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PubMed2006

Manganese-enhanced magnetic resonance imaging for in vivo assessment of damage and functional improvement following spinal cord injury in mice.

In past decades, much effort has been invested in developing therapies for spinal injuries. Lack of standardization of clinical read-out measures, however, makes direct comparison of experimental therapies difficult. Damage and therapeutic effects in vivo are routinely evaluated using rather subjective behavioral tests. Here we show that manganese-enhanced magnetic resonance imaging (MEMRI) can be used to examine the extent of damage following spinal cord injury (SCI) in mice in vivo. Injection of MnCl2 solution into the cerebrospinal fluid leads to manganese uptake into the spinal cord. Furthermore, after injury MEMRI-derived quantitative measures correlate closely with clinical locomotor scores. Improved locomotion due to treating the detrimental effects of SCI with an established therapy (neutralization of CD95Ligand) is reflected in an increase of manganese uptake into the injured spinal cord. Therefore, we demonstrate that MEMRI is a sensitive and objective tool for in vivo visualization and quantification of damage and functional improvement after SCI. Thus, MEMRI can serve as a reproducible surrogate measure of the clinical status of the spinal cord in mice, potentially becoming a standard approach for evaluating experimental therapies.

Algorithms↗
PubMed2005

Antimicrobial activity of antibiotics in combination with natural flavonoids against clinical extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae.

Extended-spectrum beta-lactamases (ESBLs) are plasmid-mediated class A enzymes commonly found in the family Enterobacteriaceae, mainly in Klebsiella pneumoniae. Flavonoids have also been reported to possess antimicrobial activity. In this study, the in vitro activities of 18 antibiotics and 12 flavonoids against 20 ESBL-producing K. pneumoniae isolates were evaluated. All of these isolates were susceptible to imipenem and cefmetazole, but were resistant to ampicillin, ampicillin/sulbactam, aztreonam, cefazolin, cefoperazone, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, piperacillin and ticarcillin. Susceptibilities to amikacin, amoxicillin/clavulanate, cefoxitin, ciprofloxacin and gentamicin were variable. Myricetin, a flavonol, inhibited ESBL-producing K. pneumoniae isolates at a high minimum inhibitory concentration (MIC) (MIC(90) value 256 mg/mL), but exhibited significant synergic activity against ESBL-producing K. pneumoniae in separate combination with amoxicillin/clavulanate, ampicillin/sulbactam and cefoxitin. Because of the low-toxic nature of flavonoids, the combination of antibiotics and flavonoids is a potential new strategy for developing therapies for infections caused by ESBL-producing bacteria in the future.

Anti-Bacterial Agents↗
PubMed2002

Protein kinase C induces motility of breast cancers by upregulating secretion of urokinase-type plasminogen activator through activation of AP-1 and NF-kappaB.

Cell migration is a crucial process in cancer metastasis that does not require extracellular matrix degradation-a characteristic of cell invasion. The urokinase-type plasminogen activator (uPA) system is responsible for invasion through uPA enzymatic activity and for migration through the binding of uPA to the uPA receptor (uPAR). Constitutively high levels of uPA are characteristic of the highly metastatic breast cancer cells MDA-MB-231, but the mechanisms underlying constitutive uPA expression are not fully characterized. In this report we show that inhibition of protein kinase C (PKC) represses constitutive (nonstimulated) migration of MDA-MB-231 cells. Bisindolylmaleimide I (Bis I) inhibits cell migration and constitutive activation of transcription factors AP-1 and NF-kappaB, suggesting that PKC is responsible for increased migration of MDA-MB-231 cells. It is clear that the inhibition of PKC occurs at the transactivation levels of AP-1 and NF-kappaB because Bis I did not affect constitutive DNA binding of AP-1 and NF-kappaB. Furthermore, we show that Bis I did not affect the levels of IkappaBalpha, suggesting that PKC-mediated cell migration is IkappaBalpha independent. Finally, we demonstrate that constitutive secretion of uPA is repressed by Bis I, implying an important role for AP-1 and NF-kappaB in cell migration. Our data demonstrate a connection among PKC, constitutively active AP-1 and NF-kappaB, constitutive secretion of uPA, and cell migration of highly invasive breast cancer cells. Thus, PKC controls cell motility by regulating expression of uPA through the activation of AP-1 and NF-kappaB. The disruption of PKC, AP- 1, and NF-kappaB signaling in breast cancer may be used to develop therapies for breast cancer prevention and intervention by reducing the secretion of uPA.

