Prnp(o/o) mice, but were restored to wild-type levels upon reconstitution of the host lymphohaemopoietic system with PrP-expressing cells. Surprisingly, however, i.p. or i.v. inoculation failed to produce scrapie pathology in the neurografts of 27 out of 28 reconstituted animals, in contrast to intracerebral inoculation. We conclude that transfer of infectivity from the spleen to the central nervous system is crucially dependent on the expression of PrP in a tissue compartment that cannot be reconstituted by bone marrow transfer. Thus the requirement for the normal isoform of PrP in peripheral tissues represents a bottleneck for the spread of prions from peripheral sites to the central nervous system.

Bone Marrow↗

PubMed1997

Transforming activity and mitosis-related expression of the AKT2 oncogene: evidence suggesting a link between cell cycle regulation and oncogenesis.

The AKT2 oncogene encodes a protein-serine/threonine kinase containing a pleckstrin homology domain characteristic of many signaling proteins. Recently, it was shown that AKT2 kinase activity can be induced by platelet-derived growth factor through phosphatidylinositol-3-OH kinase, suggesting that AKT2 may be an important signal mediator that contributes to the control of cell proliferation. We previously reported amplification and overexpression of AKT2 in human cancers. To investigate the transforming activity of AKT2, we used a retrovirus-based construct to express AKT2 in NIH3T3 cells. Overexpression of AKT2 was found to transform NIH3T3 cells, as determined by growth in soft agar and tumor formation in nude mice. The oncogenic activity of AKT2 was diminished by truncation of a 70-amino acid proline-rich region at the carboxyl-terminus. To facilitate the characterization of AKT2, we generated monoclonal and polyclonal antibodies against this protein. AKT2 was localized to the cytoplasm by cell fractionation experiments, immunocytochemistry, and immunofluorescence. Protein levels were more abundant in mitotic cells than in interphase cells. Western blot analysis of synchronized pancreatic cancer cells demonstrated that the expression level of AKT2 protein in mitotic cells is three to fivefold higher than in their interphase counterparts. A time-course study of phytohemagglutinin-stimulated lymphocytes revealed that AKT2 mRNA and AKT2 protein levels are highest 48-72 h after addition of mitogen, when cells are actively dividing. These data suggest that AKT2 could play a significant role in cell cycle progression and that the oncogenic activity of overexpressed AKT2 may be mediated by aberrant regulation of cellular proliferation.

3T3 Cells↗

PubMed1997

Impaired neuroglial activation in interleukin-6 deficient mice.

Astrocyte activation is a ubiquitous hallmark of the damaged brain and has been suggested to play an important regulatory role in the activation, survival, and regeneration of adjacent neurons, microglia, and oligodendrocytes. Little is known, however, about the endogenous signals that lead to this activation of astrocytes. Here we examined the regulation of interleukin 6 (IL6), a proinflammatory cytokine, its receptors, and the effects of IL6-deficiency in a model of traumatic central nervous system injury in the axotomized mouse facial motor nucleus. Facial nerve transection led to a massive but transient upregulation of IL6 mRNA in the disconnected motor nucleus, while IL6-receptor subunits were constitutively expressed on motoneurons and astrocytes. Absence of IL6 in genetically IL6-deficient mice led to massive reduction in the number of activated GFAP-positive astrocytes, a more moderate decrease in microglial activation and proliferation, and an increase in the late neuronal response to axotomy. These results emphasize the role of IL6 in the global regulation of neurons, astrocytes, and microglia and their activation in the injured nervous system.

Animals↗

PubMed1997

Tracking prions: the neurografting approach.

