IL-12 is a pivotal cytokine that links the innate and adaptive immune responses. TNF-alpha also plays a key role in orchestrating inflammation and immunity. The reciprocal influence of these two inflammatory mediators on each other may have significant impact on the cytokine balance that shapes the type and extent of immune responses. To investigate the relationship between TNF-alpha and IL-12 production, we analyzed the effects of exposure of human monocyte-derived macrophages to TNF-alpha on LPS- or Staphylococcus aureus-induced IL-12 production in the presence or absence of IFN-gamma. TNF-alpha is a potent inhibitor of IL-12 p40 and p70 secretion from human macrophages induced by LPS or S. aureus. IL-10 is not responsible for the TNF-alpha-mediated inhibition of IL-12. TNF-alpha selectively inhibits IL-12 p40 steady-state mRNA, but not those of IL-12 p35, IL-1alpha, IL-1beta, or IL-6. Nuclear run-on analysis identified this specific inhibitory effect at the transcriptional level for IL-12 p40 without down-regulation of the IL-12 p35 gene. The major transcriptional factors identified to be involved in the regulation of IL-12 p40 gene expression by LPS and IFN-gamma, i.e., c-Rel, NF-kappaB p50 and p65, IFN regulatory factor-1, and ets-2, were not affected by TNF-alpha when examined by nuclear translocation and DNA binding. These data demonstrate a selective negative regulation on IL-12 by TNF-alpha, identifying a direct negative feedback mechanism for inflammation-induced suppression of IL-12 gene expression.

Biological Transport↗

PubMed2000

Guide to IVF. Born free?

Explore the source record for details and available documents.

Eligibility Determination↗

PubMed2000

Anticonvulsant drugs for acute and chronic pain.

BACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for neuropathic pain, especially when the pain is lancinating or burning. OBJECTIVES: To evaluate the analgesic effectiveness of anticonvulsant drugs compared to either placebo or other drugs in order to provide evidence-based recommendations for pain management in clinical practice and to identify a clinical research agenda. Adverse effects are also considered. SEARCH STRATEGY: Randomised trials of anticonvulsants in acute, chronic or cancer pain were identified by Medline (Silver Platter 3.0, 3.1 and 3.11) from 1966 to February 1994. In addition, 40 medical journals were hand searched (published between 1950 and 1990). Additional reports were identified from the reference list of the retrieved papers, and contacting investigators. Date of the most recent searches: 1994. SELECTION CRITERIA: Randomised trials reporting the analgesic effects of anticonvulsant drugs in patients, with pain assessment as either the primary or a secondary outcome. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal, for individual studies and for pooled data. MAIN RESULTS: Twenty trials of four anticonvulsants were considered eligible (746 patients). The only placebo-controlled study in acute pain found no analgesic effect of sodium valproate. Three placebo-controlled studies of carbamazepine in trigeminal neuralgia had a combined NNT for effectiveness of 2.6, for adverse effects 3.4, and for severe effects (withdrawal from study) 24. Three placebo-controlled studies of diabetic neuropathy had a combined NNT for effectiveness of 3, for adverse effects 2.5, and for severe effects 20. Three placebo-controlled studies of migraine prophylaxis had a combined NNT for effectiveness of 2.4, for adverse effects 2.4 and for severe effects 39. Phenytoin had no effect in irritable bowel syndrome, and carbamazepine little effect in post-stroke pain. Clonazepam was effective in one study of temporomandibular joint dysfunction. No study compared one anticonvulsant with another. Anticonvulsants fared poorly against other treatments. REVIEWER'S CONCLUSIONS: Although anticonvulsants are used widely in chronic pain surprisingly few trials show analgesic effectiveness. No trial compared different anticonvulsants. There is no evidence that anticonvulsants are effective for acute pain. In chronic pain syndromes other than trigeminal neuralgia anticonvulsants should be withheld until other interventions have been tried.

Acute Disease↗

PubMed2000

Single dose paracetamol (acetaminophen), with and without codeine, for postoperative pain.

