Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis.

An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.

Growth factors as active participants in carcinogenesis: a perspective.

Growth factors are low molecular peptides active in the stimulation of cell proliferation and in the regulation of embryonic development and cellular differentiation. Significant progress has been made in developing effective strategies to treat human malignancies with new chemical compounds based on a rationale directed against various components of signaling pathways. Many of these drugs target a growth factor receptor--for instance, in the form of monoclonal antibodies or inhibitors of tyrosine kinases, such as monoclonal antibodies against epidermal growth factor receptors used in treating certain types of breast cancer. Imatinib mesylate [Gleevec]) is an excellent example of mediators of signal transduction, such as tyrosine kinases. Growth factors proper are used to ameliorate various and sometimes fatal side effects of cytotoxic and/or myelosuppressive chemotherapy. Basic characteristics of several growth families are discussed with therapeutic modalities based on growth factor activity or, more often, inhibition of such activity.

Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study.

BACKGROUND: There are no published MRI studies comparing interferon beta 1b (IFNbeta-1b) and glatiramer acetate (GA) for treatment of relapsing multiple sclerosis (MS). OBJECTIVE: To compare the efficacy of IFNbeta-1b and GA for suppression of MS disease activity as evidenced on frequent brain MRI. METHODS: A total of 75 patients with relapsing-remitting MS or clinically isolated syndromes were randomized to standard doses of IFNbeta-1b or GA and followed by monthly brain MRI for up to 2 years with a protocol optimized to detect enhancement. The primary outcome was the number of combined active lesions (CAL) per patient per scan during the first year, which included all enhancing lesions and nonenhancing new T2/fluid-attenuated inversion recovery (FLAIR) lesions. Secondary outcomes were the number of new lesions and clinical exacerbations over 2 years. RESULTS: Baseline characteristics were similar between the groups. The primary outcome showed similar median (75th percentile) CAL per patient per scan for months 1-12, 0.63 (2.76) for IFNbeta-1b, and 0.58 (2.45) for GA (p = 0.58). There were no differences in new lesion or clinical relapses for 2 years. Only 4.4% of CAL on monthly MRI scans were nonenhancing new T2/FLAIR lesions. CONCLUSION: Patients with relapsing multiple sclerosis randomized to interferon beta 1b or glatiramer acetate showed similar MRI and clinical activity.

Electrophysiological subtypes of psychotic states.

OBJECTIVE: This research sought neurobiological features common to psychotic states displayed by patients with different clinical diagnoses. METHOD: Cluster analysis with quantitative electroencephalographic (QEEG) variables was used to subtype drug-naïve, non-medicated, and medicated schizophrenic, depressed and alcoholic patients with psychotic symptoms, from the USA and Germany. QEEG source localization brain images were computed for each cluster. RESULTS: Psychotic patients with schizophrenia, depression and alcoholism, and drug- naïve schizophrenic patients, were distributed among six clusters. QEEG images revealed one set of brain regions differentially upregulated in each cluster and another group of structures downregulated in the same way in every cluster. CONCLUSION: Subtypes previously found among 94 schizophrenic patients were replicated in a sample of 390 non-schizophrenic as well as schizophrenic psychotics, and displayed common neurobiological abnormalities. Collaborative longitudinal studies using these economical methods might improve differential understanding and treatment of patients based upon these features rather than clinical symptoms.

Effects of immobilization on the biomechanical properties of the broiler tibia and gastrocnemius tendon.

Researchers have provided much insight into the various factors that influence the incidence of musculoskeletal problems in the poultry industry. However, a better understanding of the mechanobiology of broiler bone and tendon can have a positive effect on the welfare of the production bird and assist in the development of improved production practices. This study investigated the mechanical adaptability responses due to disuse on the biomechanical properties of the broiler tibia and gastrocnemius tendon. Beginning at 3 wk of age, broilers were placed in a harness system designed to eliminate load bearing of the leg. After 2 wk of this treatment, the average values for body mass and shank length of the birds were 58 and 85% of the values for the controls, respectively. The treatment reduced the mineral content of the tibia by approximately 50%, tibia structural strength by 40%, and tibia material strength by 8%. The structural strength and toughness of the gastrocnemius tendon were reduced by 10 and 30%, respectively, whereas the material strength, material toughness, and material stiffness of the tendon increased by approximately 75, 65, and 70%, respectively.