Breast Neoplasms↗
PubMed1992

Subclinical impairment of distal renal acidification induced by low-dose cyclosporin A therapy.

Twenty-nine psoriasis patients on 5 mg/kg cyclosporin A (CyA) therapy were studied for 3 months using the furosemide test. Five of them (17%) showed an abnormal renal acidification capacity after furosemide administration: The urinary pH did not sink under 5.3 after furosemide, while the ammonium and titrable acid levels were significantly low. There were no significant differences from controls regarding the serum potassium or fractional potassium excretion. Nevertheless, the transtubular potassium gradient was lower in patients with an abnormal furosemide test result. We conclude that some patients treated with a low dose CyA therapy developed an abnormality in the distal tubular acidification.

Adult↗
PubMed1993

Monoamine neurons in aging and Alzheimer's disease.

The integrity of dopaminergic, noradrenergic and serotonergic neurons in normal aging and Alzheimer's disease is reviewed. Loss of dopaminergic innervation of the neostriatum is a prominent age-related change, which corresponds with the age-related loss of dopaminergic cell bodies from the substantia nigra. This change is regionally specific, since dopaminergic innervation of the neocortex and the neostriatum are not affected. Although there is an age-related loss of noradrenergic cell bodies from the locus coeruleus, most studies indicate normal concentrations of noradrenaline in target areas. There is also evidence for reduced serotonergic innervation of the neocortex and, less convincingly, the neostriatum. Alzheimer's disease is associated with more pronounced noradrenergic and serotonergic denervation but, unlike normal aging, dopaminergic innervation of neostriatum is intact; although dopamine neurons are probably dysfunctional in this region. Studies relating neuronal markers to the symptomatology of Alzheimer's disease indicate that dysfunction of monoamine neurons is more closely linked to non-cognitive than to cognitive changes in behavior. In addition, monoaminergic therapies have been successful in ameliorating affective and psychotic behaviors along with sleep disturbances in both Alzheimer's disease and senescence. It seems likely that monoaminergic therapies (developed as we learn more about alterations in dopamine, noradrenaline and serotonin) will continue to be necessary to treat such behavioral disturbances.

Adult↗
PubMed1991

A case of arthropathy and hypothyroidism during recombinant alpha-interferon therapy.

Late side effects of alpha-interferon therapy include some autoimmune diseases, such as thyroiditis. We present the case of a patient with severe chronic active hepatitis and hepatitis-C-virus positivity, who during alpha-interferon therapy developed an autoimmune thyroiditis and at the same time arthropathy with some characteristics of rheumatoid arthritis (several articular stations simultaneously affected, involvement of the hand joints and morning stiffness).

Aged↗
PubMed1995

Chronic active hepatitis and liver cirrhosis in association with combined tamoxifen/tegafur adjuvant therapy.

Two female breast cancer patients who received combined tamoxifen and tegafur as postsurgical adjuvant therapy developed severe hepatotoxicity after being treated for three and eight months, respectively. Shortly after the cessation of the treatment, routine liver tests showed gradual recovery, but liver biopsies revealed chronic active hepatitis in one patient and liver cirrhosis in the other. Four and five years, respectively, after the cessation of the treatment, the results of liver tests were normal and distinct histological improvement was observed in both patients. Because these patients had no viral and immunoserological markers nor any history of alcohol abuse, this study suggested that the tamoxifen and tegafur regimen induced reversible chronic active liver disease.

Adult↗
PubMed1997

[Penetrating duodenal ulcer as a complication of a hepatic artery port catheter in hepatic metastasis of sigmoid carcinoma].

CASE REPORT: We report a typical complication of hepatic artery infusion therapy (HAI) in a patient with colon cancer metastatic to the liver. One year after the last HAI-therapy the patient presented with upper gastrointestinal bleeding. Endoscopy showed a large duodenic ulcer penetrating into an adjacent hepatic colon cancer metastasis. The hepatic artery catheter was visible at the ground of the duodenic ulcer. CONCLUSION: Thirty-five percent of patients under HAI-therapy develop gastric/duodenic ulcers. The severity of the HAI complication presented here, however, is quite uncommon.

