Mapping neuronal inputs to Kiss1 neurons in the arcuate nucleus of the mouse.

The normal function of the mammalian reproductive axis is strongly influenced by physiological, metabolic and environmental factors. Kisspeptin neuropeptides, encoded by the Kiss1 gene, are potent regulators of the mammalian reproductive axis by stimulating gonadodropin releasing hormone secretion from the hypothalamus. To understand how the reproductive axis is modulated by higher order neuronal inputs we have mapped the afferent circuits into arcuate (ARC) Kiss1 neurons.

Kv4.2 channel activity controls intrinsic firing dynamics of arcuate kisspeptin neurons.

Key Points: Neurons in the hypothalamus of the brain which secrete the peptide kisspeptin are important regulators of reproduction, and normal reproductive development. Electrical activity, in the form of action potentials, or spikes, leads to secretion of peptides and neurotransmitters, influencing the activity of downstream neurons; in kisspeptin neurons, this activity is highly irregular, but the mechanism of this is not known. In this study, we show that irregularity depends on the presence of a particular type of potassium ion channel in the membrane, which opens transiently in response to electrical excitation.

Visualisation of Kiss1 Neurone Distribution Using a Kiss1-CRE Transgenic Mouse.

Kisspeptin neuropeptides are encoded by the Kiss1 gene and play a critical role in the regulation of the mammalian reproductive axis. Kiss1 neurones are found in two locations in the rodent hypothalamus: one in the arcuate nucleus (ARC) and another in the RP3V region, which includes the anteroventral periventricular nucleus (AVPV). Detailed mapping of the fibre distribution of Kiss1 neurones will help with our understanding of the action of these neurones in other regions of the brain.

Mfsd14a (Hiat1) gene disruption causes globozoospermia and infertility in male mice.

The Mfsd14a gene, previously called Hiat1, encodes a transmembrane protein of unknown function with homology to the solute carrier protein family. To study the function of the MFSD14A protein, mutant mice (Mus musculus, strain 129S6Sv/Ev) were generated with the Mfsd14a gene disrupted with a LacZ reporter gene. Homozygous mutant mice are viable and healthy, but males are sterile due to a 100-fold reduction in the number of spermatozoa in the vas deferens.

Kiss1 mutant placentas show normal structure and function in the mouse.

Introduction: Kisspeptins, encoded by the Kiss1 gene, are a set of related neuropeptides that are required for activation of the mammalian reproductive axis at puberty and to maintain fertility. In addition, kisspeptin signaling via the G-protein coupled receptor GPR54 (KISS1R) has been suggested to regulate human placental formation and correlations have been found between altered kisspeptin levels in the maternal blood and the development of pre-eclampsia.

Methods: We have used Kiss1 and Gpr54 mutant mice to investigate the role of kisspeptin signaling in the structure and function of the mouse placenta.

Does Kisspeptin Signaling have a Role in the Testes?

Kisspeptins are a family of overlapping neuropeptides encoded by the Kiss1 gene that regulate the mammalian reproductive axis by a central action in the hypothalamus to stimulate GnRH release. Kisspeptins and their receptor (GPR54 also called KISS1R) are also expressed in the testes but a functional role in this tissue has not been confirmed. We examined which cell types in the testes expressed kisspeptin and its receptor by staining for β-galactosidase activity using tissue from transgenic mice with LacZ targeted to either the Kiss1 or the Gpr54 genes.

Identification of single nucleotide polymorphisms in human DNA repair genes.

Variation in gene coding sequence represents a significant factor in predisposition to disease, including cancer. Variants of some DNA repair genes (e.g.

Cytidine deaminase may be a useful marker in differentiating elderly onset rheumatoid arthritis from polymyalgia rheumatica/giant cell arteritis.

Objective: PMR/GCA is a relatively common inflammatory disease in the elderly population. Clinical differentiation from a polymyalgic onset of RA in the elderly can be difficult. We have examined in a preliminary study the hypothesis that serum cytidine deaminase (CD) may be valuable in the differential diagnosis of these disorders.

The levels of collagenase, tissue inhibitor of metalloproteinases-1 (TIMP-1), collagenase approximately TIMP-1 complexes and glycosaminoglycan (GAG) in sequential samples of synovial fluid aspirated from patients with osteoarthritis.

