Assessment of factors affecting quality of life in patients with chronic pain due to knee osteoarthritis and spondylosis: spine versus knee?

OBJECTIVE: There is no study comparing knee and spine osteoarthritis. The purpose of the study is to examine the effects of pain and disability on quality of life (QoL) and the factors affecting QoL in patients with knee osteoarthritis and spondylosis. METHODS: This cross-sectional study included 114 patients with spondylosis and 126 patients with knee osteoarthritis. Demographic data were recorded. The visual analog scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Roland Morris Questionnaire (RMQ), and the Short Form Health Questionnaire (SF-36) were filled out. RESULTS: Statistically, patients with spondylosis and knee osteoarthritis did not differ significantly in terms of gender, age, body mass index, number of concomitant conditions, marital status, years of schooling, pain scores, or SF-36 characteristics. SF-36 physical function, vitality, and mental health assessments were lower in women than men, while VAS scores were higher. There was no correlation between marital status, educational level, and QoL subscales. WOMAC and RMQ scores were negatively correlated with the SF-36 subscales. RMS scores were not related to mental health. CONCLUSIONS: Spondylosis and knee osteoarthritis affect all subscales of QoL in the same way. The management of patients with spondylosis and knee osteoarthritis should focus on pain and functionality to improve QoL.

The impact of fibromyalgia syndrome on obstructive sleep apnea syndrome in terms of pain threshold, daytime symptoms, anxiety, depression, disease severity, and sleep quality: a polysomnographic study.

BACKGROUND: Current studies have focused on the association of fibromyalgia syndrome (FMS) and obsctructive sleep apnea syndrome (OSAS). Results of these studies on the effect of this association have been inconsistent. The current study aimed to investigate the effect of FMS on OSAS regarding sleep quality, pressure pain threshold, fatigue, daytime symptoms, anxiety, and depression, and also to determine the relationship between OSAS severity and FMS. METHODS: In a cross-sectional design, patients diagnosed with OSAS were evaluated in two groups comparing those with and those without FMS. Data on demographics, headache, morning fatigue, and chronic pain duration were collected. Questionnaires including the Fatigue Severity Scale (FSS), Fibromyalgia Impact Questionnaire (FIQ), Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI) were completed. Pressure pain threshold, tender points, and polysomnographic data were recorded. RESULTS: Of 69 patients, 27 were diagnosed with FMS + OSAS and 42 were diagnosed as OSAS only. Statistically significant differences were found between the two groups in VAS, pain duration, morning fatigue, headache, BAI, tender point count, FIQ and FSS scores, and algometer measurements. All polysomnografic data were compared, and no statistically significant differences were found between the two groups. There were no statistically significant differences in the algometer, BDI, BAI, FIQ, and FSS scores when analyzed according to the severity of OSAS. CONCLUSION: The findings suggest that FMS has no effect on polysomnographic parameters of OSAS. Headache, daytime fatigue, anxiety, depression, pain duration, and pain intensity are higher while the pressure pain threshold is lower when FMS is present. No correlation was found between OSAS severity and FMS, fatigue, pressure pain threshold, depression, and anxiety. CLINICAL TRIAL REGISTRATION NUMBER: NCT05367167/date: April 8, 2022.

The vicious cycle of physical inactivity, fatigue and kinesiophobia in patients with fibromyalgia syndrome.

This study aims to determine the association between fatigue, kinesiophobia, disease severity, and physical inactivity by comparing fibromyalgia syndrome (FMS) patients with healthy controls. Pain and fatigue are significant barriers to the participation in functional activities. Inactivity is a result of fatigue, but exercise is the foundation of FMS treatment. This case-control study included a total of 203 participants (107 patients with FMS and 96 healthy volunteers). The fibromyalgia impact questionnaire, the fatigue severity scale, the international physical activity questionnaire, and the Tampa scale for kinesiophobia were assessed. The FMS group scored significantly higher on the fatigue severity scale and kinesiophobia than the control group (p<0.001). Significantly lower metabolic task equivalent (MET) scale values were observed in the FMS group compared to the control group (p<0.001). The severity of fatigue and kinesiophobia correlated positively with the FMS impact questionnaire (p=0.001, r=0.621) and negatively with the MET scale (p=0.009, r= -0.287). Patients with FMS experience greater fatigue, kinesiophobia, and inactivity. As the severity of FMS worsens, so do disability, kinesiophobia, and fatigue. This study highlights the importance of breaking the cycle of fatigue and inactivity in the treatment of FMS.