Adenocarcinoma↗
PubMed1998

Adhesion molecules mediating neutrophil migration to arthritis in vivo and across endothelium and connective tissue barriers in vitro.

Neutrophils, or polymorphonuclear leukocytes (PMNLs), migrate through vascular endothelium and in connective tissue during inflammation. In rats with adjuvant arthritis, migration to joints of radiolabeled (111In) blood PMNLs was examined to define the role of specific selectin and integrin adhesion molecules in this process. Based on monoclonal antibody studies, P-selectin was required for normal PMNL migration to the joints. Although E-selectin alone was not essential, it mediated PMNL accumulation when the P-selectin mechanism was blocked. However, 30% to 40% of the PMNL accumulation was L-, P-, and E-selectin-independent. The integrins, LFA-1 and Mac-1 (CD11/CD18), and VLA-4 mediated PMNL migration to arthritic joints. However, 20% to 40% of PMNL accumulation was via CD18- and VLA-4-independent mechanisms. Human PMNL migration in vitro across unstimulated human umbilical vein endothelial cells (HUVEC), induced by C5a or IL-8, was virtually all mediated by the CD18 (beta2) integrins, LFA-1 and Mac-1. PMNL transendothelial migration was partly CD18-independent (35%) when endothelium was activated with cytokines, such as interleukin-1, and a chemotactic gradient, such as C5a, was also present. This CD18-independent migration was partially E-selectin-dependent in vitro. PMNL migration across synovial fibroblasts induced by C5a was mediated by Mac-1, VLA-4, VLA-5, and VLA-6, functioning in concert. However, up to 30% of migration was via mechanisms as yet to be defined. Thus, PMNL transendothelial and extravascular migration involves some shared, and some distinct mechanisms, as well as some yet to be identified. Defining these mechanisms may help develop therapies for controlling PMNL involvement in inflammation in the vascular and extravascular spaces.

Animals↗
PubMed2006

Sequential maintenance treatment with glatiramer acetate after mitoxantrone is safe and can limit exposure to immunosuppression in very active, relapsing remitting multiple sclerosis.

Mitoxantrone has been approved by the FDA for worsening relapsing remitting and secondary progressive Multiple Sclerosis. However the benefits of this agent in reducing disease progression and relapse rate cannot be sustained in the long-term, as treatment is limited by the potential for cumulative cardiotoxicity. We report our experience utilising Glatiramer Acetate as maintenance immuno-modulatory treatment following initial immunosuppression with Mitoxantrone in a consecutive series of 27 patients with very active relapsing remitting disease, eight of whom had experienced continuing relapse activity on first-line treatment. Duration of treatment with Mitoxantrone and thereby cumulative dose were reduced as our experience with the combination increased.No unanticipated side effects of combination treatment were encountered over a follow-up period of 66 months. A single patient developed therapy related acute leukaemia (TRAL) 9 months after completion of Mitoxantrone.A sustained 90% reduction in annualised relapse rate (p < 0.001) has been observed. Disability is stable or improved in all patients a mean of 36 (16-66) months from initiation of treatment. Early suppression of relapse activity with Mitoxantrone has been maintained at a mean of 22 months from last dose of this agent. Only two relapses have occurred in the cohort since withdrawal of Mitoxantrone, occurring in the two patients who had previously been treated with Glatiramer Acetate. In 9 of the first 10 patients treated, imaged a mean of 27 months after withdrawal of Mitoxantrone, no enhancing lesions were identified on MRI brain scans. Glatiramer Acetate appears a safe and effective option for continuing disease modification in patients with relapsing remitting multiple sclerosis treated with Mitoxantrone. The treatment protocol utilised in later patients in this series appears to have the potential to limit exposure to this agent.

Adolescent↗
PubMed2003

Serum sIL-2r, IL-6, IL-10 and TNF-alpha level in familial Mediterranean fever patients.

