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Biomedical subjects

M Weir

Publications and source records attributed to M Weir.

At least 19 recordsLinked to original sources
PubMed2002

Psychiatric health in a sexually transmitted infections clinic: effect on reattendance.

BACKGROUND AND OBJECTIVES: Sexually transmitted infections (STIs) remain a public health priority, but associated psychological morbidity has recently been ignored. One aspect of STI control is test of cure and further treatment at follow-up clinic appointments. We chose reattendance rates as a measure of compliance and assessed whether reattendance was related to psychological morbidity. METHODS: 938 STI clinic patients were offered the Hospital Anxiety and Depression Scale (HAD) and staff rated each patient's psychological health. Predictors of attendance, caseness and staff recognition were assessed by logistic regression. RESULTS: 401/774 [51.9%; 95% confidence interval (CI): 48.3-55.4%] patients, who completed the HAD, scored above threshold. Staff rated 151/743 (20.4%) patients as having "psychological problems." HAD caseness was not associated with attending arranged follow-up [adjusted odds ratio (adj. OR): 0.83 (0.49-2.05)]. Patients rated with psychological problems by staff were more likely to attend [adj. OR: 1.91 (1.02-3.60)]. CONCLUSIONS: Half of our sample had significant anxiety and staff should be more aware of this suffering. Our work suggests that such awareness might improve subsequent attendance.

Adolescent↗
PubMed2002

Priorities and satisfaction on the help needed and provided in a first episode of psychosis. A survey in five European Family Associations.

In the case of a first episode of psychosis among members of different associations of families of mentally ill people, little is known about their priorities and how satisfied they are with the help provided to them. A survey was conducted in five European family associations. Respondents emphasized the need for early (ambulant) intervention through outreach with very practical goals directed at creating stability and social functioning. About one-third of the respondents are unsatisfied or very unsatisfied. The highest percentage of unsatisfied respondents was in the following five areas of care: advice on how to handle specific problems; help with preserving or regaining social functioning; help with regaining structure and routine; information; prompt assistance preferably in patients own environment. The agreement of these findings with findings from earlier studies underlines the importance of suggesting specific changes in the delivery of care.

Adult↗
PubMed2001

Nicastrin, a presenilin-interacting protein, contains an aminopeptidase/transferrin receptor superfamily domain.

Nicastrin, a protein implicated in Alzheimer's disease, has a domain that is found in the aminopeptidase/transferrin receptor superfamily. In nicastrin, this domain might possess catalytic activity (as observed with aminopeptidases) or it could serve merely as a binding domain (with analogy to the transferrin receptors) for the beta-amyloid precursor protein.

Amino Acid Sequence↗
PubMed2001

A prospective randomized controlled trial comparing nonstented versus stented ureteroscopic lithotripsy.

PURPOSE: A prospective randomized controlled trial was performed to determine whether stents may be eliminated after uncomplicated ureteroscopic lithotripsy for ureteral stones. MATERIALS AND METHODS: A total of 58 patients underwent uncomplicated ureteroscopic intracorporeal lithotripsy. After stone fragmentation patients were randomized to a nonstented (29) or a stented (29) treatment group. Intracorporeal lithotripsy was performed with the holmium laser in 57 cases and by electrohydraulic lithotripsy in 1 without balloon dilation or the extraction of stone fragments. Patients were followed 1, 6 and 12 weeks postoperatively. In stented cases the stent was removed at 1 week. Outcome measures included postoperative symptoms assessed with a visual analog scale, postoperative analgesic requirements, complications and the stone-free rate. RESULTS: At 1 week the symptoms of flank pain, abdominal pain, dysuria and frequency were significantly greater in the stented group (p <0.005). There were no differences in symptoms in the groups at subsequent followup visits. There was no difference in treatment groups in terms of the amount of analgesic required in the recovery room or during 1 week after ureteroscopy. Similarly there was no difference in the number of patients requiring antiemetics. One patient in the stented group required hospitalization for genitourinary sepsis and 1 patient in the nonstented group visited the emergency room for postoperative vomiting. The stone-free rate was 100% in each group. CONCLUSIONS: These results demonstrate that after ureteroscopic intracorporeal lithotripsy with the holmium laser patients with a stent have significantly greater irritative and painful symptoms than those without a stent in the early postoperative period. There was no difference in nonstented and stented ureteroscopy with respect to complications or stone-free status. Therefore, we believe that routine stenting after ureteroscopic intracorporeal lithotripsy with the holmium laser is not required as long as the procedure is uncomplicated and performed without balloon dilation of the ureteral orifice.

Adult↗
PubMed2000

Targeted localized degradation of Paired protein in Drosophila development.

