Comparing outcomes in renal replacement therapy: how should we correct for case mix?

The need to evaluate the effectiveness of clinical practice to justify expensive therapy in the face of financial constraints in all areas of health care delivery makes it necessary to identify groups of patients who are likely to benefit most from treatment. Various risk stratification methods have been used for analyzing survival probabilities for patients receiving renal replacement therapy. Complicated risk stratification methods produce large numbers of risk groups of small sizes, which makes comparison between individual centers difficult. We compared three simple methods of risk stratification, that divided patients into low-, medium-, and high-risk groups, in a cohort of 1,407 patients who commenced renal replacement therapy in five European countries during a 7-year period. Method 1 considered age (>55 years) and diabetes alone; method 2 used a higher age limit (>70 years) and comorbid illnesses, including those other than diabetes; and method 3 used only the number of comorbidities (none, 1, or > or =2) for stratification. Kaplan-Meier survival curves were constructed for comparison between risk groups and Cox's regression model used to assess strength of relationship with mortality. Although patient survival was significantly different between the low-, medium-, and high-risk groups using all three methods, Cox's regression analysis showed that method 2 provided the greatest discrimination between risk groups. In predicting mortality, method 2 (based on comorbidities and age) showed the highest sensitivity and specificity (84% and 80%, respectively) compared with method 1 (80% and 74%) and method 3 (64% and 82%). Validation of this approach in other populations in a prospective study is required before this method, which takes into account the influences of both age and comorbidity for risk stratification, can be used for comparing survival data and for presenting results of renal replacement therapy.     

Isolation of inhibin alpha-subunit precursor proteins from bovine follicular fluid

Two proteins with structural characteristics similar to peptide sequences identified in the inhibin alpha-subunit precursor sequence have been isolated from bovine follicular fluid. A side-fraction from the purification of bovine follicular fluid inhibin with high levels of inhibin immunoactivity relative to its inhibin bioactivity was fractionated through a sequence of procedures which included triazine dye affinity and phenyl-Sepharose chromatography, gel permeation chromatography on Sephadex G-100, reverse phase HPLC, and preparative polyacrylamide gel electrophoresis. The first of the two proteins identified had a molecular mass of 25-26K under reducing and nonreducing conditions and a NH2-terminal sequence identical to that of 43K inhibin alpha-subunit and showed minimal activity (less than 2% activity) compared with bovine 31K inhibin in either the inhibin in vitro bioassay or the RIA. These data suggest that this protein is the alpha 1-166 sequence of the bovine inhibin alpha-subunit (designated alpha N-subunit), most likely released after processing of either the inhibin alpha-subunit precursor or the 43K alpha-subunit involved in the conversion of 58K to 31K inhibin. The other protein identified (designated pro-alpha C-subunit) has a molecular mass of 27K under nonreducing conditions and 20K and 6K under reducing conditions. It is inactive in the in vitro bioassay, although highly reactive in the inhibin RIA, and has NH2-termini identical to the pro sequence of the inhibin alpha-subunit precursor and the 20K alpha-subunit sequence. These results suggest that pro-alpha C is a disulfide-linked structure and may represent an intermediate in the dimerisation of alpha- and beta-subunits to form inhibin while the alpha N-subunit is probably a proteolytic product of either the alpha-subunit precursor or 58K inhibin.     

Isolation of a 31 kDa form of inhibin from bovine follicular fluid

The introduction of a pH 4.75 precipitation step to a previously described purification procedure from bovine follicular fluid (bFF) resulted in the isolation of a 31 kDa form of inhibin, in addition to 58 kDa inhibin. The procedure was monitored by an in vitro bioassay based on the suppression of the FSH cell content by pituitary cells in culture. The 31 kDa form was purified 5550-fold with approximately 5% recovery. On SDS-polyacrylamide gel electrophoresis a single band was detected with a molecular weight of 31 000 +/- 1500 (mean +/- SD) which upon reduction gave 2 subunits of 20 200 +/- 300 and 14 800 +/- 600. The biological activity expressed on mg protein basis was similar for both 31 kDa and 58 kDa inhibin although on a molar basis the 58 kDa inhibin was 2-3 times higher. A high degree of cross-reaction was observed between both forms in a radioimmunoassay of bovine inhibin using an antiserum raised against the larger form with either iodinated 31 kDa or 58 kDa inhibin as tracer. Based on the subunit composition of the 31 kDa and 58 kDa inhibin, their similar cross-reaction in a radioimmunoassay system and the apparent generation of the 31 kDa inhibin following a pH precipitation step, it is concluded that 31 kDa inhibin is a smaller form of the 58 kDa inhibin resulting from a shortening of the 43 kDa subunit to a 20 kDa subunit.(ABSTRACT TRUNCATED AT 250 WORDS)     