BACKGROUND: Patient surveys have shown that postoperative pain is often not managed well, and there is a need to assess the efficacy and safety of commonly used analgesics as newer treatments become available. Paracetamol (acetaminophen) is an important non-opiate analgesic, commonly prescribed, as well as being available for retail sale. This review seeks to examine the efficacy of paracetamol alone and in combination with codeine, and also considers adverse effects. OBJECTIVES: To assess the analgesic efficacy and adverse effects of a single dose of oral paracetamol (acetaminophen) alone and in combination with codeine for moderate to severe postoperative pain. SEARCH STRATEGY: Published trials were identified from: Medline (1966 to May 1996), Embase (1980 to 1996), Cochrane Library (Issue 2 1996) and the Oxford Pain Relief Database (1950 to 1994). Additional trials were identified from reference lists of retrieved studies. Date of most recent searches: July 1998. SELECTION CRITERIA: Inclusion criteria were: full journal publication, postoperative pain, postoperative oral administration, adult patients, baseline pain of moderate to severe intensity, double-blind design, and random allocation to treatment groups which compared paracetamol with placebo or a combination of paracetamol and codeine with either placebo or the same dose of paracetamol alone. DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of patients with at least 50% pain relief. This was used to calculate the relative benefit and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief over 4 to 6 hours compared with placebo. Adverse effects were used to calculate relative risk and number-needed-to-harm (NNH). MAIN RESULTS: We found 40 trials of paracetamol against placebo (4171 patients), 22 trials of paracetamol plus codeine against placebo (1407 patients) and 12 trials of paracetamol plus codeine against the same dose of paracetamol (794 patients). In postoperative pain paracetamol 1000 mg had an NNT of 4.6 (3.8-5.4) for at least 50% pain relief when compared with placebo, and paracetamol 600/650 mg had an NNT of 5.3 (4.1-7.2). Paracetamol 600/650 mg plus codeine 60 mg had an NNT of 3. 6 (2.9-4.5). Comparing paracetamol plus codeine 60 mg with the same dose of paracetamol alone gave an NNT of 7.7 (5.1-17) for at least 50% pain relief. Adverse effects: Relative risk estimates for paracetamol 600/650 mg plus codeine 60 mg versus placebo showed a significant difference for 'drowsiness'/somnolence (NNH 11 (7.5- 0)) and dizziness (NNH 27 (15-164)) but no significant difference for nausea/vomiting. REVIEWER'S CONCLUSIONS: Paracetamol is an effective analgesic with a low incidence of adverse effects. The addition of codeine 60 mg to paracetamol produces additional pain relief even in single oral doses, but may be accompanied by an increase in drowsiness and dizziness.

Acetaminophen↗

PubMed2000

Liver transplantation in a Jehovah's Witness with ankylosing spondylitis.

PURPOSE: Orthotopic liver transplantation is typically associated with large volume blood loss. Technological and pharmacological advances permit liver transplantation in patients who formerly were not candidates for this surgery because of strict limitations on blood product administration. We describe a liver transplant in a Jehovah's Witness with ankylosing spondylitis. CLINICAL FEATURE: A 49-yr-old Jehovah's Witness with ankylosing spondylitis and end stage liver disease secondary to sclerosing cholangitis underwent orthotopic liver transplantation. Recombinant human erythropoietin (4,000 IU sc every two days for four weeks, then 4,000 IU sc every week) established a normal hemoglobin concentration preoperatively (> 140 g x L(-1) compared with 120 g x L(-1) baseline). Intraoperatively, strategies for reducing risk of blood product transfusion included avoidance of hypothermia (T>35 degrees C), minimal blood sampling (four 1 ml samples), normovolemic hemodilution (two units), administration of Aprotinin (2 million units bolus dose followed by infusion of 500,000 u x hr(-1)), and return of blood (1,500 ml) scavenged from the operative field. Estimated blood loss was 2,200 mi. The preoperative and postoperative hemoglobin concentration was 147 g x L(-1) (hematocrit 0.45) and 123 g x L(-1) (hematocrit 0.37), respectively. No blood products were required and he was discharged three weeks postoperatively without complication. CONCLUSION: Technological and pharmacological advances allow patients to undergo surgery traditionally associated with large volume blood loss with reduced risk of blood product administration.

Blood Loss, Surgical↗

PubMed2000

Science funding and infrastructures in Europe.