BACKGROUND: Selective spatial regulation of gene expression lies at the core of pattern formation in the embryo. In the fruit fly Drosophila, localized transcriptional regulation accounts for much of the embryonic pattern. RESULTS: We identified a gene, partner of paired (ppa), whose properties suggest that localized receptors for protein degradation are integrated into regulatory networks of transcription factors to ensure robust spatial regulation of gene expression. We found that the Ppa protein interacts with the Pax transcription factor Paired (Prd) and contains an F-box, a motif found in receptors for ubiquitin-mediated protein degradation. In normal development, Prd functions only in cells in which ppa mRNA expression has been repressed by another segmentation protein, Even-skipped (Eve). When ppa was expressed ectopically in these cells, Prd protein, but not mRNA, levels diminished. When ppa function was removed from cells that express prd mRNA, Prd protein levels increased. CONCLUSIONS: Ppa co-ordinates Prd degradation and is important for expression of Prd to be correctly localized. In the presence of Ppa, Prd protein is targeted for degradation at sites where its mis-expression would disrupt development. In the absence of Ppa, Prd is longer-lived and regulates downstream target genes.

Amino Acid Sequence↗
PubMed2000

Applications of protein mass spectrometry in cell biology.

Advances in mass spectrometry combined with accelerated progress in genome sequencing projects have facilitated the rapid identification of proteins by enzymatic digestion, mass analysis, and sequence database searching. Applications for this technology range from the surveillance of protein expression in cells, tissues, and whole organisms, to the identification of proteins and posttranslational modifications. Here we consider practical aspects of the application of mass spectrometry in cell biology and illustrate these with examples from our own laboratories.

Amino Acid Sequence↗
PubMed2000

Effects of pulsatile intravenous insulin therapy on the progression of diabetic nephropathy.

The purpose of this study was to assess the effects of pulsatile intravenous insulin therapy (PIVIT) on the progression of diabetic nephropathy in patients with type 1 diabetes mellitus (DM). This 18-month multicenter, prospective, controlled study involved 49 type 1 DM patients with nephropathy who were following the Diabetes Control and Complications Trial (DCCT) intensive therapy (IT) regimen. Of these, 26 patients formed the control group (C), which continued on IT, while 23 patients formed the treatment group (T) and underwent, in addition to IT, weekly PIVIT. Blood pressure in all patients was maintained below 140/90 mm Hg on antihypertensive medication, preferentially using angiotensin-converting enzyme (ACE) inhibitors. All study patients were seen in the clinic weekly for 18 months, had monthly glycohemoglobin (HbA1c), and every 3 months, 24-hour urinary protein excretion and creatinine clearance (CrCl) determinations. The HbA1c levels declined from 8.61% +/- 0.33% to 7.68% +/- 0.31% (P = .0028) in the T group and from 9.13% +/- 0.36% to 8.19% +/- 0.33% (P = .0015) in the C group during the study period. CrCl declined significantly in both groups, as expected, but the rate of CrCl decline in the T group (2.21 +/- 1.62 mL/min/yr) was significantly less than in the C group (7.69 +/- 1.88 mL/min/yr, P = .0343). We conclude that when PIVIT is added to IT in type 1 DM patients with overt nephropathy, it appears to markedly reduce the progression of diabetic nephropathy. The effect appears independent of ACE inhibitor therapy, blood pressure, or glycemic control.

Adult↗
PubMed2000

The future of clinical trials in chronic renal disease: outcome of an NIH/FDA/Physician Specialist Conference. Evaluation of Clinical Trial Endpoints in Chronic Renal Disease Study Group.

For people with chronic renal insufficiency, the therapeutic goal is to prevent progression to end-stage renal disease, a serious condition that can only be treated with dialysis and kidney transplantation. Although restriction of dietary protein slows the progression of renal disease somewhat, the principal treatment to slow chronic renal disease is appropriate reduction of blood pressure. Antihypertensive agents, particularly those that produce sustained, long-term reductions in proteinuria, such as angiotensin-converting enzyme inhibitors, not only decrease blood pressure but also preserve renal function. Clinical trials to evaluate these and other drug therapies in renal disease progression have used both "hard end points" (e.g., dialysis, transplantation, death) and intermediate end points of renal disease progression (e.g., doubling of serum creatinine concentration, reductions in proteinuria). Trials that have used hard end points typically recruited patients with advanced renal disease to demonstrate a difference in therapies within a period of 2 to 5 years. However, proteinuria reduction, along with a decrease in the time to doubling of serum creatinine in very early diabetic renal disease, could demonstrate an altered natural history of renal disease. Although hard end points are indicators of a drug's efficacy in reducing cardiovascular events or preserving renal function, they do not assess the impact of a treatment on altering the natural history of early renal disease. For clinical trials of people with all but the most advanced renal disease, use of intermediate end points of renal disease progression is the only practical option for assessment of treatment efficacy and effectiveness. Given the available data on proteinuria reduction and doubling of serum creatinine from clinical trials, these end points, taken together, appear to provide an acceptable means of assessing a treatment's impact on slowing renal disease progression.

