Surgically induced osteoarthritis in the rat results in the development of both osteoarthritis-like joint pain and secondary hyperalgesia

OBJECTIVE: In the present study, we sought to develop/characterize the pain profile of a rat model of surgically induced osteoarthritis (OA). METHODS: OA was surgically induced in male Lewis rats (200-225 g) by transection of the medial collateral ligament and medial meniscus of the femoro-tibial joint. In order to characterize the pain profile, animals were assessed for a change in hind paw weight distribution (HPWD), development of mechanical allodynia, and the presence of thermal and mechanical hyperalgesia. Rofecoxib and gabapentin were examined for their ability to decrease change in weight distribution and tactile allodynia. RESULTS: Transection of the medial collateral ligament and medial meniscus of male Lewis rats resulted in rapid (<3 days) changes in hind paw weight bearing and the development of tactile allodynia (secondary hyperalgesia). There was, however, no appreciable effect on thermal hyperalgesia or mechanical hyperalgesia. Treatment with a single dose of rofecoxib (10 mg/kg, PO, day 21 post surgery) or gabapentin (100mg/kg, PO, day 21 post surgery) significantly attenuated the change in HPWD, however, only gabapentin significantly decreased tactile allodynia. CONCLUSION: The rat medial meniscal tear (MMT) model mimics both nociceptive and neuropathic OA pain and is responsive to both a selective cylooxygenase-2 (COX-2) inhibitor commonly utilized for OA pain (rofecoxib) and a widely prescribed drug for neuropathic pain (gabapentin). The rat MMT model may therefore represent a predictive tool for the development of pharmacologic interventions for the treatment of the symptoms associated with OA.     

Use of the HEp-2 cell substrate in the detection of antinuclear antibodies in juvenile rheumatoid arthritis

Presence and titer of antinuclear antibodies (ANA) were determined in 217 juvenile rheumatoid arthritis (JRA) patients, by indirect immunofluorescence using HEp-2 cells as substrate. Positive ANA titers (greater than or equal to 1:40) were present in 131 (60%) of the JRA patients. All 3 JRA onset types demonstrated increased percentages of ANA positivity compared with healthy children. Sixty-seven percent of the patients in the polyarticular onset group had positive titers; titers were positive in 62% of the pauciarticular onset group and in 32% of the systemic onset group. ANA were also found in 45% of control patients with other connective tissue diseases. In JRA patients, the speckled pattern occurred most commonly (72%). Fourteen patients (8 with pauciarticular onset and 6 with polyarticular onset) had iridocyclitis; all of them had high titers (greater than or equal to 1:80) of ANA. The use of HEp-2 cells provided a sensitive substrate for detecting ANA in JRA. It proved to be of value in differentiating JRA patients from healthy controls, but not from patients with other connective tissue diseases.     

Endothelial leukocyte adhesion molecule 1: direct expression cloning and functional interactions.

A cDNA for endothelial leukocyte adhesion molecule 1 (ELAM-1) was isolated by transient expression in COS-7 cells of a subtracted cDNA library from cytokine-treated human umbilical vein endothelial cells (HUVECs), with selection of ELAM-1-expressing clones by adhesion of transfected cells to the human promyelocytic cell line HL-60. This cloning method requires neither antibody nor purified ligand. ELAM-1-expressing COS cells bind the promyelocytic cell line HL-60 by a Ca2(+)-dependent but temperature-independent mechanism. Although ELAM-1 is homologous to mammalian lectins, its interaction with HL-60 cells is not inhibited by simple carbohydrate structures. ELAM-1-expressing COS cells also bind human neutrophils and the human colon carcinoma cell line HT-29, but not the B-cell line Ramos. However, Ramos cells adhere to cytokine-treated HUVECs but not control HUVECs, confirming the existence of other inducible adhesion molecules. In addition, the binding of HL-60 cells or neutrophils to ELAM-1-expressing COS cells is not inhibited by a monoclonal antibody (60.3) directed to an inhibitory epitope on CD18, indicating that the ELAM-1 ligand, although uncharacterized, is not a member of the CD11/CD18 family.     

Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells.

The expression and function of a new cytokine-induced endothelial cell adhesion protein, vascular cell adhesion molecule-1 (VCAM-1), was characterized in vitro by using a monoclonal antibody, MoAb 4B9, which recognizes a functional epitope on this protein. As determined by enzyme-linked immunosorbent assay and radioimmunoprecipitation of metabolically labeled cells, VCAM-1 was minimally expressed on unstimulated human umbilical vein endothelium (HUVE), but was rapidly induced by recombinant human tumor necrosis factor-alpha (rhTNF-alpha), rh interleukin-1, and lipopolysaccharide. In contrast to intercellular adhesion molecule-1, VCAM-1 was not induced on dermal fibroblasts or arterial smooth muscle cells after stimulation with rhTNF, or on keratinocytes after stimulation with rh interferon-gamma. MoAb 4B9 significantly inhibited the adherence of peripheral blood lymphocytes (PBL) and lymphocytic cell lines, but not neutrophils, to rhTNF-activated HUVE. The inhibitory effect of MoAb 4B9 on PBL adherence to HUVE was additive to that produced by the CD18 MoAb 60.3. These results show that VCAM-1 mediates a CD18-independent pathway of peripheral blood lymphocyte adherence to cytokine-stimulated HUVE. We propose that lymphocyte binding to VCAM-1, induced on endothelium by cytokines, may be an important component of lymphocyte emigration at sites of inflammation or immune reaction.     

Genetic analysis of treated and untreated phenylketonuria in one family.

We describe a family in which four subjects in two generations have a disorder of phenylalanine metabolism. Two first cousins had different biochemical presentations in the neonatal period. The older child was thought to have a more severe form of phenylketonuria (PKU), and the younger child a milder form. While carrying out family studies we discovered that their mutual grandfather and his older unmarried brother, both of normal intelligence, had a marked and previously undiagnosed hyperphenylalaninaemia. DNA analysis using RFLP haplotypes has shown that there are four independent mutant PKU alleles in this family which are found on three haplotype patterns. None of the affected family members carries a previously defined mutation at the phenylalanine hydroxylase (PAH) locus and so DNA analysis was not able to explain the apparently different biochemical phenotypes in the affected members of this family.     

Cryopreservation of mouse and human oocytes using 1, 2-propanediol and the configuration of the meiotic spindle

Human and mouse oocytes were cryopreserved by a slow freeze,rapid thaw method, using propanediol (PROH) as the cryoprotectant.A simulated cryopreservation was also included in the studyto detect the level of damage attributable to the PROH alone.Comparison of the mouse and human oocytes cryopreserved by thesame method showed opposing results, with a poor morphologicalsurvival rate of 4% observed for mouse oocytes and a subsequentnormal fertilization rate of 0%. In 171 cryopreserved humanoocytes a higher survival rate of 64% was achieved, and thisshowed more similarity to the mouse pronuclear oocytes survivalof 53%. A comparison of human oocytes, cryopreserved withinthe cumulus and denuded of cumulus and corona prior to cryopreservation,demonstrated a higher survival rate in the denuded oocytes of69% compared to 48%. A delay prior to cryopreservation of 1or 2 days had no effect on the immediate survival of oocytes,but culture for a further 24 h after thawing reduced survival,with the day 1 oocytes exhibiting the most dramatic reductionin survival (28%). Using a lectin binding method, abundant corticalgranules were observed in all cryopreserved oocytes analysed.The meiotic spindle and chromosomes were examined in cryopreservedoocytes using fluorescence microscopy and 60% of the survivingoocytes had a normal spindle and chromosome configuration.     