The physical nature of the agent that causes transmissible spongiform encephalopathies (the 'prion'), is the subject of passionate controversy. Investigation of it has benefited tremendously from the use of transgenic and knockout technologies. However, prion diseases present several other enigmas, including the mechanism of brain damage and how the affinity of the agent for the central nervous system is controlled. Here we show that such questions can be effectively addressed in transgenic and knockout systems, and that pathogenesis may be clarified even before we can be certain about the nature of the infectious agent. Availability of mice overexpressing the Prnp gene (which encodes the normal prion protein) and Prnp knockout mice allows for selective reconstitution experiments aimed at expressing PrP in specific portions of the brain or in selected populations of hemato- and lymphopoietic origin. We summarize how such studies can offer insights into how prions administered to peripheral sites can gain access to central nervous tissue, and into the molecular requirements for spongiform brain damage.

Animals↗

PubMed1997

Acute and chronic cocaine exposure can produce myocardial ischemia and infarction in Yucatan swine.

The purpose of this study was to determine whether the acute and chronic administration of cocaine could induce myocardial infarction. Twenty-five minipigs were studied before and 4 months after balloon angioplasty of the left anterior descending artery (LAD) and balloon denudation of the left circumflex artery (LCx). Minipigs received cocaine in the initial and in the 4-month study (0.1, 0.5, and 3 mg/kg i.v.). Minipigs were randomized to group I (high-cholesterol diet + daily cocaine; 500 mg i.m.; n = 8), group II (high-cholesterol diet + no i.v. cocaine; n = 5), group III (chow diet + daily cocaine; 500 mg i.m.; n = 6), group IV (chow diet + no i.v. or i.m. cocaine; n = 6). In vivo, coronary flow significantly decreased and vascular resistance significantly increased after the administration of cocaine. Histamine significantly decreased the luminal diameters (LAD and LCx) in groups I, II and III. There were a total of five acute and 16 chronic infarctions among the three groups that received either short- or long-term cocaine; however, no infarct occurred in group IV. The combination of daily cocaine abuse with a cholesterol-rich diet enhanced coronary vasoreactivity in vivo and in vitro. We conclude that long-term or sporadic cocaine abuse can induce myocardial infarction.

Animals↗

PubMed1997

MR imaging of miscellaneous disorders of the shoulder.

During the course of routine MR imaging of the shoulder, a wide variety of abnormalities may be encountered owing to the technique's broad soft-tissue contrast resolution and multiplanar tomographic capability. In this article, the authors provide an overview of the lesions that might be encountered in this setting.

Adolescent↗

PubMed1996

Regulation of thrombospondin in the regenerating mouse facial motor nucleus.

Thrombospondin (TSP) is a multifunctional extracellular matrix protein that plays a role in neuronal migration and axonal outgrowth in the developing central nervous system. In the current study we have examined the localization and regulation of TSP immunoreactivity (TSP-IR) during neuronal regeneration in the axotomized facial motor nucleus using Western blotting and light and electron microscopy. Transection of the facial nerve led to a gradual increase in TSP-IR in the regenerating motoneurons, peaking 4-7 days after injury (DAI). In addition to regenerating neurons, axotomy also caused a rapid upregulation of TSP-IR on activated microglia throughout the facial nucleus, with a maximum of 2-3 DAI, and a second increase at 14-21 DAI on microglial aggregates surrounding degenerating motoneurons and in neuronophagic microglia. In summary, injury leads to the induction of thrombospondin on axotomized neurons and activated microglia, peaking at the times of maximal posttraumatic microglial proliferation and during neuronal phagocytosis. Since thrombospondin is a multimodal extracellular matrix protein with a variety of cell attachment sites, thrombospondin might serve to link microglia and injured neurons, followed by microglial proliferation and removal of the neuronal debris.

Animals↗

PubMed1996

Phenotype of lymphocytes associated with the inflammatory reaction to silicone gel breast implants.