DcR2 (TRAIL-R4) siRNA and adenovirus delivery of TRAIL (Ad5hTRAIL) break down in vitro tumorigenic potential of prostate carcinoma cells.

High levels of decoy receptor 2 (DcR2; TRAIL-R4) expression are correlated with TRAIL resistance in prostate cancer cells. In addition, upregulation of TRAIL death receptor (DR4 and DR5) expression, either by ionizing radiation or chemotherapy, can sensitize cancer cells to TRAIL. Considering more than half of human cancers are TRAIL resistant, modulation of surface TRAIL receptor expression appears to be an attractive treatment modality to counteract TRAIL resistance. In this study, three siRNA duplexes targeting DcR2 receptor were tested. Ad5hTRAIL infections were performed to overexpress human full-length TRAIL to induce cell death, and the in vitro tumorigenic potential of prostate cancer cells was assessed using colony-forming assays on soft agar. The DU145 and LNCaP prostate cancer cell lines, which express high levels of DcR2, were resistant to Ad5hTRAIL-induced death. Downregulation of surface DcR2 expression by siRNA sensitized these prostate cancer cell lines to Ad5hTRAIL. In addition, DcR2 siRNA-mediated knockdown of DcR2, followed by Ad5hTRAIL infection, dramatically reduced the in vitro tumorigenic potential of prostate cancer cells. Collectively, our results suggest the potential for combining receptor-specific siRNA with TRAIL in the treatment of certain cancers.

Adenovirus-mediated IKKbetaKA expression sensitizes prostate carcinoma cells to TRAIL-induced apoptosis.

Despite the fact that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in cancer cells, TRAIL resistance in cancer cells has challenged the use of TRAIL as a therapeutic agent. First, prostate carcinoma cell lines (DU145, LNCaP and PC3) were screened for sensitivity to adenovirus delivery of TRAIL (Ad5hTRAIL). As amplified Ikappa B kinase (IKK) activity is responsible for the constitutive nuclear factor-kappaB (NF-kappaB) activation leading to uncontrolled cell growth and metastasis, a dual vector approach using both an adenovirus vector (Ad) expressing the dominant-negative mutant of IKKbeta (AdIKKbetaKA) and Ad5hTRAIL was employed to determine if prostate cancer cells were sensitized to TRAIL in the setting of IKK inhibition. Inhibition of the NF-kappaB pathway through IKK blockade sensitized all three prostate cancer cell lines to TRAIL, regardless of NF-kappaB activation or decoy receptor gene expression. Moreover, a novel quantitative real-time RT-PCR assay and conventional flow cytometry analysis indicated that TRAIL-resistant DU145 and LNCaP cells, but not TRAIL-sensitive PC3 cells, expressed substantial amounts of TRAIL Decoy Receptor 4. In conclusion, TRAIL decoy receptor expression appeared to be the chief determinant of TRAIL resistance encountered in prostate carcinoma cell lines.

Caspase 8L, a novel inhibitory isoform of caspase 8, is associated with undifferentiated neuroblastoma.