Effects of activity on avian gastrocnemius tendon.

Physical activity and its relationship to animal health is a continuous concern of the food animal industry. This study investigated the relationship between broiler (meat-type chicken) activity to the structural integrity of the gastrocnemius tendon. Birds were exposed to treadmill pacing to determine if increased mobilization would increase tendon strength and improve its resistance to soft tissue injury. One hundred eighty broilers raised under normal commercial housing conditions were forced to walk on a treadmill 30 min/d, 5 d/wk for 3 wk, beginning at 3 wk of age. The treadmill treatment did affect the growth rate of the broilers. At the end of the study, the average body mass of the treatment birds was 9% less than the average body mass of the control birds, and the average length of the treatment shanks was 5% less than those from the control birds. Biomechanical parameters were measured and used to determine changes in the structural and material integrity of the tendons. The treadmill treatment did not affect tendon toughness, stiffness, relaxation behavior, and failure strength, but treatment did appear to affect tendon geometry, in which 33% of the treadmill treatment tendons had an increased amount of tissue near the bifurcation. The treadmill treatment did not affect the amount of procollagen within the tendon, and no cellular anomalies were found.

Tendon proteoglycans: biochemistry and function.

Tendon remodeling occurs in response to changes in loading and mobilization. Though the normal mechanical function depends on precise alignment of collagen fibrils, it is proteoglycans that regulate collagen fibrillogenesis and thus, indirectly, tendon function. In this paper we discuss the basic biochemical structure of several members of two proteoglycans families. Decorin, biglycan, fibromodulin and lumican, all members of the small leucine-rich proteoglycans family, bind to collagen fibrils and are active participants in fibrillogenesis. Aggrecan and versican, two members of large modular proteoglycans or lecticans, and their partner hyaluronan likely provide tendon tissues with a high capacity to resist high compressive and tensile forces associated with loading and mobilization. We present data from our laboratory showing that proteoglycans and glycosaminoglycan content increases not only with growth but also with loading of young avian gastrocnemius tendons. Specifically, an increase in the content of keratan sulfate, chondroitin sulfate and hyaluronan was observed. Moderate exercise for several weeks led not only to a further increase in total proteoglycans content but also to qualitative changes in proteoglycan make up.

In vitro culture decreases the expression of TGF(beta), Hsp47 and type I procollagen and increases the expression of CTGF in avian tendon explants.

Weight-bearing tendons in many species, including humans, chickens and horses, are prone to failure, in many cases without a discernible cause. The normal function of the tendon depends on the proper assembly of fibrils of type I collagen, the main structural component of the tendon. We studied the effect of in vitro culture, temperature (37 degrees C vs. 43 degrees C) and wounding on the expression of mRNAs for several collagen regulators, transforming growth factor beta (TGF(beta)), heat shock protein 47 (Hsp47) and connective tissue growth factor (CTGF), in chicken embryonic gastrocnemius tendon explants. The expression of mRNAs for TGF(beta) and Hsp47, a chaperone of collagen assembly, remained strong during the first day of in vitro culture, but then it decreased, slightly more at higher temperature. Additional injury in selected tendons had no significant effect on the levels of TGF(beta) and Hsp47 mRNAs. Likewise, the level of immunostained type I procollagen also decreased with the length of culture. The expression of CTGF gradually increased from 0 at the time of tendon removal with the duration of culture to strong after three days of culture when the expression of TGF(beta) and Hsp47 was low. We conclude that in vitro culture over the period of several days rather than an increase in temperature or additional wounding decreases the expression of TGF(beta), Hsp47 and type I procollagen and increases the expression of CTGF.

The effect of enrofloxacin on cell proliferation and proteoglycans in horse tendon cells.

