The Prediction of Immediate Survival after Porcine Hepatic Transplantation

The course; of nine pigs which died shortly after liver transplantation was compared with that of the other nine which survived in a series of 18 consecutive transplants. The only significant differences were found to be the development of an inexorable metabolic acidosis, and the recognition of focal hepatic necrosis observed histologically in the non-survivors. The suggestion is made that progressive hepatic damage may develop, and may cause death in some animals which is not explained on obvious mechanical grounds.     

A clinical and epidemiologic study morsicatio buccarum/labiorum

abstract – A study of habitual self mutilation of the buccal and/or labial mucosa by biting was conducted on 8,589 persons attending the Royal Dental College, Copenhagen. Forty-two cases were found. The youngest patient was 5 years old and the oldest was 47. The condition occurred most frequently (1.77%) among persons aged 15–19 years. There was no difference in prevalence between males and females. Combined mutilation of cheek(s) and lip(s) was more frequent (62%) than isolated mutilation of the cheek(s) (24%) or isolated mutilation of the lip(s) (14%). Bilateral biting of the cheeks was more frequent than unilateral biting, and biting of the lower lip was more frequent than biting of the upper lip. Ninety-three per cent of the patients were aware of their habit, and most of them stated that they had been biting for years. Twenty patients were re-examined; in all but one patients the biting persisted but in 7 patients the location of the lesions had changed. In several cases a link could be traced to personal problems and mental stress. It was further noticed that many patients were students and white-collar workers, suggesting that "intellectual" work may predispose for the habit.     

Oral controlled-release delivery of ivermectin in cattle via an osmotic pump

Ivermectin, a potent antiparasitic agent with activity against internal and external parasites, was delivered to cattle at a controlled zero-order rate for 35 d via orally administered, specially weighted, ALZET 2ML4 osmotic pumps. The osmotic pumps delivered the drug consistently over the trial period. Steady-state levels in plasma were achieved in 7-14 d, and plasma concentration depletion curves were observed to start at approximately day 35, the theoretical delivery lifetime of the osmotic pumps. Bioavailability was estimated to be 40%, and dose rate-plasma steady-state interrelationships were shown to be linear.     

Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist

Vanilloid receptor-1 (TRPV1) is a non-selective cation channel, predominantly expressed by peripheral sensory neurones, which is known to play a key role in the detection of noxious painful stimuli, such as capsaicin, acid and heat. To date, a number of antagonists have been used to study the physiological role of TRPV1; however, antagonists such as capsazepine are somewhat compromised by non-selective actions at other receptors and apparent modality-specific properties. SB-366791 is a novel, potent, and selective, cinnamide TRPV1 antagonist isolated via high-throughput screening of a large chemical library. In a FLIPR-based Ca(2+)-assay, SB-366791 produced a concentration-dependent inhibition of the response to capsaicin with an apparent pK(b) of 7.74 +/- 0.08. Schild analysis indicated a competitive mechanism of action with a pA2 of 7.71. In electrophysiological experiments, SB-366791 was demonstrated to be an effective antagonist of hTRPV1 when activated by different modalities, such as capsaicin, acid or noxious heat (50 degrees C). Unlike capsazepine, SB-366791 was also an effective antagonist vs. the acid-mediated activation of rTRPV1. With the aim of defining a useful tool compound, we also profiled SB-366791 in a wide range of selectivity assays. SB-366791 had a good selectivity profile exhibiting little or no effect in a panel of 47 binding assays (containing a wide range of G-protein-coupled receptors and ion channels) and a number of electrophysiological assays including hippocampal synaptic transmission and action potential firing of locus coeruleus or dorsal raphe neurones. Furthermore, unlike capsazepine, SB-366791 had no effect on either the hyperpolarisation-activated current (I(h)) or Voltage-gated Ca(2+)-channels (VGCC) in cultured rodent sensory neurones. In summary, SB-366791 is a new TRPV1 antagonist with high potency and an improved selectivity profile with respect to other commonly used TRPV1 antagonists. SB-366791 may therefore prove to be a useful tool to further study the biology of TRPV1.     