European science in crisis. Scared? Then read on; you should be. I argue that we cannot sit back for much longer and watch our best scientists emigrate to the USA for the most productive part of their career, and that European scientists should not tolerate a funding system that neither rewards an investigator's brilliance nor the innovative nature of their research. The EC Framework Programme is due for a face lift: scientists should wield the scalpel this time.

Europe↗

PubMed2000

Transgenic Trifolium repens with foliage accumulating the high sulphur protein, sunflower seed albumin.

With the aim of increasing the rumen-protected level of the sulphur amino acids cysteine and methionine in Trifolium repens, we introduced the coding sequence of the sunflower seed albumin (SSA) into T. repens by Agrobacterium tumefaciens-mediated transformation. The SSA gene was modified such that the protein would be localised to the endoplasmic reticulum (ER). Four different T-DNA constructions all containing the SSA gene driven by either the promoter of a gene encoding the small subunit of ribulose bisphosphate carboxylase (Rubisco) from Arabidopsis thaliana (Assu), the promoter of the gene encoding the small subunit of Rubisco of Medicago sativa (Lssu), or the Cauliflower Mosaic Virus 35S promoter (CaMV35S), were transferred to T. repens cv. Haifa. Transgenic T0-plants and inter-transgenic hybrids were analysed for the level of SSA accumulation in the leaves by western blotting. The highest observed level of SSA accumulation was 0.1% of total extractable leaf protein. We observed that the promoter had a substantive effect on the level of SSA accumulation with Assu > CaMV35S > Lssu. Results from the inter-transgenic hybrids showed that the capacity to synthesise SSA was inherited. However the level of SSA accumulation in the leaves generally appears not to be additive with extra transgenic loci. During this work, we attempted to improve the efficiency of A. tumefaciens-mediated transformation of T. repens using the SAAT-method (Sonication Assisted Agrobacterium-mediated Transformation) on cotyledons of T. repens. T-DNA transfer was in general not enhanced by sonication compared to traditional A. tumefaciens-mediated transformation. Furthermore, Southern blot analyses of plants regenerated from the same cotyledon after A. tumefaciens treatment and under selection, indicated that multiple shoots were usually derived from the same transformation event. We concluded from these results that only one plant from each A. tumefaciens-treated cotyledon should be taken to avoid transgenic clones.

2S Albumins, Plant↗

PubMed2000

In vivo magnetic resonance imaging of transgene expression.

Explore the source record for details and available documents.

Animals↗

PubMed2000

Missense mutations in MIP underlie autosomal dominant 'polymorphic' and lamellar cataracts linked to 12q.

Human inherited cataract is both clinically diverse and genetically heterogeneous. Here we report the identification of the first mutations affecting the major intrinsic protein of the lens, MIP, encoded by the gene MIP on 12q14. MIP is a member of the aquaporin family of membrane-bound water channels. The mutations identified are predicted to disturb water flux across the lens cell membrane.

Adult↗

PubMed2000

OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28.

Autosomal dominant optic atrophy (ADOA) is the most prevalent hereditary optic neuropathy resulting in progressive loss of visual acuity, centrocoecal scotoma and bilateral temporal atrophy of the optic nerve with an onset within the first two decades of life. The predominant locus for this disorder (OPA1; MIM 165500) has been mapped to a 1.4-cM interval on chromosome 3q28-q29 flanked by markers D3S3669 and D3S3562 (ref. 3). We established a PAC contig covering the entire OPA1 candidate region of approximately 1 Mb and a sequence skimming approach allowed us to identify a gene encoding a polypeptide of 960 amino acids with homology to dynamin-related GTPases. The gene comprises 28 coding exons and spans more than 40 kb of genomic sequence. Upon sequence analysis, we identified mutations in seven independent families with ADOA. The mutations include missense and nonsense alterations, deletions and insertions, which all segregate with the disease in these families. Because most mutations probably represent null alleles, dominant inheritance of the disease may result from haploinsufficiency of OPA1. OPA1 is widely expressed and is most abundant in the retina. The presence of consensus signal peptide sequences suggests that the product of the gene OPA1 is targeted to mitochondria and may exert its function in mitochondrial biogenesis and stabilization of mitochondrial membrane integrity.

Amino Acid Sequence↗

PubMed2000