In this study we investigated cytokine levels in patients with familial Mediterranean fever (FMF). Twenty patients and 20 healthy controls were included. Ten patients had acute attacks of FMF, whereas the other 10 were in the silent period. Patients with the acute exacerbation of FMF had higher soluble interleukin-2 receptor (sIL-2r), interleukin-6 (IL-6), tumour necrosis factor-alpha, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and fibrinogen levels than those in the silent period ( P<0.001) and controls ( P<0.001). In patients with acute attacks of FMF, interleukin-10 (IL-10) levels were not significantly different from those in the other patients or the controls ( P>0.05). In FMF patients IL-6, TNF-alpha, sIL-2r, ESR, CRP and fibrinogen levels increased with the acute-phase reaction, especially in the attack period. On the other hand, anti-inflammatory cytokine IL-10 levels did not increase as much as did the inflammatory cytokines. The balance between the cytokines may help us to understand the pathophysiology of FMF and to develop therapies. We conclude that the levels of the acute-phase reactants and the cytokines could be useful for diagnosis of acute exacerbations, follow-up and treatment. However, the cost of cytokine measurement analyses seems disadvantageous at present.

Acute-Phase Proteins↗
PubMed2006

The production of transgenic mice expressing human cystathionine beta-synthase to study Down syndrome.

Down syndrome (DS) is the most common genetic cause of significant cognitive disability. We hypothesize that by identifying metabolic alterations associated with cognitive impairment, it may be possible to develop medical or dietary interventions to ameliorate cognitive disabilities in persons with DS. Evidence suggests that one-carbon/transsulfuration (1C-TS) metabolism is abnormal in persons with DS. Cystathionine beta-synthase (CBS) plays a critical role in this metabolic system. The gene for CBS is on human chromosome 21, and there is evidence of elevated CBS enzyme activity in tissues and cells from individuals with DS. To analyze the possible role of CBS in Down syndrome, we have produced several lines of transgenic mice expressing the human CBS gene. We describe the use of Florescence Situ Hybridization (FISH) analysis to characterize the transgene insertion site for each line. Our initial expression analysis of each transgenic line by RT-PCR shows that the tissue specificity of human CBS mRNA levels in these mice may differ from the tissue specificity of mouse CBS mRNA levels in the same animals. These mice will be invaluable for assessing the regulation of the CBS gene and the role of CBS in cognition. They can also be used to develop therapies that target abnormalities in 1C-TS metabolism to improve cognition in persons with DS.

Animals↗
PubMed2022

Suppression of trinucleotide repeat expansion in spermatogenic cells in Huntington's disease.

Trinucleotide repeats (TNRs) are dispersed throughout the human genome. About 20 loci are related to human diseases, such as Huntington's disease (HD). A larger TNR instability is predominantly observed in the paternal germ cells in some TNR disorders. Suppressing the expansion during spermatogenesis can provide a unique opportunity to end the vicious cycle of genetic anticipation. Here, using an in vitro differentiation method to derive advanced spermatogenic cells, we investigated the efficacy of two therapeutic agents, araC (cytarabine) and aspirin, on stabilizing TNRs in spermatogenic cells. Two WT patient-derived induced pluripotent stem cell (iPSC) lines and two HD hiPSC lines, with 44 Q and 180 Q, were differentiated into spermatogonial stem cell-like cells (SSCLCs). Both HD cell lines showed CAG tract expansion in SSCLC. When treated with araC and aspirin, HD1 showed moderate but not statistically significant stabilization of TNR. In HD2, 10&#xa0;nM of aspirin and araC showed significant stabilization of TNR. All cell lines showed increased DNA damage response (DDR) gene expression in SSCLCs while more genes were significantly induced in HD SSCLC. In HD1, araC and aspirin treatment showed general suppression of DNA damage response genes. In HD2, only FAN1, OGG1, and PCNA showed significant suppression. When the methylation profile of HD cells was analyzed, FAN1 and OGG1 showed significant hypermethylation after the aspirin and araC treatment in SSCLC compared to the control. This study underscores the utility of our in vitro spermatogenesis model to study and develop therapies for TNR disorders such as HD.

Male↗
PubMed2006

Enzymatic characterization of a trypsin-like serine protease encoded by the genome of cell fusing agent virus.