Pharmacology of vanilloids at recombinant and endogenous rat vanilloid receptors

This study compared the actions of members of five different chemical classes of vanilloid agonists at the recombinant rat vanilloid VR1 receptor expressed in HEK293 cells, and at endogenous vanilloid receptors on dorsal root ganglion cells and sensory nerves in the rat isolated mesenteric arterial bed. In mesenteric beds, vanilloids elicited dose-dependent vasorelaxation with the rank order of potency: resiniferatoxin>capsaicin=olvanil>phorbol 12-phenyl-acetate 13-acetate 20-homovanillate (PPAHV)>isovelleral. Scutigeral was inactive. Responses were abolished by capsaicin pretreatment and inhibited by ruthenium red. In VR1-HEK293 cells and dorsal root ganglion neurones, Ca(2+) responses were induced by resiniferatoxin>capsaicin=olvanil>PPAHV; all four were full agonists. Isovelleral and scutigeral were inactive. The resiniferatoxin-induced Ca(2+) response had a distinct kinetic profile. Olvanil had a Hill coefficient of approximately 1 whilst capsaicin, resiniferatoxin and PPAHV had Hill coefficients of approximately 2 in VR1-HEK293 cells. The capsaicin-induced Ca(2+) response was inhibited in a concentration-dependent manner by ruthenium red>capsazepine>isovelleral. These data show that resiniferatoxin, capsaicin, olvanil and PPAHV, but not scutigeral and isovelleral, are agonists at recombinant rat VR1 receptors and endogenous vanilloid receptors on dorsal root ganglion neurones and in the rat mesenteric arterial bed. The vanilloids display the same relative potencies (resiniferatoxin>capsaicin=olvanil>PPAHV) in all of the bioassays.     

Agonist-dependent internalization of D2 receptors: Imaging quantification by confocal microscopy

In positron emission tomography and single photon emission computed tomography studies using D2 dopamine (DA) receptor radiotracers, a decrease in radiotracer binding potential (BP) is usually interpreted in terms of increased competition with synaptic DA. However, some data suggest that this signal may also reflect agonist (DA)-induced increases in D2 receptor (D2R) internalization, a process which would presumably also decrease the population of receptors available for binding to hydrophilic radioligands. To advance interpretation of alterations in D2 radiotracer BP, direct methods of assessment of D2R internalization are required. Here, we describe a confocal microscopy-based approach for the quantification of agonist-dependent receptor internalization. The method relies upon double-labeling of the receptors with antibodies directed against intracellular as well as extracellular epitopes. Following agonist stimulation, DA D2R internalization was quantified by differentiating, in optical cell sections, the signal due to the staining of the extracellular from intracellular epitopes of D2Rs. Receptor internalization was increased in the presence of the D2 agonists DA and bromocriptine, but not the D1 agonist SKF38393. Pretreatment with either the D2 antagonist sulpiride, or inhibitors of internalization (phenylarsine oxide and high molarity sucrose), blocked D2-agonist induced receptor internalization, thus validating this method in vitro. This approach therefore provides a direct and streamlined methodology for investigating the pharmacological and mechanistic aspects of D2R internalization, and should inform the interpretation of results from in vivo receptor imaging studies.     

Protection against cataract by aspirin, paracetamol and ibuprofen

Results of a case-control of 423 cataract patients and 608 controls in Oxfordshire shows that the protective effect against cataract associated with consumption of aspirin-like analgesics (aspirin, paracetamol and ibuprofen family) is manifest even at low doses. Less than 150 g total dose was associated with a halving of the risk of cataract extraction.     

Risk factors for cataract in Oxfordshire: diabetes, peripheral neuropathy, myopia, glaucoma and diarrhoea

423 cataract patients and 608 controls between the ages of 50 and 79 were interviewed in a case-control study in Oxfordshire. Diabetes, myopia, glaucoma, peripheral neuropathy and severe diarrhoea were identified as risk factors. The excess risk experienced by females with diabetes was confirmed. The trauma of surgery for glaucoma may be largely responsible for the appearance of glaucoma as a risk factor. Severe diarrhoea has now been identified as a risk factor in England and in India. The risk associated with peripheral neuropathy may indicate a common aetiology at least for some proportions of the two conditions.