Caspase 8 is a key apoptotic factor in the receptor/ligand apoptosis-signaling cascade. Absent caspase 8 expression is shown to correlate with poor prognosis in neuroblastoma. Paradoxically, the caspase 8 gene can produce as plice variant and novel inhibitor of itself-caspase 8l. The presence of caspase 8 alone in tumors may not necessarily portend a good prognosis. We sought to determine whether caspase 8l is present in neuroblastoma and whether over-expression of this protein could inhibit caspase 8-dependent apoptosis. Six of 6 histologically undifferentiated and 2 of 5 differentiated neuroblastoma tumors expressed the caspase 8l isoform, whereas caspase 8l was absent in 3 of 3 ganglioneuromas. Seven human neuroblastoma cell lines were surveyed. Two of the 5 cell lines that expressed caspase 8 also expressed the caspase 8l isoform and both were of a less differentiated neuronal phenotype. Over-expression of caspase 8l in cell lines afforded protection against TRAIL, but not against etoposide induced apoptosis. Conversely, blockade of Caspase 8l in cells that express this splice variant made them more sensitive to apoptosis induced cell death. We demonstrate the caspase 8l isoform is present in neuroblastoma and appears to be associated with undifferentiated cell lines and tumors. Furthermore, it suppresses caspase 8-dependent apoptosis.

Alcohol exposure during the brain growth spurt promotes hippocampal seizures, rapid kindling, and spreading depression.

BACKGROUND: Epilepsy is a prominent sign of brain dysfunction and a cause of substantial disability in some children with fetal alcohol syndrome. The hippocampal formation is vulnerable to alcohol-induced pathologic changes and is the source of seizure activity in a variety of epileptic conditions. This study tests the hypothesis that developmental alcohol exposure facilitates epileptic activity and promotes kindling within hippocampal circuitry. METHODS: Rat pups received either a moderate dose (2.0 g/kg) or a high dose (3.75 g/kg) of alcohol via intragastric intubation over postnatal days 4 to 10. Intubated control and suckle control groups were also included. Upon reaching adulthood (postnatal days 85-100), the rats underwent electrophysiologic testing. A double-barrel potassium-sensitive microelectrode was placed into the right dentate gyrus stratum granulosum for the recording of extracellular field potential and extracellular potassium concentration. Stimuli were delivered via an electrode positioned in the CA3 subregion of the left hippocampus. To assess whether alcohol promotes hippocampal seizures and rapid kindling, the parameters of maximal dentate activation (MDA) were measured before, during, and after a series of stimulation-induced seizures. RESULTS: Developmental exposure to the high dose of alcohol permanently altered several parameters of MDA. Time to onset of MDA and stimulus threshold for afterdischarge production were both decreased, whereas the duration of the afterdischarge was increased. Although the moderate alcohol dose reduced time to onset of MDA, it did not affect any other MDA parameters. Over the course of the repeated induced seizures, spreading depression occurred more often and with fewer stimuli in the high-dose alcohol group than in any other group. The series of repeated electrographic seizures induced rapid kindling in all of the treatment groups. However, the kindling effect was enhanced in a dose-response manner by the previous alcohol exposures. CONCLUSIONS: These findings demonstrate that exposure to alcohol during brain development can permanently alter the physiology of the hippocampal formation, thus promoting epileptic activity, enhancing kindling, and facilitating spreading depression. The relative roles of alcohol intoxication and withdrawal in these abnormal physiologic responses remain unknown.

Selective gene expression and activation-dependent regulation of vasoactive intestinal peptide receptor type 1 and type 2 in human T cells.

