Lessons from the pandemic: An innovative scheme to support research in the North West Coast.

In 2021, a Clinical Research Fellow (CRF) scheme was created to serve the North West Coast (NWC) region in line with the key health priorities set out by the Clinical Research Network. Five doctors in pre-specialist training were placed in NHS trust research departments across the NWC. The scheme aimed to provide early career research experience while also enhancing the provision of research across the region. The CRFs were involved in writing clinical trial grant applications and study protocols, with the scheme providing additional experience in leadership roles and time management. In addition, the CRF scheme has had a positive impact in adopted NHS trusts, which have seen their overall research capacity and capability improve, through increased flexibility and medical oversight. Research departments have benefited from increased financial income and improved national reputations. Overall, this real-world experience provided a vital 'foot in the door', which is essential for research-interested medics to advance in a future academic career. In the wider NWC region, the CRF scheme successfully delivered achievable and financially sustainable research. Innovative programmes such as this one should be seen as a viable option for research provision through the NHS, in the UK.

Treatment with neutralizing antibodies specific for IL-1beta prevents cyclophosphamide-induced diabetes in nonobese diabetic mice.

Interleukin-1 (IL-1) has been shown to be involved in the pathogenesis of IDDM, but it is not clear which form, IL-1alpha or IL-1beta, is predominantly implicated. In this study, we have evaluated the contribution of IL-1beta by treating diabetes-prone nonobese diabetic (NOD) mice with specific neutralizing antibodies. First, we assessed the neutralizing potential of these antibodies in C57BL/6 mice under acute septic shock by measuring IL-1beta in sera 4 h after lipopolysaccharide injection. One milligram and 0.1 mg of anti-IL-1beta antibodies (Abs) were capable of neutralizing the IL-1beta produced, and the effect persisted for at least 5 days. Second, we evaluated the role of IL-1beta in the cyclophosphamide (CY)-accelerated model of diabetes. Nondiabetic male NOD mice were injected with 200 mg/kg CY and treated twice weekly with anti-IL-1beta Ab. The incidence of diabetes reached 76 and 100% in the control groups treated with 0.25 and 0.1 mg rabbit IgG, respectively. In contrast, only 34% of mice treated with 0.25 mg of anti-IL-1beta Ab became diabetic. In the group treated with 0.1 mg of anti-IL-1beta Ab, 89% of the mice became diabetic in the same period of time, demonstrating that the protective effect was dose dependent. Our results show that IL-1beta is a critical effector molecule in this model of IDDM and that its specific inhibition could be an attractive target for therapeutic intervention.

2-(oxadiazolyl)- and 2-(thiazolyl)imidazo[1,2-a]pyrimidines as agonists and inverse agonists at benzodiazepine receptors.

Oxadiazoles, like the benzoyl group in a series of imidazo[1,2-a]pyrimidines, have been found to be metabolically stable alternatives to ester groups in benzodiazepine-receptor ligands. This change has lead to a number of compounds which bind to the receptors and which exhibit potent agonist activity in a food-motivated conflict test thought to predict anxiolytic properties. Compounds 4, 5, and 13 were equipotent with chlordiazepoxide but showed little or no myorelaxant effects. Replacing the oxadiazole group by thiazole gave compounds such as 23 which binds to the benzodiazepine receptor but exhibits the intrinsic activity of a partial inverse agonist in vivo.

Synthesis and antitussive activity of aminotetra- (and -hexa-) hydrodibenzofurans.

The synthesis of a novel series of antitussive agents is described. Two series of amino-substituted tetra- and hexahydrodibenzofurans were prepared and examined for antitussive activity in the guinea pig after cough elicited by electrical stimulation of the vagus nerve. A significant level of activity, comparable with that of codeine, was found in the 4alpha-amino series. The 4-methylpiperazin-1-ylpropionamide (28) was found to be the most active of the compounds synthesized and was equipment with codeine. The effects of structural modification upon antitussive activity were investigated in numerous analogues but no enhancement of activity was achieved over that of 28.

(Imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones and related compounds as potential nonsedative anxiolytics.