Antihypertensive Agents↗
PubMed2000

Adolescent urinary tract infections.

Urinary symptoms in adolescents are common, particularly in females. Urinary tract infections (UTIs) cause many of these symptoms. For uncomplicated UTIs, both lower and upper tract, therapy is straightforward. Commonly used antibiotics are trimethoprim/sulfamethoxazole (TMP/SMX), cefixime, and ciprofloxacin (off-label use) for 3 days for lower tract infections and 10ñ14 days for upper tract infections. Adolescent UTIs are markers for sexual activity, just as UTIs in younger children are often markers for anatomic defects, e.g., congenital abnormalities. Adolescents with upper and lower UTIs often have concurrent sexual activity or a complication of that activity. Issues among adolescents with UTIs are more similar to those of young adults than to those of younger children. It is as important to counsel adolescents about sexual activity and its consequences as it is to treat the UTIs. All adolescents with UTIs should be queried for sexual activity; evidence of sexually transmitted diseases (STDs) should be sought; and counseling for STDs and responsible sexual activity is recommended. Complicated UTIs include those in patients who have grown into adolescence after a childhood of infections or who have anatomic abnormalities, recurrent infections, reflux and reflux nephropathy, spina bifida and neurogenic bladder, transplanted kidneys, diabetes, and urolithiasis. These patients require individualized medical programs, unique for their condition, history, and microbiology.

Adolescent↗
PubMed1999

Recreation of neuronal Kv1 channel oligomers by expression in mammalian cells using Semliki Forest virus.

The multiple roles of voltage-sensitive K(+) channels (Kv1 subfamily) in brain are served by subtypes containing pore-forming alpha (1.1-1.6) and auxiliary beta subunits, usually in an (alpha)(4)(beta)(4) stoichiometry. To facilitate structure/activity analysis, combinations that are prevalent in neurones and susceptible to alpha-dendrotoxin (alphaDTX) were reproduced in mammalian cells, using Semliki Forest virus. Infected Chinese hamster ovary cells expressed N-glycosylated Kv1.1 and 1.2 alpha subunits (M(r) approximately 60 and 62 K) that assembled and bound [(125)I]-alphaDTX with high affinity; an appreciable proportion appeared on the cell surface, with Kv1.2 showing a 5-fold enrichment in a plasma membrane fraction. To obtain 'native-like' alpha/beta complexes, beta1.1 or 2.1 (M(r) approximately 42 and 39 K, respectively) was co-expressed with Kv1.1 or 1.2. This slightly enhanced N-glycosylation and toxin binding, most notable with beta2. 1 and Kv1.2. Solubilization of membranes from cells infected with Kv. 1.2 and beta2.1, followed by Ni(2+) chromatography, gave a purified alpha1.2/beta2.1 complex with a size of approximately 405 K and S(20, W) = 15.8 S. Importantly, these values indicate that four alpha and beta subunits co-assembled as in neurones, a conclusion supported by the size ( approximately 260 K) of the homo-tetramer formed by Kv1.2 alone. Thus, an authentic K(+) channel octomer has been reconstructed; oligomeric species were also found in plasma membranes. To create 'authentic-like' hetero-oligomeric channels, Kv1.1 and 1.2 were co-expressed and shown to have assembled by the precipitation of both with IgGs specific for either. Consistently, confocal microscopy of cells labeled with these antibodies showed that the relatively low surface content of Kv1.1 was increased by Kv1.2. [(125)I]-alphaDTX binding to these complexes was antagonized by DTX(k), a probe selective for Kv1.1, in a manner that mimicks the pattern observed for the Kv1.1/1.2-containing channels in neuronal membranes.

Animals↗
PubMed1999

Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.

The binding modes of four active site-directed, acylating inhibitors of human alpha-thrombin have been determined using X-ray crystallography. These inhibitors (GR157368, GR166081, GR167088, and GR179849) are representatives of a series utilizing a novel 5, 5-trans-lactone template to specifically acylate Ser195 of thrombin, resulting in an acyl complex. In each case the crystal structure of the complex reveals a binding mode which is consistent with the formation of a covalent bond between the ring-opened lactone of the inhibitor and residue Ser195. Improvements in potency and selectivity of these inhibitors for thrombin are rationalized on the basis of the observed protein/inhibitor interactions identified in these complexes. Occupation of the thrombin S2 and S3 pockets is shown to be directly correlated with improved binding and a degree of selectivity. The binding mode of GR179849 to thrombin is compared with the thrombin/PPACK complex [Bode, W., Turk, D., and Karshikov, A. (1992) Protein Sci. 1, 426-471] as this represents the archetypal binding mode for a thrombin inhibitor. This series of crystal structures is the first to be reported of synthetic, nonpeptidic acylating inhibitors bound to thrombin and provides details of the molecular recognition features that resulted in nanomolar potency.