Vasoactive intestinal peptide (VIP) has potent antiproliferative and anti-inflammatory functions in the immune system. Two structurally distinct G-protein-associated receptors, VIP receptor type 1 (VPAC1) and VIP receptor type 2 (VPAC2), mediate the biological effects of VIP. The regulation of VIP receptor gene expression and the distribution of these receptors in different compartments of the human immune systems are unknown. This study reports, for the first time, a quantitative analysis of VPAC1 and VPAC2 mRNA expression in resting and activated T cells as well as in resting monocytes. Purified human peripheral blood CD4(+) T cells and CD8(+) T cells were stimulated via the TCR/CD3 receptor complex. Using the novel fluorometric-based kinetic (real-time) RT-PCR, we determined that VPAC1 is constitutively expressed in resting T cells and monocytes; the levels of expression were significantly higher in monocytes and CD4(+) T cells than in CD8(+) T cells. VPAC1 mRNA expression is significantly higher relative to VPAC2 in resting CD4(+) T cells and CD8(+) T cells. VPAC2 is expressed at very low levels in resting T cells but is not detectable in resting monocytes. In vitro stimulation of Th cells with soluble anti-CD3 plus PMA induced a T cell activation-dependent down-regulation of VPAC1. VPAC1 is down-regulated under conditions of optimal T cell stimulation. Our results suggest that selective VIP effects on T cell function may be mediated via selective expression of VPAC1 and VPAC2 on T cells and monocytes. Furthermore, down-regulation of VPAC1 in CD4(+) T cell subpopulations is highly correlated with T cell activation.

Expression and fine mapping of murine vasoactive intestinal peptide receptor 1.

Vasoactive intestinal peptide (VIP) plays multiple roles in the nervous, endocrine, and immune systems as a neurotransmitter, a hormone, and a cytokine. VIP is widely distributed in neurons of the central and peripheral nervous systems (CNS/PNS), and recently has been found to be an important neuroprotective agent. VIP actions are mediated through specific G protein-coupled receptors. We have cloned the cDNA of VIP receptor subtype 1 (VIPR1 or VPAC1) and have demonstrated the quantitative expression profile in mice. Fluorometric real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that VPAC1 is expressed in all tissues examined. Expression was highest in the small intestine and colon followed by the liver and brain. The high level of VPAC1 expression in forebrain and cerebellum suggests that VPAC1 may mediate the neuroprotective effect of VIP. We have refined the chromosomal localization of the mouse, rat, and human VPAC1 genes. This fine mapping of the VPAC1 gene extends the respective regions of synteny between the distal region of mouse chromosome 9, rat chromosome 8q32, and human chromosome 3p21.33-p21.31. Thus, VPAC, constitutes a functional-positional candidate for the tumor-suppressor function mapped to human 3p22-p21 where loss-of-heterozygosity is observed in small-cell lung carcinoma (SCLC) cell lines and primary tumors. Availability of the cDNA sequences for mouse VPAC1 will facilitate the generation of VPAC1 null mutant animals. Such studies will ultimately enhance our understanding of the role of VIP in the nervous system.

Regulation of vasoactive intestinal peptide receptor expression in developing nervous systems.

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide that has several functions, including the regulation of water and electrolyte secretion, hormone and cytokine release, bronchodilitation, and neurogenesis. VIP effects are mediated by specific G-protein coupled receptors. Three distinct receptor subtypes, with differing affinity for VIP, have been cloned and characterized as receptors 1 and 2 (VPAC1 and VPAC2) and pituitary adenylate cyclase activating polypeptide receptor (PAC1). Our laboratory has demonstrated that upregulation of VPAC1 in SK-N-SH neuroblastoma cells results in marked shift in cell type to the glial lineage with a corresponding loss of neuronal lineage and suppression of xenograft tumor growth. To understand the molecular mechanisms responsible for regulation of the VPAC1 gene in neuronal lineage, we have cloned and sequenced 2.6-kb of the 5'-flanking sequences of the human VPAC1 gene. Sequence analysis demonstrated that the human VPAC1 promoter sequence contains putative binding sites for several known transcription factors, including Sp1, NFkB, and cETS-1. To study the temporal and spatial expression pattern of human VPAC1 promoter sequences, we have generated transgenic mice expressing the bacterial beta-galactosidase gene under the control of the 2.6-kb 5'-flanking and promoter sequence of the human VPAC1 gene. Transgene expression was detected in brain, spinal cord, and lung in 14-day-old animals. Taken together, these results demonstrate that VPAC1 may play an important role in the nervous system, and suggest a role for VIP in neuronal differentiation.