Several series of heterocyclic carboxylic esters were found to be active in the benzodiazepine receptor binding assay, a typical example being ethyl 7-ethyl-5-methoxyimidazo[1,2-a]quinoline-2-carboxylate (4b) with an IC50 of 150 nM. The corresponding phenylmethanone 5d was more potent with an IC50 of 14 nM and was orally active in animal models thought to predict anxiolytic effects. The synthesis of a large number of compounds resulted in the optimization of this activity in a series of (imidazo[1,2-a]pyrimidin-2-yl)phenylmethanones of which compounds 7e, 8b, 8h, 8j, and 8k were equipotent with chlordiazepoxide while exhibiting reduced anticonvulsant activity, little or no muscle relaxation, and negligible sedative effects.

Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ] propenamide and related compounds.

The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.

Inhibition of stimulated Jurkat cell adenosine 3',5'-cyclic monophosphate synthesis by the immunomodulatory compound HR325.

HR325 (2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'(trifluoromethyl)-phenyl]-propenamide) is an immunomodulatory compound through pyrimidine biosynthesis inhibition with antiproliferative properties which was derived from the isoxazol compound A77 1726 [2-cyano-3-cyclopropyl-3-hydroxy-enoic acid (4-trifluoromethylphenyl)-amide]. During studies of the effects on early signal transduction events of this type of compound, it was found that HR325 dose-dependently inhibited adenosine 3',5'-cyclic monophosphate (cAMP) synthesis by Jurkat cells stimulated with prostaglandin E(2), (PGE(2)), cholera toxin (CTX), or forskolin (FKN). The potency of inhibition by HR325 of FKN-stimulated cells (IC(50) 30.4 microM) was approximately 3-fold higher than that of the other agonists (11.6 and 11.7 microM) and was independent of time of preincubation for both PGE(2) and FKN. Interestingly, A77 1726, an analogue of HR325, displayed a markedly different profile of stimulus-dependent potencies. The inhibition of cAMP synthesis by HR325 when stimulated by both PGE(2) and FKN was unaffected by glucose supplementation, in contrast to HR325-inhibited ATP levels, which were restored under such conditions. Further studies revealed that HR325 reduced intracellular ATP levels by uncoupling oxidative phosphorylation, albeit with a 1000-fold lower potency than the antihelmintic drug niclosamide. In addition, glucose supplementation experiments showed that, in contrast to HR325, the niclosamide-mediated reduction of ATP levels was wholly responsible for its inhibition of PGE(2)- and FKN-stimulated cAMP synthesis.

Implants in adolescents: a literature review and case reports.

A retrospective review of a limited number of adolescents with implants was conducted to compare the behavior of these implants with studies in which implants had been placed in growing animals. Growth of the facial skeleton is also reviewed. Implants placed in the growing alveolus behave like ankylosed teeth and become submerged as the surrounding bone grows. Cessation of facial growth should occur prior to implant placement in adolescents.

Ridge widening for the thin maxilla: a clinical report.

The thin maxilla may present an anatomic limitation to the placement of endosseous implants. Separating the cortical plates and widening the alveolar ridge with simultaneous placement of implants is one surgical method for management of this problem. Guided tissue regeneration techniques may be used in conjunction with this ridge widening procedure.

Developing a new wound care formulary and guidelines.

Following an audit of the existing wound care formulary and guidelines, an updated version was developed, containing additional products and information. This was revised following advice from a range of professionals, then pilot tested on ward-based nurses. The nurses found the updated formulary useful, and made recommendations for changes to the wound care ordering system in the trust. Future guidelines will be regularly updated as developments in wound care occur.

Acute Intermittent Porphyria: Some Diagnoses are Only Made If Thought of.

A 20-year-old Asian, female, student nurse of thin body habitus (Body Mass Index 16.5) but otherwise previously well had numerous admissions to our centre under a variety of surgical sub-specialities over a 5-month period. Each month, coinciding with menses, she complained of non-specific abdominal discomfort in the absence of any other symptoms. With the exception of the presence of a sinus tachycardia coupled with incidental hyponatraemia full physical examinations and routine baseline investigations were unremarkable.

