Glatiramer acetate (GA), the immunomodulatory drug, inhibits inflammatory mediators and collagen degradation in osteoarthritis (OA) cartilage.

OBJECTIVE: Glatiramer acetate (GA), the generic name for Copaxone, an immunomodulatory agent, has been shown to induce interleukin-1 receptor antagonist (IL-1Ra) production in macrophages. We therefore tested the effects of GA on the catabolic activities of osteoarthritis (OA) chondrocytes. DESIGN: Primary human chondrocytes and OA cartilage explants were utilized in this study. IL-1Ra, pro-matrix metalloproteinase-13 (proMMP-13) and prostaglandin E(2) (PGE(2)) were estimated in the cell culture supernatants and in vitro MMP-13 activity was measured using fluorogenic substrate. TaqMan Real-Time quantitative polymerase chain reaction (RT-qPCR) was performed to estimate relative expression levels of genes. RESULTS: GA treatment significantly increased transcription and production of sIL-1Ra (P=0.001) in both culture models. Furthermore, addition of GA (100 µg) inhibited: (1) spontaneous collagen degradation as assayed by CTX II enzyme-linked immunosorbent assay (ELISA) [mean CTX II (ng/g cartilage)] in control was 7.79 [95% confidence interval (CI) 2.57-13.02]-3.415 (95% CI 0.81-6.02) (P=0.0286); (2) spontaneous proMMP-13 secretion [mean MMP-13 (ng/g cartilage)] in control was 16.98 (95% CI 7.739-26.23)-6.973 (95% CI 1.632-12.31) (P=0.0286); (3) production of IL-1ß-induced inflammatory mediators such as nitric oxide (NO) [mean NO (µM)] in IL-1 cultures was 11.47 (95% CI 7.10-15.83)-0.87 (95% CI 0.18-1.56) (P=0.0022); and (4) recombinant MMP-13 in vitro activity (15-25%; P=0.004). CONCLUSIONS: These data suggest that GA effects may be due to upregulation of IL-1Ra as well as direct inhibition of MMP-13 activity. Based on these studies, we propose that GA has potential for disease modifying properties in OA and should be evaluated in vivo in animal studies.

FtsY binds to the Escherichia coli inner membrane via interactions with phosphatidylethanolamine and membrane proteins.

Targeting of many polytopic proteins to the inner membrane of prokaryotes occurs via an essential signal recognition particle-like pathway. FtsY, the Escherichia coli homolog of the eukaryotic signal recognition particle receptor alpha-subunit, binds to membranes via its amino-terminal AN domain. We demonstrate that FtsY assembles on membranes via interactions with phosphatidylethanolamine and with a trypsin-sensitive component. Both interactions are mediated by the AN domain of FtsY. In the absence of phosphatidylethanolamine, the trypsin-sensitive component is sufficient for binding and function of FtsY in the targeting of membrane proteins. We propose a two-step mechanism for the assembly of FtsY on the membrane similar to that of SecA on the E. coli inner membrane.

A site-specific, membrane-dependent cleavage event defines the membrane binding domain of FtsY.

Targeting of many polytopic proteins to the inner membrane of prokaryotes occurs via an essential signal recognition particle-like pathway. Unlike the general secretory pathway, the proteins involved in this pathway and their activities appear in many respects to mirror closely those of their eukaryotic homologues. However, the Escherichia coli signal recognition particle receptor, FtsY, differs significantly at the amino terminus from the eukaryote homologue alpha-subunit of the signal recognition particle receptor. In addition, there is no prokaryote homologue of the transmembrane beta-subunit of the receptor. Therefore, FtsY must assemble on the membrane in a unique manner. Using assays designed to accurately discriminate membrane-bound proteins from aggregated material, we found that in contrast to a previous report, only amino acids 1-284 of FtsY are necessary and sufficient for membrane assembly. These amino acids together constitute a bona fide membrane binding domain that includes both the regions originally designated A and N based on sequence comparisons. Furthermore, we found that a membrane-bound factor mediates specific cleavage of some membrane-bound FtsY molecules between the N and G regions previously believed to be functionally linked to generate a novel membrane-bound isoform composed of only the AN domain.