Objective: Collagen turnover in connective tissues is thought to be controlled by the balance between the levels of interstitial collagenase and tissue inhibitor of metalloproteinases (TIMP-1). The aim of this study was to measure the level of total collagenase (MMP-1), TIMP-1, collagenase approximately TIMP-1 complex and glycosaminoglycan (GAG) in sequential samples of osteoarthritic knee synovial fluid from well documented patients to determine if these parameters changed with time and correlated with clinical indices.

Methods: Twenty-one patients were recruited and randomly allocated to receive tiaprofenic acid, indomethacin or naproxen.

The clinical and laboratory course of polymyalgia rheumatica/giant cell arteritis after the first two months of treatment.

Objectives: To examine the clinical course of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) in a prospective study, after the initial two months.

Methods: Seventy four patients with PMR/GCA were followed for a median of 60 weeks. Detailed clinical and laboratory records were made on each visit.

Treatment of polymyalgia rheumatica/giant cell arteritis.

Corticosteroids control arteritis in GCA and suppress polymyalgic symptoms within days of starting treatment. PMR patients can be treated with approximately 15 mg prednisolone/day, reducing the dose to 7.5-10 mg by 8 weeks.

Laboratory investigations including liver in polymyalgia rheumatica/giant cell arteritis.

The most useful investigation in supporting the clinical diagnosis of PMR/GCA is elevation of the ESR or viscosity. Acute phase proteins, particularly C-reactive protein, are also elevated but in most cases are not more helpful than the ESR in either diagnosis or follow-up. The definitive investigation is the demonstration of giant cell arteritis histologically, usually from temporal artery biopsy.

Humanized monoclonal antibody treatment in rheumatoid arthritis.

A 41-year-old woman with active, seropositive erosive rheumatoid arthritis was treated with the humanized monoclonal antibody Campath 1H. She had not responded or developed side effects to myocrisin, sulfasalazine and penicillamine, and had not responded to inpatient bedrest and physiotherapy. There was a rapid clinical improvement within 24 hours of infusion, which was maintained for about 12-14 weeks after the infusion.

Liver scan abnormalities in polymyalgia rheumatica/giant cell arteritis.

Liver involvement in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) before treatment and during follow-up of up to 3 1/2 years was assessed in 74 patients clinically, with liver function tests, isotope scans and blood flow studies. Twenty-seven patients had elevated alkaline phosphatase levels which fell to normal after 2.6 weeks treatment.

Salmonella enteritidis causing joint sepsis.

A 22-year-old male taking dexamethasone following resection of a medulloblastoma developed an acutely painful swollen knee from which salmonella enteritidis was cultured. He had no gastrointestinal symptoms; one stool culture was positive. Active metalloproteinases without inhibitors were detected in the synovial fluid, a characteristic finding in septic joints.

Rarity of synovitis in polymyalgia rheumatica.

The joints of 56 patients with polymyalgia rheumatica were examined for evidence of inflammatory synovitis. x Rays, isotope scans, and thermography supplemented clinical examination. Control sternoclavicular joints were examined at necropsy.

Synovial fluids from infected joints contain metalloproteinase--tissue inhibitor of metalloproteinase (TIMP) complexes.

Samples of synovial fluids aspirated from patients with septic arthritis prior to the commencement of any treatment contained active metalloproteinases but no proteinase inhibitory activity. We therefore assayed these samples for proteinase-inhibitor complexes. Although no biologically active alpha 2-macroglobulin or tissue inhibitor of metalloproteinase (TIMP) was present in the fluids, immunoassay of the samples clearly showed that high molecular weight proteinase-TIMP complexes were present.

Erythrocyte sedimentation rate and C reactive protein in the assessment of polymyalgia rheumatica/giant cell arteritis on presentation and during follow up.

The erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) were measured in 74 patients with polymyalgia rheumatica (PMR)/giant cell arteritis (GCA) on presentation, in the first month of treatment, and at long term follow up (up to 177 weeks). Before treatment the ESR was raised (greater than 30 mm/h) in all cases and the CRP was raised (greater than 6 mg/l) in 49/55 cases. The ESR was a better indicator of clinical disease activity except in patients who felt completely well at week 1.