The tissue response to silicone gel breast implants typically includes an inflammatory infiltrate that consists of macrophages, foreign body-type giant cells, and a variable number of lymphocytes and plasma cells. The phenotype of the lymphocytic component was investigated with three-color flow cytometry. Lymphocytes were obtained by collecting fluid from the space between the implant and the fibrous capsule or by washing cells from the fibrous capsule at the time of implant removal with total capsulectomy. Eighty-nine percent of the implant-associated lymphocytes were T cells. Twenty-five percent of the CD3+ T cells coexpressed HLA-DR compared with only 7.9% of matched peripheral blood lymphocytes. Sixty-eight percent of the implant-associated T cells coexpressed CD4 and CD29, while only 3% of the T cells coexpressed CD4 and CD45RO. The expression of HLA-DR and the predominance of CD29+ CD4+ T cells indicate that there is immune activation with the potential for stimulating antigen-specific antibody production. The role of silicone gel breast implants in immune activation and its clinical significance require further investigation.

Adult↗

PubMed1996

Interobserver variability in the diagnosis of high-grade prostatic intraepithelial neoplasia and adenocarcinoma.

High-grade prostatic intraepithelial neoplasia (PIN) is a strong predictor of carcinoma when identified in small-needle biopsy specimens. However, the diagnostic variability of PIN is unknown. Eight pathologists reviewed 321 prostatic biopsy specimens to assess the variability of the diagnosis of high-grade PIN and carcinoma. All of the specimens were classified as negative, high-grade PIN, suspicious for high-grade PIN, carcinoma, or suspicious for carcinoma, more than one diagnosis was permitted, except for negative. We compared diagnoses made by two observers by pairing them for negative versus high-grade PIN, negative versus carcinoma, high-grade PIN versus carcinoma, and all diagnostic categories together. Mean kappa coefficient values for 28 interobserver combinations were 0.451, 0.845, 0.669, and 0.482, respectively, for each of the four comparison combinations considered. Our results indicate a high level of agreement, "almost perfect" (kappa = 0.81-1.0) for carcinoma, "moderate" (kappa = 0.41-0.60) for high-grade PIN, and "substantial" (kappa = 0.61-0.81) for high-grade PIN versus carcinoma. We found that variability was related to the level of interest in prostatic pathology, the conditions of the study, the subjective application of diagnostic criteria, and the influence of peers and clinical colleagues.

Adenocarcinoma↗

PubMed1995

MR imaging of the normal sternoclavicular joint: spectrum of findings.

Although MR imaging has become an important imaging method in the evaluation of most joints, it is rarely used to evaluate the sternoclavicular joint. The purpose of this study was to determine the spectrum of findings identified on MR images of the normal sternoclavicular joint as seen on images of cadavers, healthy volunteers, and patients with normal joints. Knowledge of these findings can prevent misdiagnosis of a normal variant as an abnormality.

Adolescent↗

PubMed1995

Drug use patterns and risk factors of adolescents with physical disabilities.

This study examined demographic, behavioral, and attitudinal variables and drug use in adolescents with physical disabilities as measured by the Primary Prevention Awareness, Attitude and Usage Scales (PPAAUS). When compared to the same age students in the general population, the students with physical disabilities responded differently. A chi-square analysis was performed between drug use and demographic, behavioral, and attitudinal variables. Results found for physically disabled students drug use correlated at p < .05 with feelings toward school, negative disruptive behaviors, reported activities attended, and reported grade average.

Adolescent↗

PubMed1994

Cocaine-induced microvascular spasm in Yucatan miniature swine. In vivo and in vitro evidence of spasm.