Occupational sensitization to lactase.

Occupational sensitization to lactase is reported in workers formulating and packaging this consumer product, which is used for the relief of gastrointestinal symptoms caused by intolerance to lactose. Allergic rhinitis, conjunctivitis, and some cases of asthma were noted. There was suggestive evidence that atopic individuals may be at greater risk of sensitization. Lactase should be added to the list of potential occupational respiratory sensitizers.

The parenting partnership: The evaluation of a human service/corporate workplace collaboration for the prevention of substance abuse and mental health problems, and the promotion of family and work adjustment.

A partnership between corporate worksites, a community-based prevention agency, and families in those worksites is described. Its primary goals were the reduction of family risk and enhancement of family protective factors that predispose children and youth to substance abuse and related social and emotional difficulties. A related goal of the program is to reduce family stress levels and attitudes that may influence the parents' levels of risk for substance abuse and related disorder. The program delivery strategy is conceived of as part of the necessart efforts of prevention programs to reach target populations in host settings in which they may naturally participate, thereby reducing obstacles and barriers to participation that often impede prevention efforts. Evaluation revealed that the program was generally better able to retain parents for a fairly lengthy period, and with high rates of attendance. Program attendance was also not affected by parental background characteristics that, in other delivery approaches, are often associated with poor attendance and high drop-out levels. Results also indicated that levels of program exposure (dosage) do make a significant difference in the efficacy of such efforts as those parents in the program who participated in higher percentages and numbers of sessions (i.e. more than 80% of sessions) showed both short-term and longer-term (i.e. across 18 month follow-ups) gains in their ratings of the target child's behavior problems and strengths, substance abuse resistance related knowledge and attitudes, reduced parental stress, depression and irritability, and increased utilization of social support. By contrast, parents who received a low program exposure exhibited a more restricted set of short-term gains. The findings are discussed in terms of their importance for consideration of program dosage for prevention programs, and the need to attend to the context in which programming is offered as it may facilitate or impede efforts to provide levels of dosage and fidelity to create enduring impacts.

Diagnosis of physical illness in psychiatric patients using axis III and a standardized medical history.

Psychiatrists' axis III diagnoses of physical illnesses in 357 psychiatric patients were compared with diagnoses by a physician's assistant using a standardized medical history form. The physician's assistant detected nearly three times as many physical illnesses as the psychiatrists. The psychiatrists were significantly more likely to miss diagnoses among older patients and women. Patients who met criteria for depressive disorders appeared to be at greatest risk for undetected illnesses, followed by patients with bipolar disorders and schizophrenia. Patients with a secondary diagnosis of substance abuse had significantly more undetected illness than those who did not abuse substances. The authors suggest that current axis III guidelines are inadequate and that a systematic review of physical health problems should be part of the psychiatric diagnostic assessment.

Stability and anchorage considerations for cementless tibial components.

The ability of several idealized tibial anchorage systems to resist distractive relative motion between the substrate and the component when subjected to eccentric loads was assessed using mechanical tests employing a urethane foam as a bone substitute and finite element models. Eccentric loads had to be placed within 30-35% of the edge of the tibial plate for separation to occur between an unanchored plate and the substrate. The finite element model predicted that a 90%/10% medial/lateral load distribution was required to maintain compressive vertical stresses beneath the unanchored plate. An anchorage system with four pegs each 10 mm in diameter and 20 mm long and an anchorage system with four cancellous bone screws each 6.5 mm in diameter were loaded eccentrically, and both systems prevented distraction of greater than 76 microns when mounted on urethane foam. Shorter pegs (10 mm) or a single central peg allowed distractions of 150 microns or greater to occur. These data are relevant to the design and testing of tibial components for total knee arthroplasty.

Atypical echocardiographic and angiographic presentation of a postoperative pseudoaneurysm of the left ventricle after repair of a true aneurysm.

Subsequent to the repair of a true aneurysm from the posteromedial-basal aspect of the left ventricle, a 58 year old man developed a draining wound at the site of the sternotomy. Two-dimensional echocardiography revealed recurrence of the aneurysm at the site of the previous aneurysm repair. This aneurysm had a wide neck and looked similar in appearance to the previous true aneurysm. However, at surgery the patient was found to have a ventricular pseudoaneurysm with a cardiocutaneous fistula.

