Anorexia Nervosa and Respecting a refusal of life-prolonging Therapy: A Limited Justification

People who suffer from eating disorders often have to be treated against their will, perhaps by being detained, perhaps by being forced to eat. In this paper it is argued that whilst forcing compliance is generally acceptable, there may be circumstances under which a sufferer's refusal of consent to treatment should be respected. This argument will hinge upon whether someone in the grip of an eating disorder can actually make competent decisions about their quality of life. If so, then the decision to refuse therapy may be on a par with other decisions to refuse life-prolonging therapy made by sufferers of debilitating chronic, or acute onset terminal illness. In such cases, palliation might justifiably replace aggressive therapy. The argument will also draw heavily on the distinction between competent refusal of therapy and passive euthanasia, and the distinction between incompetent and irrational decisions. Both distinctions will then be applied to decisions to refuse food. The extent to which sufferers from anorexia nervosa can be categorised as either incompetent or irrational will be examined. It is against this background that it will be argued that at least some of those who suffer from eating disorders should have their refusals respected, even if they may die as a result.     

Characterization of a transferrin-diphtheria toxin conjugate

We report here the synthesis and properties of a hybrid toxin prepared by covalently coupling diphtheria toxin to transferrin. The purified material contained two major hybrid protein species and was highly cytotoxic to mouse LMTK- cells in culture, reducing protein synthesis by 50% in 24 h at a concentration of 1 ng/ml. Cytotoxic activity was completely abolished in the presence of exogenous transferrin or anti-transferrin or anti-diphtheria toxin, thus demonstrating that the hybrid toxin was intoxicating cells via their transferrin receptors and that both the diphtheria toxin and transferrin components of the conjugate were necessary for activity. NH4Cl, a drug that elevates the pH within acidic intracellular vesicles, also blocked cytotoxic activity, suggesting that a low intravesicular pH was required for activity. The inhibitory effect of NH4Cl could be abolished by exposing toxin-treated cells to acidic culture medium, further implicating an acid-dependent step in the mechanism of the hybrid toxin action. Studies on the kinetics of intoxication also implied that endocytosis and exposure to a low pH within vesicles were necessary for cytotoxicity. Altogether, the results suggest that the transferrin-diphtheria toxin conjugate binds to transferrin receptors and is internalized into acidic endocytic vesicles. The enzymatic moiety of diphtheria toxin then apparently enters the cytosol in response to the low pH and subsequently arrests protein synthesis.     

A comparison of three methods for the determination of available lysine in barley

The protein quality of barley was determined by the measurement of the protein efficiency ratio (PER). Available lysine in the same samples was determined chemically and by microbiological assay, and relationships were obtained between PER and either total or available lysine content.In the PER test, groundnut meal was found to be a suitable protein supplement to barley for the purpose of detecting differences in the protein quality of barley. The method was sufficiently sensitive to detect a reduction in protein quality of one variety as a result of micronization. Available lysine values obtained by the modified Tetrahymena method were significantly correlated (r = 0.99) with PER values; there was no significant correlation between total lysine content and the PER value.The available lysine values measured by the two chemical methods were higher than the Tetrahymena values. The Silcock method gave results better correlated (r = 0.93) with the Tetrahymena values than did the Carpenter method (r = 0.82). The results of chemical methods were not significantly related with PER values, but the methods ranked the barleys in an order similar to that obtained with the PER and Tetrahymena tests.     

Self-complementary regions in human albumin mRNA encode important structural regions within the human albumin protein

An analysis of the human albumin mRNA structure revealed a nonrandom distribution of self-complementary regions within the mRNA. The majority of these self-complementary mRNA stretches encode important structural regions of the human albumin protein. The amino acids contained within these regions of the protein exhibit a high degree of hydrophobic complementarity which could influence local protein conformation and contribute to the biological importance of the protein structures.     

The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada

Mutations at the hexosaminidase A (HEXA) gene which cause Tay-Sachs disease (TSD) have elevated frequency in the Ashkenazi Jewish and French-Canadian populations. We report a novel TSD allele in the French-Canadian population associated with the infantile form of the disease. The mutation, a GA transition at the +1 position of intron 7, abolishes the donor splice site. Cultured human fibroblasts from a compound heterozygote for this transition (and for a deletion mutation) produce no detectable HEXA mRNA. The intron 7+1 mutation occurs in the base adjacent to the site of the adult-onset TSD mutation (G805A). In both mutations a restriction site for the endonuclease EcoRII is abolished. Unambiguous diagnosis, therefore, requires allele-specific oligonucleotide hybridization to distinguish between these two mutant alleles. The intron 7+1 mutation has been detected in three unrelated families. Obligate heterozygotes for the intron 7+1 mutation were born in the Saguenay-Lac-St-Jean region of Quebec. The most recent ancestors common to obligate carriers of this mutation were from the Charlevoix region of the province of Quebec. This mutation thus has a different geographic centre of diffusion and is probably less common than the exon 1 deletion TSD mutation in French Canadians. Neither mutation has been detected in France, the ancestral homeland of French Canada.     

Effects of phosphorothioate capping on antisense oligonucleotide stability, hybridization and antiviral efficacy versus herpes simplex virus infection.