The purpose of the present study was to determine the maximal coronary flow reserve (CFR) before and after the administration of successive cocaine doses (0.1, 0.5, 3, and 7 mg/kg IV) for 2 minutes at 10-minute intervals in eight miniature swine. CFR was assessed by the administration of adenosine (0.03, 0.3, and 3 mg IC). Hemodynamic and flow measurements were performed 3 minutes after each dose. Coronary flow (CF) was measured with a Doppler-tipped wire in the proximal left anterior descending coronary artery (LAD). Also, microvessels were dissected, and vessel diameters were measured by a videoelectronic dimension analyzer. In vivo, LAD CF increased fourfold, CFR increased twofold, and coronary vascular resistance (CVR) decreased fourfold after the administration of adenosine. In contrast, LAD CF decreased threefold, CFR decreased onefold, and CVR increased sixfold 3 minutes after the administration of cocaine. Adenosine (3 mg) was repeated 4 minutes after the administration of cocaine, and LAD CF increased 1.4-fold, CVR increased 2.5-fold, and CFR decreased onefold. Thus, adenosine partially reversed the potent cocaine constrictor effect. In vitro, 10(-9) mol/L cocaine decreased the diameter of the coronary microvessels from 129 +/- 12 to 127 +/- 12 microns, and 10(-4) mol/L cocaine decreased coronary microvessel diameter to 114 +/- 15 microns (P < .05). In conclusion, cocaine in vivo decreases CFR, and consistent with the in vivo effect, cocaine in vitro produced constriction of vessels < 200 microns. These results indicate that cocaine can produce profound microvascular spasm. This may contribute to the ischemia/infarction reported in patients who abuse cocaine and who are subsequently found to have normal epicardial coronary arteries.

Adenosine↗

PubMed1994

MR imaging of the ankle: normal and abnormal findings in the medial collateral ligament.

The medial collateral ligament (MCL) of the ankle, also known as the deltoid ligament, attaches the medial malleolus to the tarsus. There are almost as many different descriptions of the components of the MCL as there are people describing them. Differences exist as to whether it has superficial and deep components, which ligaments are superficial and which are deep, the attachment sites of the component ligaments, and even the number and names of component ligaments [1]. Additionally, evaluation of the MCL on MR images has been largely ignored. This pictorial essay illustrates the normal component ligaments of the MCL, as well as injuries to each of these components, as seen on three-dimensional Fourier transform (3DFT) gradient-recalled echo (GRE) MR images in 81 patients (86 ankles).

Adult↗

PubMed1993

MR imaging of the tarsal sinus and canal: normal anatomy, pathologic findings, and features of the sinus tarsi syndrome.

After definition of the normal anatomic features of the tarsal sinus and canal at magnetic resonance (MR) imaging, 123 ankle MR imaging studies in 116 patients were reviewed. Abnormalities of the tarsal sinus and canal were seen on MR images in 33 cases (26.8%), were highly associated with tears of the lateral collateral ligament, and could be categorized according to the pathologic findings in patients with sinus tarsi syndrome: (a) diffuse infiltration with low T1- and T2-weighted signal intensity (n = 17) consistent with fibrosis, (b) diffuse infiltration with low T1-weighted signal intensity and increased T2-weighted signal intensity (n = 11) consistent with chronic synovitis and nonspecific inflammatory changes, and (c) multiple abnormal fluid collections (n = 5) consistent with synovial cysts. Absence of the anterior microrecesses of the posterior subtalar joint was a common finding on normal MR imaging studies (46 of 90) and may reflect lack of iatrogenic joint distention. Tears of the posterior tibial tendon may have a previously unrecognized association with the sinus tarsi syndrome.

Adult↗

PubMed1993

Detection of chronic coronary artery disease: value of pharmacologically stressed, dynamically enhanced turbo-fast low-angle shot MR images.