The seed and the soil: effect of dosage, personality and starting state on the response to delta 9 tetrahydrocannabinol in man.

1 The effects of two doses of delta 9THC (2.5 and 10 mg), delivered by paced smoking of herbal cigarettes, on CNV magnitude, subjective mood ratings and heart rate were studied in 20 subjects. 2 There were highly significant interactions between drug dosage and Extraversion and Neuroticism scores, so that the direction and degree of response to the different doses of delta 9THC depended on the personality characteristics of the subjects. 3 The effects of 9 mg delta 9THC and placebo, delivered in herbal cigarettes smoked naturally, on smoking behaviour, subjective mood ratings, measures of autonomic activity and auditory and visual cortical evoked responses were compared in 12 subjects. 4 Smoking behaviour, subjective 'high' rating and elevation of heart rates were the most significant discriminators between drug and placebo. The latency of some of the components of the visual evoked responses was also increased by delta 9THC. 5 There was a significant correlation between the effects of delta 9THC on skin conductance reactivity and the basal (pre-drug) level, reactivity increasing after drug in subjects with low basal reactivity and decreasing in those with high basal levels. 6 Both experiments provided clear evidence of dose-dependent biphasic stimulant and depressant actions of delta 9THC on both subjective and objective measures, and these effects were influenced by the personality and the starting state of the subjects.

A comparison of some physiological and psychological effects of Motival (fluphenazine and nortriptyline) and diazepam in normal subjects.

1 The effects in normal subjects of a single oral dose of Motival (one tablet, containing fluphenazine 0.5 mg and nortriptyline 10 mg) on the contingent negative variation (CNV), reaction time, heart rate, blood pressure and self-rating scales for alertness, anxiety, tension, detachment and depression were compared with those of diazepam (5 mg and 7.5 mg) and placebo or propranolol (60 mg). 2 After diazepam (5 mg: twelve subjects and 7.5 mg: seven subjects) there was a significant decrease in CNV magnitude while after Motival (twelve subjects) there was no significant alteration in CNV magnitude compared to placebo. 3 After diazepam (7.5 mg: seven subjects) there was also a fall in subjective ratings for alertness and tension; this fall was significantly greater than the changes after Motival which did not reduce subjective ratings for alterness or tension below "average" levels. Anxiety ratings did not differ significantly between the two drugs. Changes after propranolol were intermediate in all scales. 4 It is concluded that under these conditions diazepam caused central nervous system depression while Motival did not.

Progression of intraepithelial Paget's disease of the vulva to invasive carcinoma.

Sequential progression from intraepithelial Paget's disease of the vulva to invasive carcinoma after an interval of 10.8 years is documented in this report. Infiltration of the dermis with permeation of lymphatics and metastasis to regional lymph nodes are believed to have resulted directly from foci of intraepidermal Paget's cells that persisted after a simple vulvectomy. No underlying primary sweat gland carcinoma was present. Hence, this case establishes the invasive potential of intraepithelial vulvar Paget's disease and substantiates the notion that it is indeed a type of carcinoma in situ.

An electroencephalographic investigation of short-term effects of three hypothalamic hormones (TRH, LH/FSH-RH, GH-RIH) in normal subjects.

Three hypothalamic regulatory hormones, thyrotrophin-releasing hormone (TRH), luteinizing hormone/follicle-stimulating hormone-releasing hormone (LH/FSH-RH) and growth hormone-release inhibiting hormone (GH-RIH) given intravenously had no effect on the electroencephalographic response known as the contingent negative variation (CNV) in normal subjects. TRH was given as a 10 ml infusion of 600 microg over 8 min to six subjects. This produced subjective sensations and a rise in heart rate but no significant alteration of CNV magnitude. LH/FSH-RH was given in a dose of 200 microg in 10 ml over 2 min to six subjects. This had no effect on CNV magnitude or heart rate and produced no subjective effects. GH-RIH was given as a 10 ml infusion of 250 microg over 10 min to six subjects. Again there was no alteration in the magnitude of the CNV; the heart rate was slowed.