An assessment of tree health and trace element accumulation near a coal-fired generating station, Manitoba, Canada.

A forest health assessment was performed in stands dominated by bur oak and trembling aspen to study the potential effects of airborne emissions from a 132 MW coal-fired station. Forty-two stands were sampled within a 16-km radius of the station for both foliar stress symptoms and trace element toxicology. The concentrations of tracer elements (As, Ba, Sr, and V) in the leaf litter were not spatially congruent with airborne emission deposition models (except Ba, which showed elevated levels immediately SE of the station), nor were they at phytotoxic levels. Elemental concentrations were significantly related to soil parameters including organic matter and texture. No patterns were found in forest health along directional or distance gradients from the generating station. Trembling aspen stands demonstrated little decline in general, but three of the 19 bur oak plots, all located on thin sandy soils developed on calcareous till, demonstrated branch dieback. In addition to poor soil conditions, two of these sites also had high water tables, and exhibited tree mortality. The bur oak decline did not appear to be related to emissions from the station, but is suspected to be a result of poor site quality, with urban development as a confounding factor.

Complications associated with maxillary osteotomies.

There are certain complications involved in maxillary ostetomies; devitalization of teeth, loss of part or all of the osteotomized segment, and relapse are possible problems. The paramount cause of the complications in seven different cases seemed to be the interruption of the blood supply to the operative site. A seven-point guideline is formulated; it integrates preoperative planning, surgical procqedures, and postoperative care.

Eminectomy for the treatment of recurrent temporomandibular joint dislocation.

Several techniques have been used to treat chronic dislocation of the mandible. Most of these techniques represent attempts at reducing the mobility of the TMJ. The eminectomy procedure is an attempt at restoring normal joint function without reducing mobility of the joint. We have presented two cases of chronic dislocation of the mandible that were treated successfully by removal of the articular tubercle and the lateral portion of the temporal bone. Although surgery of the TMJ area may be hazardous if approached without caution, we feel that the complications associated with this procedure are minimized if adequate care is taken in flap design and tissue dissection. On the basis of the excellent results of the eminectomy procedures reported in the literature and of our own experience with this procedure, we feel that this is the preferred treatment for chronic dislocation of the mandible.

Urinary tract toxicity in rats following administration of beta 3-adrenoceptor agonists.

ZD7114, [(S)-4-[2-(2-hydroxy-3 phenoxypropylamine)ethoxy]-N-(2-methoxyethyl) phenoxyacetamide], and ZD2079, [(R)-N-(2-[4- (carboxymethyl)phenoxy]ethyl)-N-(beta-hydroxyphenethyl)ammonium chloride], are beta 3-adrenoceptor stimulants with selectivity for brown adipose tissue. ZD7144 is the hydrochloride salt of the S-enantiomer of the racemic amide ZD2079. They were developed as potential novel treatments for obesity and non-insulin-dependent diabetes mellitus. Male and female rats were dosed separately by gavage for a minimum of 28 days with 0, 10, 50, and 500 mg/kg/day of ZD7114 or with 0, 10, 30, and 150 mg/kg/day of ZD2079. Two further groups of male and female rats were dosed with 0 and 500 mg/kg/day of ZD7114 for 28 days and were then allowed a 6-wk, undosed withdrawal period. At high doses, both compounds caused urinary tract toxicity, which primarily affected the distal tubules and collecting ducts of the kidney via tubular necrosis. They also caused ureteric inflammation, cystitis, and accumulation of crystalline inclusions throughout the urinary tract. As a result of urinary tract toxicity, affected animals from one or both studies showed reduced red blood cell indices, lower platelet counts, and higher white cell counts. Blood chemistry revealed lower plasma concentrations of glucose (7.28 +/- 1.37 compared to 8.11 +/- 0.65 for the control) and total protein (63.42 +/- 3.65 compared to 69.17 +/- 3.24 for the control) and increased plasma urea (37.15 +/- 19.96 compared to 8.09 +/- 0.87 for the control). Urinalysis showed an increase in the number of crystals, blood, and protein. In the urinary tract, the severe crystalluria with accumulation of crystalline material indicated that this may have a role in the etiology of the target organ toxicity. Poor solubility of the compounds at normal urinary pH was considered a possible mechanism for the crystalluria.

