Partial characterization of the enzymatic activity associated with the binary toxin (type C2) produced by Clostridium botulinum.

Clostridium botulinum produces a binary toxin that possesses a heavy chain (approximately 100,000 daltons) and a light chain (approximately 50,000 daltons). The heavy chain is a binding component that directs the toxin to vulnerable cells, and the light chain is an enzyme that has mono(ADP-ribosyl)ating activity. A number of experiments have been done to help characterize the enzymatic activity of the toxin. The data reveal that the enzyme has a pH optimum within the range of 7.0 to 8.0. It is not inhibited or stimulated by physiological concentrations of sodium, potassium, calcium, or magnesium. The enzyme is inhibited by high concentrations of salt, however, as well as high concentrations of nicotinamide, thymidine, theophylline, and histamine; and it is stimulated by histone and lysolecithin. Boiling irreversibly denatures the light chain of the toxin, but denaturation caused by guanidine and urea is substantially reversible. Enzymatic activity is not altered by short exposure to lysosomal proteases, including cathepsin B, cathepsin H, dipeptidyl aminopeptidase, and catheptic carboxypeptidase B.     

Does hope predict adjustment to end‐stage renal failure and consequent dialysis?

Objectives Hope is important in determining positive outcomes in a range of chronic illnesses. This study examined the role of hope in adjustment to end‐stage renal failure (ESRF) and consequent dialysis. Design A cross‐sectional design examined the ability of hope to predict adjustment to ESRF over and above other relevant variables. Methods Individuals receiving dialysis at 4 units in the North‐West UK were invited to take part in the study. 103 questionnaire packs were included in the analysis. Multiple regression equations determined whether hope was able to predict significant variance in adjustment over and above that accounted for by other factors (demographic and illness‐related factors, perceived control, and social support). Measures of anxiety, depression, and quality of life constituted a multidimensional measure of adjustment to ESRF. Results Each of the regression models was significant. Hope emerged as an independent significant predictor in five of the multiple regressions: anxiety; depression; effects and symptoms of kidney disease; and mental health quality of life. Age also emerged as an important predictor of outcome. Conclusions It appears that hope is a significant predictor of adjustment to ESRF. Clinical implications of this research are discussed, along with suggestions for future research.     

Hyperexcitability and reduced low threshold potassium currents in auditory neurons of mice lacking the channel subunit Kv1.1

A low voltage-activated potassium current, I _KL, is found in auditory neuron types that have low excitability and precisely preserve the temporal pattern of activity present in their presynaptic inputs. The gene Kcna1 codes for Kv1.1 potassium channel subunits, which combine in expression systems to produce channel tetramers with properties similar to those of I _KL, including sensitivity to dendrotoxin (DTX). Kv1.1 is strongly expressed in neurons with I _KL, including auditory neurons of the medial nucleus of the trapezoid body (MNTB). We therefore decided to investigate how the absence of Kv1.1 affected channel properties and function in MNTB neurons from mice lacking Kcna1 . We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1 -null (−/−) mice and their wild-type (+/+) and heterozygous (+/−) littermates. There was an I _KL in voltage-clamped −/− MNTB neurons, but it was about half the amplitude of the I _KL in +/+ neurons, with otherwise similar properties. Consistent with this, −/− MNTB neurons were more excitable than their +/+ counterparts; they fired more than twice as many action potentials (APs) during current steps, and the threshold current amplitude required to generate an AP was roughly halved. +/− MNTB neurons had excitability and I _KL amplitudes identical to the +/+ neurons. The I _KL remaining in −/− neurons was blocked by DTX, suggesting the underlying channels contained subunits Kv1.2 and/or Kv1.6 (also DTX-sensitive). DTX increased excitability further in the already hyperexcitable −/− MNTB neurons, suggesting that −/− I _KL limited excitability despite its reduced amplitude in the absence of Kv1.1 subunits.     