Efforts have been made to improve the biological stability of phosphodiester (PO) oligonucleotides by the addition of various modifications to either the 3', 5' or both the 3' and 5' ends of an oligonucleotide. ISIS 1080, a phosphorothioate (PS) 21-mer oligonucleotide complementary to the internal AUG codon of UL13 mRNA in HSV-1, reduces the infectious yield of HSV-1 in HeLa cells to 9.0% +/- 11%. PO analogs of ISIS 1080 containing three PS linkages placed on the 3' (ISIS 1365), 5' (ISIS 1370), both the 3' and 5' (ISIS 1364) ends or with four linkages in the middle (ISIS 1400) demonstrated reduced antiviral efficacy compared to fully PS ISIS 1080. Thermal denaturation profiles demonstrated that these oligonucleotides hybridized to complementary DNA or RNA with equivalent binding affinities. All were able to support E. coli RNAse H cleavage of the HSV mRNA to which they were targeted. The stability of the congeners in cell culture medium containing 10% fetal calf serum (FCS), HeLa cytosolic extract, HeLa nuclear extract and in intact HeLa cells revealed that ISIS 1080 was most resistant to nucleolytic digestion through 48 hours. Partial PS oligonucleotides exhibited increased degradation compared to the fully thioated oligonucleotide by exonuclease activity in FCS and endonuclease activity in cell extracts or intact cells. Thus, the reduced efficacy of partial compared to fully PS oligonucleotides against HSV-1 in HeLa cells may result from increased degradation of the mixed PO/PS oligonucleotides.     

The free lipids of Mycobacterium leprae harvested from experimentally infected nine-banded armadillos

The free lipids of a sample of Mycobacterium leprae were extracted by a procedure designed to produce separate non-polar and polar fractions. The composition of these lipids was analysed semi-quantitatively by five special thin-layer chromatographic systems covering the total range of mycobacterial lipid polarities. In order of increasing polarity, the major lipids were dimycocerosates of phthiocerol A, phthiocerol B and phthiodiolone A, glycosyl phenolphthiocerol dimycocerosates and phospholipids, including monoacylphosphatidylinositol di- and pentamannosides. The diacylated forms of these latter lipids, found in most mycobacteria, were not present. The composition of the free lipids of the leprosy bacillus, surveyed over the total polarity range for the first time, showed that the patterns were particularly related to those of Mycobacterium bovis, Mycobacterium kansasii and Mycobacterium marinum.     

The innervation of the pyloric region of the crab,Cancer borealis: Homologous muscles in decapod species are differently innervated

Summary The muscles of the pyloric region of the stomach of the crab,Cancer borealis, are innervated by motorneurons found in the stomatogastric ganglion (STG). Electrophysiological recording and stimulating techniques were used to study the detailed pattern of innervation of the pyloric region muscles. Although there are two Pyloric Dilator (PD) motorneurons in lobsters, previous work reported four PD motorneurons in the crab STG (Dando et al. 1974; Hermann 1979a, b). We now find that only two of the crab PD neurons innervate muscles homologous to those innervated by the PD neurons in the lobster,Panulirus interrruptus. The remaining two PD neurons innervate muscles that are innervated by pyloric (PY) neurons inP. interruptus. The innervation patterns of the Lateral Pyloric (LP), Ventricular Dilator (VD), Inferior Cardiac (IC), and PY neurons were also determined and compared with those previously reported in lobsters. Responses of the muscles of the pyloric region to the neurotransmitters, acetylcholine (ACh) and glutamate, were determined by application of exogenous cholinergic agonists and glutamate. The effect of the cholinergic antagonist, curare, on the amplitude of the excitatory junctional potentials (EJPs) evoked by stimulation of the pyloric motor nerves was measured. These experiments suggest that the differences in innervation pattern of the pyloric muscles seen in crab and lobsters are also associated with a change in the neurotransmitter active on these muscles. Possible implications of these findings for phylogenetic relations of decapod crustaceans and for the evolution of neural circuits are discussed.Abbreviations ACh acetylcholine - Carb carbamylcholine - cpv muscles of the cardio-pyloric valve - cpv7n nerve innervating muscle cpv7 - cv muscles of the ventral cardiac ossicles - cv1n nerve innervating muscle cvl - cv2n nerve innervating muscle cv2 - EJP excitatory junctional potential - IC inferior cardiac neuron - IV inferior ventricular neuron - IVN inferior ventricular nerve - LP lateral pyloric neuron - LPG lateral posterior gastric neuron - lvn lateral ventricular nerve - mvn medial ventricular nerve - p muscles of the pylorus - PD pyloric dilator neuron - PD _in intrinsic PD neuron - PD _ex extrinsic PD neuron - pdn pyloric dilator nerve - PY pyloric neuron - pyn pyloric nerve - STG stomatogastric ganglion - VD ventricular dilator neuron     

Mechanisms for oscillation and frequency control in reciprocally inhibitory model neural networks

We describe four different mechanisms that lead to oscillations in a network of two reciprocally inhibitory cells. In two cases (intrinsic release and intrinsic escape) the frequency of the network oscillation is insensitive to the threshold voltage of the synaptic potentials. In the other two cases (synaptic release and synaptic escape) the network frequency is strongly determined by the threshold voltage of the synaptic connections. The distinction between the different mechanisms blurs as the function describing synaptic activation becomes less steep and as the model neurons are removed from the relaxation regime. These mechanisms provide insight into the parameters that control network frequency in motor systems that depend on reciprocal inhibition.