Excess in the spring and deficit in the autumn in birth rates of male schizophrenic patients in Italy: Potential role of perinatal risk factors

Objective.?The aim of this study was to evaluate whether there were different seasonal variations of births in an Italian population of patients with schizophrenia, with other psychotic disorders, and with personality disorders than in the general population.

Methods.?Birth dates of 1270 patients admitted to one university psychiatric unit in Rome between 1990 and 2003, with a diagnosis of schizophrenia, other psychotic disorder (OPD) and personality disorder/cluster A (PD) were analyzed according to seasonal variation.

Results.?A significant excess of births in spring (with a peak in May) and a deficit in autumn (with a trough in October) was found in the sample of male schizophrenics (n = 506). No statistically significant variations were found in either the sample of female schizophrenics (n = 88) or in the combined sample with OPD and PD (n = 676).

Conclusions.?The findings serve to strengthen the existing hypotheses that schizophrenia is related to environmental factors acting on the development of the central nervous system intrauterinely.     

Impact of Laparoscopic Sleeve Gastrectomy on Upper Gastrointestinal Symptoms

Background

Altered gastric anatomy following laparoscopic sleeve gastrectomy (LSG) is likely to induce upper gastrointestinal (GI) symptoms. Published studies, however, have focused mainly on gastroesophageal reflux disease (GERD). This study aims to evaluate LSG's impact on the prevalence of upper GI symptoms and to assess the effects of time from surgery, weight loss, and proton pump inhibitor (PPI) therapy.

Methods

The validated Rome III Criteria symptom questionnaire for upper GI symptoms, including quality of life items, has been self-administered to 97 patients who underwent LSG. Symptoms were analyzed either separately or altogether to classify patients in GERD or dyspepsia, subdivided in epigastric pain (EPS) and post-prandial distress (PDS) syndromes.

Results

Before LSG, 52.7 % of the patients were asymptomatic, 27.0 % had GERD, and 8.1 % had dyspepsia (2.7 % EPS, 5.4 % PDS). After a median follow-up of 13 months, 91.9 % of the patients complained of upper GI symptoms, the most prevalent being PDS (59.4 %). GERD prevalence did not differ before and after LSG. The only symptom strongly related to LSG was dysphagia (OR 4.7, 95 % CI 1.3–20.4, p?=?0.015), which was present in 19.7 % of the patients and mainly associated with PDS rather than GERD. GI symptoms, however, did not have a great impact on quality of life. Time from surgery, weight loss after surgery, as well as concomitant PPI, did not influence the symptoms.

Conclusions

After a median follow-up of 13 months, PDS-like dyspepsia, rather than GERD, was the main complaint, both poorly responding to PPI therapy. A longer follow-up will be necessary to evaluate their future persistency.     

Mirabegron for Male Lower Urinary Tract Symptoms

Benign prostatic hyperplasia (BPH) is a common cause of lower urinary tract symptoms (LUTS) in men. Patients with BPH often present with a combination of obstructive and overactive bladder (OAB) symptoms. It is postulated that bladder outlet obstruction (BOO) from BPH results in concomitant OAB symptoms through ischemic induced variations in the response to neurotransmitters of both the detrusor and the urothelium. This altered response leads to the pathologic activation of the micturition reflex, generating sensory dysfunction and involuntary bladder contractions. Alpha-1 adrenoceptor antagonists (alpha-blockers) and 5-alpha reductase inhibitors (5-ARIs) are commonly used to treat the BOO caused by BPH. Anticholinergic agents are frequently used to treat concurrently OAB symptoms caused by the BOO. Unfortunately, anticholinergic medications demonstrate bothersome side effects and a theoretical risk of urinary retention. Basic science and clinical research has led to the development of a new class of pharmaceuticals for the treatment of overactive bladder with diminished risk of urinary retention and lacking many anticholinergic side effects. This novel compound, mirabegron (Mybertriq, Astellas Pharma US, Inc.), is a β₃-adrenoceptor agonist and represents a promising new class of oral agents designed for the treatment of OAB symptoms, with minimal effect on voiding.