Vasoactive intestinal peptide (VIP) receptor type 2 (VPAC2) is the predominant receptor expressed in human thymocytes.

Vasoactive intestinal peptide (VIP) binding sites have been identified in the human thymus, but the receptor subtype and how these receptors are distributed in the human thymus subsets is unknown. To assess gene expression, distribution, and receptor regulation of the two G-protein-associated VIP receptors, VPAC1 and VPAC2 mRNAs were quantified using a novel fluorometric-based kinetic (real-time) RT-PCR. Bulk and fractionated thymocytes were stimulated via the TCR/CD3 receptor complex and anti-CD28. Our results demonstrate that thymocytes express higher levels of VPAC2 compared to VPAC1 expression in bulk thymocytes, CD4+CD8+ selected double positives (DP), and CD8 depleted thymocytes. Double negative cells express low levels of VPAC2 mRNA. We demonstrate T-cell activation-dependent down-regulation of VPAC1, but not VPAC2, in human thymocytes. This study reports the first direct evidence of a differential distribution and selective regulation of VPAC1 and VPAC2 gene expression in normal human thymocyte subsets.

Induction of erythrocyte protein 4.2 gene expression during differentiation of murine erythroleukemia cells.

Protein 4.2 (P4.2) is an important component in the erythrocyte membrane skeletal network that regulates the stability and flexibility of erythrocytes. Recently, we provided the evidence for specific P4.2 expression in erythroid cells during development (L. Zhu et al., 1998, Blood 91, 695-705). Using dimethyl sulfoxide (DMSO)-induced differentiation of murine erythroleukemia (MEL) cells as a model, transcription of the P4.2 gene was found to be induced during erythroid differentiation. To examine the mechanism for this induction, we isolated the mouse P4.2 genomic DNA containing the 5' flanking sequence and defined the location of the P4.2 promoter. Transcription of the mouse P4.2 gene initiates at multiple sites, with the major initiation site mapped at 174 nucleotides upstream of the ATG start codon. The mouse P4.2 promoter is TATA-less and contains multiple potential binding sites for erythroid transcription factors GATA-1, NF-E2, EKLF, and tal-1/SCL. Transient transfection experiments demonstrated that a 1.7-kb mouse P4.2 promoter fused with the luciferase coding regions was induced in DMSO-treated MEL cells. Deletion analysis showed that a 259-bp P4.2 promoter DNA (nucleotide position -88 to +171 relative to the major transcription initiation site designated +1), containing a GATA-binding site at position -29 to -24, could still respond to the induction in differentiated MEL cells. Importantly, mutations in the -29/-24 GATA motif rendered the promoter unresponsive to DMSO induction. Electrophoretic mobility shift assay revealed that GATA-1 could bind to the -29/-24 GATA motif and this was confirmed by the observation that the nuclear protein bound to the motif was supershifted by an anti-GATA-1 monoclonal antibody. Taken together, these results suggest that the erythroid transcription factor GATA-1 plays an important role in the induction of P4.2 gene expression during erythroid cell differentiation.

The murine erythrocyte protein-4.2-encoding gene: similarities and differences in structure and expression from its human counterpart.

We have isolated a complete cDNA encoding for the mouse erythrocyte protein 4.2 (P4.2). The entire P4.2 cDNA consists of 3465 nt with an open reading frame (ORF) of 691 amino acids. Northern blot analysis of mouse reticulocyte or spleen RNA using the P4.2 cDNA as a probe, detected a 3.5-kb message. The size of the mouse P4.2 cDNA or message that we obtained, appears to be different from those reported recently. Despite the similarity to the human P4.2 cDNAs, the mouse cDNA has a longer 3' untranslated region. A genomic clone covering the first exon and flanking sequences of the mouse P4.2 gene was isolated. Sequencing results from the first exon-intron junction region and polymerase chain reaction (PCR) experiments revealed that the mouse reticulocyte P4.2 RNA does not exhibit alternative splicing in the region identified in the human P4.2 RNA.