Fluoroquinolone antibiotics have been used widely in humans and domestic animals, including horses, because of their broad-spectrum bactericidal activity, and relative safety. The use of fluoroquinolones, however, is not without risk. Tendonitis and spontaneous tendon rupture have been reported in people during or following therapy with fluoroquinolones. We have studied the effects of enrofloxacin, a fluoroquinolone antibiotic used commonly in domestic animals, on tendon cell cultures established from equine superficial digital flexor tendons. Effects on cell proliferation and morphology were studied using cell counting and scanning electron microscopy. Monosaccharide content and composition was determined by gas chromatography-mass spectrometry analysis. Western and Northern blot analyses were utilized to evaluate the synthesis and expression of two proteoglycans, biglycan and decorin. Our data demonstrate that enrofloxacin inhibits cell proliferation, induces morphological changes, decreases total monosacharide content and alters small proteoglycan synthesis at the glycosylation level in equine tendon cell cultures. These effects are more pronounced in juvenile tendon cells than in adult equine tendon cells. We hypothesize that morphological changes and inhibition of cell proliferation are a result of impaired production of biglycan and decorin, proteoglycans involved in fibrillogenesis of collagen, the most important structural component of the tendon of enrofloxacin-treated tendon cells. Our findings suggest that fluoroquinolones should be used with caution in horses, especially in foals.

Wound healing and angiogenic properties of supernatants from Lactobacillus cultures.

Extracts or supernatants from cultures of Lactobacilli are used for their medicinal effects, including wound healing and immune system stimulating activity. We have studied the in vivo and in vitro effects of supernatants from bacterial cultures of two strains of Lactobacillus (LS) on tissue repair and angiogenesis. Subcutaneous injection of LS into rodent ears led to proliferation of blood vessels that also exhibited strong immunostaining for Flk-1 receptor. Some inflammatory cells were scattered among the blood vessels. The continuous influx of polymorphonuclear leukocytes (PMNs) and macrophages into transcutaneous wounds in mice treated with LS resulted in prolonged inflammatory phase of wound healing and delayed wound closure, including reepithelialization. Subcutaneous injection of Matrigel impregnated with LS into the abdominal wall led to rapid and transient influx of PMNs in the vicinity of the gel. LS stimulated the proliferation of murine macrophage J774.A1 cell line and porcine lymphocytes but not that of murine fibroblast AKR-2B cells. LS also induced production of TNF-alpha by J774.A1 cells and by porcine kidney epithelial LLC-PK1 cells. LS did not appear to have an effect on collagen production. In conclusion, our study demonstrates the potential of LS to function as a stimulator of the inflammatory stage of tissue repair, TNF-alpha production, and of angiogenesis.

Adherence to disease-modifying therapy in multiple sclerosis: Part I.

Multiple sclerosis (MS) is a chronic, debilitating disease for which there is no cure. However, the recent introduction of injectable immunomodulating agents has made it possible to reduce the frequency of relapsing episodes and to possibly slow its progression. The use of these agents is recommended by the National MS Society, however, their true potential cannot be realized if patients do not accept them and healthcare professionals do not promote them. Because MS is unpredictable, and treatments can produce side effects, ensuring adherence to the recommended therapy is a complex and challenging issue. A better understanding of the obstacles to adherence, and the identification of possible solutions, should be of value to nurses, who have numerous opportunities to encourage patients to initiate and continue therapy. This article, which is in two parts, describes the particular problems of treatment adherence, and proposes that the transtheoretical model of behavior change can be useful in achieving treatment goals in MS and in other chronic disease states. This model is based upon the concept that a patient's "readiness for change" is crucial, and that attempts at intervention should be sensitive to the patient's changing conditions and state of mind. Nurses who work with patients with MS and other chronic diseases can apply the model to help their patients accept and adhere to the demands of ongoing treatment.

Adherence to disease-modifying therapy in multiple sclerosis: Part II.

Multiple sclerosis (MS) is a chronic, debilitating disease for which there is no cure; however, the recent introduction of injectable immunomodulating agents has reduced the rate of relapsing episodes and possibly slowed the progression of the disease. These disease-modifying agents are recommended by the National MS Society, but their true potential cannot be realized if patients do not accept them and healthcare professionals do not promote them. Since MS has an unpredictable course, and treatments can produce side effects, adherence to the recommended therapy is a complex and challenging issue. Improved understanding of the obstacles to adherence and the identification of possible solutions should be of value to nurses, who have numerous opportunities to encourage patients to initiate and continue therapy. Part I of this article, published in the September/October 2001 issue of Rehabilitation Nursing, described the particular problems of treatment adherence in MS. Part II proposes that the transtheoretical model of behavior change can be a useful tool in achieving both patient acceptance and treatment goals. This model is founded upon the concept that readiness for change is crucial, and that attempts at intervention should be sensitive to the patients' changing conditions and states of mind.