OBJECTIVE: The potential of MR imaging for evaluating myocardial perfusion and viability may make it the imaging procedure of choice for examining patients with ischemic heart disease. Accordingly, the purpose of this study is to determine the value of pharmacologically stressed, dynamically enhanced turbo-fast low-angle shot (FLASH) MR imaging in detecting chronic coronary artery disease. SUBJECTS AND METHODS: Five patients who had coronary angiography within the past 6-12 months were included in the study. After injection of 0.56 mg/kg of dipyridamole over 4 min, a bolus of 0.05 mg/kg of gadopentetate dimeglumine and subsequently 10 mCi (370 MBq) of 99mTc-sestamibi were injected. Short-axis turbo-FLASH images were obtained before injection and immediately, 1 min, 3 min, and 5 min after the injection of contrast material. Stress single-photon emission computed tomography (SPECT) images of the heart were obtained 60 min after the 99mTc-sestamibi injection. One and a half hours after an additional 30 mCi (1110 MBq) of 99mTc-sestamibi was injected, SPECT images were obtained with patients at rest. Prospective MR imaging evaluation of these five patients was performed by radiologists who did not know any of the imaging data. The MR imaging studies were compared with the near simultaneous 99mTc-sestamibi SPECT studies and with recent coronary angiograms. RESULTS: Thirteen myocardial segments were diagnosed as abnormal when 99mTc-sestamibi SPECT was used as the gold standard (12 reversible defects and one fixed defect). Twelve segments were normal on the 99mTc-sestamibi SPECT study. With SPECT as the gold standard, prospective MR imaging had a sensitivity of 77% and a specificity of 75%, whereas retrospectively it had a sensitivity of 92% and a specificity of 75%. With recent coronary angiography as the gold standard, prospective MR imaging had a sensitivity of 81% and a specificity of 100%. The quantitative data did not improve the accuracy of the qualitative analysis. CONCLUSION: Our results suggest that accurate prospective identification of chronic coronary artery disease may be possible with dynamically enhanced, pharmacologically stressed, turbo-FLASH MR imaging. Studies of additional patients to confirm this initial impression are warranted.

Adult↗

PubMed1993

Reformatted three-dimensional Fourier transform gradient-recalled echo MR imaging of the ankle: spectrum of normal and abnormal findings.

MR imaging is the imaging technique of choice for evaluating ankle tendons and ligaments. Although reformation of three-dimensional Fourier transform (3DFT) gradient-recalled echo (GRE) MR images on an independent console has been evaluated in other joints, little attention has been given to use of this technique for evaluation of the ankle. In this essay, we illustrate the spectrum of normal appearances of the posterior tibial tendon (PTT), flexor digitorum longus tendon, flexor hallucis longus tendon, and plantar calcaneonavicular ligament (PCNL) on 3DFT GRE images. Also, we describe the advantages of evaluating these structures with 3DFT GRE vs spin-echo (SE) MR images, demonstrate the spectrum of abnormal findings seen in these structures on 3DFT GRE MR images in a large clinical series, and show the relationship of the accessory navicular bone to PTT abnormalities.

Ankle Joint↗

PubMed1992

Vitamin C intake and mortality among a sample of the United States population.

We examined the relation between vitamin C intake and mortality in the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study cohort. This cohort is based on a representative sample of 11,348 noninstitutionalized U.S. adults age 25-74 years who were nutritionally examined during 1971-1974 and followed up for mortality (1,809 deaths) through 1984, a median of 10 years. An index of vitamin C intake has been formed from detailed dietary measurements and use of vitamin supplements. The relation of the standardized mortality ratio (SMR) for all causes of death to increasing vitamin C intake is strongly inverse for males and weakly inverse for females. Among those with the highest vitamin C intake, males have an SMR (95% confidence interval) of 0.65 (0.52-0.80) for all causes, 0.78 (0.50-1.17) for all cancers, and 0.58 (0.41-0.78) for all cardiovascular diseases; females have an SMR of 0.90 (0.74-1.09) for all causes, 0.86 (0.55-1.27) for all cancers, and 0.75 (0.55-0.99) for all cardiovascular diseases. Comparisons are made relative to all U.S. whites, for whom the SMR is defined to be 1.00. There is no clear relation for individual cancer sites, except possibly an inverse relation for esophagus and stomach cancer among males. The relation with all causes of death among males remains after adjustment for age, sex, and 10 potentially confounding variables (including cigarette smoking, education, race, and disease history).

Adult↗