Binding Sites↗
PubMed1999

Low levels of interferon-alpha induce CD86 (B7.2) expression and accelerates dendritic cell maturation from human peripheral blood mononuclear cells.

Interferon-alpha (IFN-alpha) (IFN-alpha2b) is an immunoregulatory cytokine that is presently used in a recombinant form for the treatment of tumours and chronic viral infection. However, its mechanism of action remains largely undefined. In this paper, we studied the effects of low doses of IFN-alpha (0-100 U/ml) on the generation of dendritic cells with granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-4 (IL-4), and tumour necrosis factor (TNF)-alpha in cultures of human peripheral blood mononuclear cells (PBMCs). An addition of IFN-alpha to the PBMC cultures greatly increased the HLA class II and the CD86 expression on developing dendritic cells (DCs) during a 7-day culture period. When added at the initiation of the PBMC culture, as little as 10 U/ml dramatically increased the HLA class II and CD86 expression, with maximal effects observed between 50 and 100 U/ml in all PBMC preparations tested. Almost all of the nonadherent cells induced with added IFN-alpha possessed a phenotype of mature DCs, being CD1a(low), CD83+, HLA class IIhigh, CD86high, CD40high, and CD80low, while being negative for the monocyte/macrophage and lymphocyte markers. In contrast, the floating cells isolated from cultures grown without IFN-alpha were mostly immature DCs with a CD1a(high), CD83-, HLA class IIint/high, CD86low/int, CD80low phenotype. An addition of 50 U/ml IFN-alpha at the time of the culture initiation greatly increased both the number of mature DCs generated and their rate of appearance; by 3 days of culture, many large floating aggregates were present containing mature CD83+, CD1a(low) DCs, while much fewer aggregates of mature DCs were found without added IFN-alpha. Histochemical staining confirmed that the floating cells induced with IFN-alpha had typical DC features, including irregularly shaped nuclei, few cytoplasmic granules, and absent or diffuse perinuclear staining for esterase. Our results suggest that IFN-alpha is a potent accelerator of DC maturation in vitro. These effects on DC maturation may explain its clinical success in the treatment of cancer and viral infection as well as its ability to promote autoimmunity.

Antigens, CD↗
PubMed1998

Plasticity of Drosophila paired function.

The Drosophila Paired (Prd) transcription factor has homeodomain (HD) and paired domain (PD) DNA-binding activities required for in vivo function. Correspondingly, Prd activation of late even-skipped (eve) expression occurs through a conserved target sequence (PTE) with HD and PD half sites, both of which are required for activation. To investigate the relationship between the HD and PD, and their roles in conferring specificity to Prd function, we tested altered versions of the Prd protein and of the PTE target site using in vivo assays in embryos. We found that function through PTE was constrained by the targeting specifications of both the HD and PD as well as the spatial relationship between these two domains. PTE function was also constrained by the spacing between the target half sites for the PD and HD, although surprisingly, late eve activation was retained when PTE was replaced by in vitro optimized binding sites for either the PD alone or for an HD dimer. In contrast to late eve regulation, other Prd targets tolerated more changes in the Prd protein, suggesting that their target sequences may be qualitatively different from PTE.

Animals↗
PubMed1998

HIV infection among homosexual/bisexual males attending genitourinary clinics in Scotland.

BACKGROUND: Since 1991, unlinked anonymous HIV testing of homosexual/bisexual males attending genitourinary clinics in Edinburgh and Glasgow has been conducted and resulting prevalence data have been published annually. More detailed information which provides an understanding of what proportion of HIV infected men attending genitourinary clinics in central Scotland (i) remain undetected, (ii) acquire sexually transmitted infections following HIV diagnosis, and (iii) possibly become HIV infected either abroad or following sex with someone from abroad, is reported by the authors. METHODS: Unlinked anonymous HIV testing of syphilis serology specimens from homosexual/bisexual males attending genitourinary clinics during 1991-5. RESULTS: Of 3468 specimens tested, 165 (4.8%) were HIV positive. Thirty five per cent (57) of all HIV positive specimens were from men whose infection remained undetected following clinic attendance. Of the 80 attenders who knew themselves to be HIV positive before their clinic visit, 13 had clinical and/or laboratory evidence of a sexually transmitted infection. Men who had a sexual risk associated with America or who were American, had a 2.4-fold greater risk of being HIV infected than those with United Kingdom only connections. CONCLUSION: Increased efforts should be made to ensure that HIV infected men are diagnosed early after infection and do not engage in high risk sexual behaviour, and that all homosexual men are educated about the particular risks of acquiring HIV infection abroad. More effective interventions to prevent indigenous HIV transmissions need to be developed.

Bisexuality↗