Cellular localization of gene expression for progranulin.

Granulins, also called epithelins, are 6-kD peptides with growth modulatory effects on a variety of cells. The granulin/epithelin precursor supports tumorigenesis in appropriate cell models and is the only growth factor able to overcome the cell cycle block that occurs in murine fibroblasts after deletion of a functional IGF-1 receptor. However, little is known of the role of granulin/epithelin gene products in vivo. To understand the physiological role of granulins it is essential to know the cell types and conditions in which it is expressed. We examined granulin/epithelin gene expression in adult rodents by in situ hybridization. The granulin/epithelin precursor is constitutively expressed in a number of epithelia, particularly in the skin, GI tract, and reproductive system. Other epithelia express the gene less strongly. Progranulin is expressed in immune cells in vivo and in specific neurons in the brain, including Purkinje cells, pyramidal cells of the hippocampus, and some cerebral cortical neurons. Little expression was detected in muscle cell, connective tissue, or endothelium. Cumulatively, these results define the basal gene expression of a new growth factor system and suggest that the progranulin/epithelin gene is multifunctional, with important constitutive roles in epithelial homeostasis, reproductive, immunological, and neuronal function.

The presence of transforming growth factor e in bovine mammary gland.

Transforming growth factor e (TGFe) was demonstrated immunohistochemically in the bovine mammary gland, mainly in the glandular and ductal epithelium. In the teat, its expression was largely limited to the skin keratinocytes, ductal epithelium and ductal glands. It is suggested that this growth factor plays a role in lactation.

Development of chicken antibodies to bovine interferon alpha.

We have developed chicken polyclonal antibody to bovine interferon alpha (IFNalpha). Five hundred microg of recombinant bovine IFNalpha suspended with complete Freund's adjuvant was used in the first immunization round. A suspension of the same amount of IFNalpha and incomplete Freund's adjuvant was used for all subsequent boosters. The antibody was purified from egg yolks using polyethylene glycol precipitation. The first reactive antibody appeared several weeks after the first immunization. The antibody is specific for IFNalpha in immunoblotting, it is also useful in ELISA and immunohistochemistry. This method provides a fast, cheap and efficient alternative to development of monoclonal antibodies to conserved mammalian antigens.

Expression of TGFalpha in meningiomas.

The objective of this study was to examine the expression of transforming growth factor alpha (TGFalpha), a mitogen for many cell types, and its receptor in basic subtypes of meningiomas as well as in meningiomas of varying grade. Formalin-fixed tissues from 26 meningiomas including 15 benign (5 meningothelial, 5 transitional, and 5 fibrous variants), 6 atypical, and 5 malignant examples were immunohistochemically examined for both TGFalpha protein and EGF/TGFalpha receptor protein. In addition, in situ hybridization (ISH) was used to detect TGFalpha mRNA expression. Immunostaining for TGFalpha was strongest in fibrous and atypical meningiomas, followed closely by transitional and malignant tumors. Only weak reactivity was observed in the meningothelial variant. In all but 4 tumors (2 fibrous, 2 atypical), ISH showed TGFalpha mRNA to be present, the signal being stronger in malignant than in conventional or atypical tumors. Lastly, immunostaining for EGF/TGFalpha receptor was positive in all tumors studied. Strong TGFalpha protein expression in meningiomas is commonly associated with fibrous morphology. Although the frequent detection of both TGFalpha protein and its mRNA, as well as of EGF/TGFalpha receptor within tumors of all type and grades, suggests that TGFalpha serves to promote tumor growth, its possible role in tumorigenesis or malignant progression is uncertain. In summary, demonstration of these substances is of no utility in the classification or grading of this common tumor because the differences in their expression among the various meningioma subtypes were not statistically significant.