Cell fusing agent virus (CFAV) is a positive strand RNA insect virus first isolated from a mosquito cell line. Based on viral morphology, phenotypic and phylogenetic studies, CFAV had been tentatively assigned to the genus Flavivirus (family Flaviviridae). The determination of the CFAV polyprotein complete sequence showed a putative serine protease domain analogue to the flaviviral NS2B/NS3 complex. This complex had been extensively studied, because it represented one of the main targets for antiflavivirus therapy development. We report herein the biochemical characterization of CFAV DeltaNS2B-NS3pro protease complex. CFAV polyprotein sequence was computationally analysed to identify the amino-acid regions involved in protease activity. We designed, expressed and purified a catalytically active protease whose enzymatic properties were determined using fluorogenic substrates. Our results showed that, despite the low level of conservation of its amino-acid sequence, CFAV protease exhibited physico-chemical properties of other flaviviruses (high pH value requirement for optimal activity, inhibition by salt and preference for substrates featuring a basic residue at P(1) position).

Amino Acid Sequence↗
PubMed2003

New strategies for prevention of ischemic stroke: the LIFE study.

New strategies to lower the risk of stroke among high-risk persons are being developed. Therapies such as cholesterol-lowering medications and newer antihypertensive agents appear to complement traditional antithrombotic drugs and surgical procedures. Of particular interest is the use of the newer angiotensin-converting enzyme (ACE) inhibitors, which appear to have an effect on stabilizing the vascular endothelium. The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study provides additional data to support the use of the ACE inhibitors to lower the risk of stroke among patients with hypertension and vascular diseases.

Aged↗
PubMed2026

Mechanisms of Hematopoietic Stem Cell Aging and Emerging Rejuvenation Strategies.

Hematopoietic stem cell (HSCs) aging is a complex biological process driven by both cell-intrinsic alterations and extrinsic cues from the bone marrow niche. Understanding these mechanisms is critical for developing therapies against aging-related hematopoietic disorders. This review synthesizes recent advances in the molecular mechanisms underlying HSCs aging, including microenvironmental aging, genomic instability, epigenetic dysregulation, mitochondrial dysfunction, and aberrant nuclear mechanotransduction. We summarize that the functional decline of HSCs during aging drives a compensatory expansion of the phenotypically defined stem cell pool, leading to an aberrant increase in cell number. We also highlight aging-associated HSCs heterogeneity, including CD150high and P-selectin-positive subsets that enrich for myeloid-biased or functionally compromised HSCs states while emphasizing that surface phenotype alone may not fully indicate functional rejuvenation. Finally, we discuss emerging rejuvenation strategies-including targeting myeloid-biased HSCs, modulating inflammatory pathways, and implementing epigenetic or metabolic interventions-supported by cutting-edge technologies such as single-cell multi-omics, gene editing, and computational modeling. These approaches hold promise for counteracting age-related hematopoietic decline and restoring immune competence.

Humans↗
PubMed1992

Nonresolving pneumonia in steroid-treated patients with obstructive lung disease.

PURPOSE: To review autopsy-proven cases of opportunistic pneumonia and determine how many of these patients had received corticosteroid therapy for obstructive lung disease in order to define whether this therapy was the major risk factor predisposing to infection. PATIENTS AND METHODS: All autopsies performed at Winthrop-University Hospital over a 5-year period were reviewed, and 30 cases of opportunistic pneumonia were identified. In eight of 30 cases, corticosteroid therapy for chronic obstructive pulmonary disease (COPD) was the only identifiable risk factor for opportunistic infection. The other 22 patients had other well-defined risk factors for infection. Chart review of the eight patients with COPD was undertaken to define the clinical features of their infections. RESULTS: All eight patients had a progressive multilobar pneumonia that failed to resolve, either clinically or radiographically, despite the use of multiple broad-spectrum antibiotics. In four cases, the infection was community-acquired, while in the other four cases, it was nosocomial in origin. Despite the presence of a nonresolving pneumonia, opportunistic infection was generally not considered as a diagnostic possibility, with only one case being correctly diagnosed antemortem. Autopsy examination documented Aspergillus species as being responsible for six episodes of pneumonia, Candida albicans accounting for one episode, and cytomegalovirus accounting for one episode. CONCLUSION: Based on this experience, it is clear that corticosteroid therapy of COPD can lead to opportunistic pulmonary infection, in or out of the hospital. This diagnosis should be considered when patients receiving this therapy develop a pneumonia that fails to respond to broad-spectrum antibiotics.

Aged↗