The diagnostic significance of the microhematocrit as an office screening test.

The microhematocrit provides accurate and reproducible test results. This laboratory procedure is useful not only in determining the hematocrit value, but also in the identification of conditions that may be of primary interest to the clinician. The information it provides is valuable in treatment planning, in choosing an anesthetic technique, and in helping to avoid operative and postoperative complications. This test can be easily and inexpensively performed and can be incorporated into the normal office routine with little difficulty.

Further evidence to support the melanocytic origin of MDA-MB-435.

BACKGROUND/AIMS: Until recently, the cell line MDA-MB-435 was widely accepted as originating from a breast cancer. However, microarray derived data have suggested that this cell line may in fact originate from an occult melanoma. This study was designed to investigate this hypothesis further. METHODS: Quantitative reverse transcription polymerase chain reaction and immunohistochemistry were used to investigate the tissue of origin of two sublines of MDA-MB-435 (MDA-MB-435 S and MDA-MB-435 HGF). The expression of a panel of genes typical of breast cells or melanocytes was analysed. RESULTS: The MDA-MD-435 cell lines expressed none of the genes characteristic of breast cancer cells but did express several genes commonly expressed by melanocytes. CONCLUSIONS: These results strongly suggest that MDA-MB-435 is indeed of melanoma origin.

Potencies of leflunomide and HR325 as inhibitors of prostaglandin endoperoxide H synthase-1 and -2: comparison with nonsteroidal anti-inflammatory drugs.

The relative anti-inflammatory activities of the immunomodulators HR325 and leflunomide, or its active metabolite A77 1726, were examined by determining potencies in vitro on prostaglandin endoperoxide H synthase (PGHS) and in vivo in rat air pouch inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) were used as comparators. HR325 was more potent than A77 1726 as an inhibitor of PGHS in guinea pig polymorphonuclear leukocytes (IC50 = 415 and 4400 nM, respectively) and on isolated ovine PGHS-1 (IC50 = 64 and 742 microM) and PGHS-2 (IC50 = 100 and 2766 microM). In vivo, in rat carrageenan air pouch inflammation, HR325 but not leflunomide at 25 mg/kg inhibited accumulation of leukocytes (48%) and PGE2 (61%). HR325 was also more potent than A77 1726 against human peripheral blood mononuclear cell PGHS-1 [IC50 = 1.6 and 25.6 microM (thromboxane B2 production) or 1.1 and 8 microM (PGE2 production)] and lipopolysaccharide-induced PGHS-2 in human adherent peripheral blood mononuclear cells (IC50 = 435 nM and 9.5 microM) and peripheral blood polymorphonuclear leukocytes (IC50 = 91 nM and 3.2 microM). HR325 had low PGHS-2 selectivity in the human (2.5-12-fold) and was a more potent PGHS-2 inhibitor than naproxen, ibuprofen and piroxicam (28-fold). Assays using endogenous arachidonic acid as substrate yielded IC50 values for NSAIDs that were in general markedly lower than those published for assays using 10 microM substrate. With this approach, piroxicam had reasonable activity on human PGHS-2 (IC50 = 260-290 nM). Only NS398 and flufenamic acid were PGHS-2 selective in the human (90-330-fold and 37-60-fold, respectively); the other NSAIDs were either PGHS-1-selective (naproxen, ibuprofen, flurbiprofen and indomethacin) or nonselective (piroxicam and diclofenac). Inclusion of 10% human plasma reduced HR325 potency against PGHS-1 in human peripheral blood mononuclear cells approximately 32-fold (IC50 = 36 microM). Plasma protein binding further reduced HR325 potency (IC50 = 164 microM) and minimized the difference between HR325 and A77 1726 (IC50 = 292 microM) in a whole blood PGHS assay. Whether the greater activity against human PGHS-2 would allow HR325 to exhibit NSAID-like therapeutic effects in humans remains unclear.