Dental abnormalities in individuals with pathogenic germline variation in DICER1

Pathogenic germline variation in the microRNA processing gene DICER1 gives rise to an autosomal dominant, tumor‐predisposition disorder. Conditional deletion of Dicer1 in murine dental epithelium shows that it controls tooth patterning, size, number, and shape. The human dental phenotype of people with germline pathogenic variation in DICER1 is unknown. DICER1‐carriers (n = 57) and family controls (n = 55) were evaluated at the NIH Clinical Center dental clinic as part of a comprehensive medical evaluation. Digital panoramic radiographs, bite‐wing radiographs, and oral photographs were collected. A single observer, blind to DICER1 status, reviewed the dental records and determined the presence or absence of 11 dental characteristics as described in the clinic notes, radiographs, or oral photographs. Subjective phenotypes were reviewed on radiographs by two examiners (blind to DICER1 status) for the presence or absence of the dental characteristics to reduce inconsistencies. By simple association, bulbous crown, periodontitis, and taurodontism were all significant (p < .05). Logistic regression with chi‐square maximum likelihood estimates showed that bulbous crown and periodontitis remained significant. Recognition of these phenotypes may aid identification of individuals and families at risk for DICER1‐associated neoplasms. These findings may also guide dental care for individuals with germline DICER1 pathogenic variation.     

Antigenic interrelationships among mite allergens (Blomia andDermatophagoides spp)

Conclusions Asthma can occur as a result of allergy to both house dust mites and to storage mites. Many people worldwide are exposed to more than one mite species in the domestic environment. The most common domestic mites areD. pteronyssinus, D. farinae, E. maynei, andB. tropicalis; other storage mites are found in homes much less frequently, even in tropical climates. Because of the ready availability of allergen extracts for skin testing and immunotherapy, patients with respiratory symptoms are generally evaluated for sensitization toD. pteronyssinus andD. farinae only. The evidence reviewed here suggests, however, that, although there are crossreactive allergens between many mite species, most species have specific allergens that can be an important cause of IgE responses. Therefore, the role ofB. tropicalis andE. maynei in the etiology of asthma merits further investigation. Identification of species-specific and crossreactive allergens and production of recombinant allergens would be useful tools in allergy practice. By skin-testing patients, physicians would then be able to evaluate whether patients recognize crossreactive allergens or species-specific allergens and whether or not there is a need for immunotherapy to more than one mite species.     

Acetylcholinesterase undergoes autolysis to generate trypsin-like activity

Acetylcholinesterase (AChE) is one of the most highly studied enzymes, although its function in many tissues has remained obscure. AChE purified from eel or foetal bovine serum possesses proteolytic activity in addition to esterase activity. The presence of trypsin-like and metallocarboxypeptidase-like activities associated with AChE accounts for its ability to convert enkephalin peptide precursors into enkephalins. Several lines of evidence indicate that AChE's trypsin-like activity is an integral component of the molecule and that it is activated by autolysis. Incubation of affinity-purified eel AChE generated several fragments of low relative molecular mass (Mr). One of these low Mr fragments (Mr = 25,000 Da, 25K) cleaved from the 70K form of AChE, possessed considerable sequence similarity to the N-terminal sequence of pancreatic trypsin. Autolysis of eel AChE may give rise to a neuropeptide processing enzyme.     

Women physicians in dual-physician relationships compared with those in other dual-career relationships.

This study compared the career and domestic responsibilities of women physicians whose domestic partners were physicians (WP-Ps) with those of women physicians whose domestic partners were not physicians (WP-NPs). In 1988 the authors surveyed 602 women physicians in a large midwestern city regarding their career and domestic roles; 390 were physicians in training (students and residents), and 212 were physicians in practice (academic medicine and private practice). Overall, 382 (63%) responded; of the 382, 247 (65%) had domestic partners; of these 247, 91 (37%) were WP-Ps and 156 (63%) were WP-NPs. The WP-Ps were found to be twice as likely as the WP-NPs to interrupt their careers to accommodate their partners' careers. The WP-Ps also assumed significantly more domestic responsibilities and worked fewer hours practicing medicine than did the WP-NPs. The 163 women physicians in training (44-48%-of the WP-Ps and 119-76%-of the WP-NPs) demonstrated a more egalitarian division of labor overall, with no significant differences between the WP-Ps and the WP-NPs. The authors recommend that longitudinal studies be undertaken to determine whether women physicians in training continue this trend as they enter the practice of medicine.