PAPSS2‐related brachyolmia: Clinical and radiological phenotype in 18 new cases

Brachyolmia is a skeletal dysplasia characterized by short spine‐short stature, platyspondyly, and minor long bone abnormalities. We describe 18 patients, from different ethnic backgrounds and ages ranging from infancy to 19 years, with the autosomal recessive form, associated with PAPSS2. The main clinical features include disproportionate short stature with short spine associated with variable symptoms of pain, stiffness, and spinal deformity. Eight patients presented prenatally with short femora, whereas later in childhood their short‐spine phenotype emerged. We observed the same pattern of changing skeletal proportion in other patients. The radiological findings included platyspondyly, irregular end plates of the elongated vertebral bodies, narrow disc spaces and short over‐faced pedicles. In the limbs, there was mild shortening of femoral necks and tibiae in some patients, whereas others had minor epiphyseal or metaphyseal changes. In all patients, exome and Sanger sequencing identified homozygous or compound heterozygous PAPSS2 variants, including c.809G>A, common to white European patients. Bi‐parental inheritance was established where possible. Low serum DHEAS, but not overt androgen excess was identified. Our study indicates that autosomal recessive brachyolmia occurs across continents and may be under‐recognized in infancy. This condition should be considered in the differential diagnosis of short femora presenting in the second trimester.     

The analysis of human cortical bone by terahertz time-domain spectroscopy

Samples of cortical bone, derived from human femur, have been studied using terahertz time-domain transmission spectroscopy. The relationship between the broadband THz parameters and the previously acquired values of Young's modulus and x-ray attenuation (CT number), and the density of each bone sample, is investigated. The only significant correlation is that between THz transmission and sample density, suggesting that the potential use of THz radiation as a non-invasive probe of bone quality is limited. The spectra of absorption coefficient and refractive index are plotted over the frequency range 0.1-1.25 THz. There is evidence that the sample hydration state is a factor in the resultant THz parameters.     

The cholecystokinin-A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight

Food intake and body weight are determined by a complex interaction of regulatory pathways. To elucidate the contribution of the endogenous peptide cholecystokinin, mice lacking functional cholecystokinin-A receptors were generated by targeted gene disruption. To explore the role of the cholecystokinin-A receptor in mediating satiety, food intake of cholecystokinin-A receptor^–/– mice was compared with the corresponding intakes of wild-type animals and mice lacking the other known cholecystokinin receptor subtype, cholecystokinin-B/gastrin. Intraperitoneal administration of cholecystokinin failed to decrease food intake in mice lacking cholecystokinin-A receptors. In contrast, cholecystokinin diminished food intake by up to 90% in wild-type and cholecystokinin-B/gastrin receptor^–/– mice. Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor. To explore the long-term consequences of either cholecystokinin-A or cholecystokinin-B/gastrin receptor absence, body weight as a function of age was compared between freely fed wild-type and mutant animals. Both cholecystokinin-A and cholecystokinin-B/gastrin receptor^–/– mice maintained normal body weight well into adult life. In addition, each of the two receptor^–/– strains had normal pancreatic morphology and were normoglycemic. Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight.     

3. FIXED AND MODIFIABLE RISK FACTORS FOR BREAST CANCER

Likely pathogenesis of breast cancer is in two phases, initiation and promotion. Initiating factors include ionising irradiation, dietary factors and possibly alcohol consumption causing DNA mutations uncorrected by repair mechanisms. Subsequent promotional factors include exposure to oestrogens, reduced by late menarche, early pregnancy and lactation and increased by nulliparity, oral contraceptive use and hormone replacement therapy. Only 5% of breast cancers result from inherited genetic mutations of BRCA1 and BRCA2, but individuals with such mutations have a high risk (66–80%) of developing the disease. Most patients with benign breast problems are not at increased risk of breast cancer, but those with atypical epithelial hyperplasia have an increased risk and should be kept under surveillance or asked to participate in trials of prevention.     

A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler

Rationale: Nicotine replacement therapy (NRT) in varying forms is becoming widely used. Clinicians, therapists and regulatory authorities are interested in the abuse liability and dependence potential of the different forms. Objectives: To compare the abuse liability and dependence potential of nicotine gum, transdermal patch, spray and inhaler. Methods: 504 male and female smokers seeking help with stopping smoking were randomly allocated to the four products. Measures were taken at the designated quit date, then 1 week, 4 weeks, 12 weeks and 15 weeks later. Smokers were advised to use the product for up to 12 weeks. Those still using the product at the 12-week visit were advised to cease use by week 14. Measures included: pleasantness and satisfaction ratings at weeks 1 and 4 (used as a marker of abuse liability); ratings of feeling dependent on NRT at weeks 1, 4, 12 and 15 (used as a marker of subjective dependence); mood and physical symptoms ratings at weeks 12 and 15 (the change being used to assess physical dependence on NRT), continued usage of NRT at week 15 (used as an marker of behavioural dependence). Results: Average ratings of pleasantness were low. The nicotine patch was rated as less unpleasant to use than all other products. There were no significant differences between the products in terms of satisfaction or subjective dependence except at week 15 when no patch users rated themselves as dependent. Continued use of NRT at week 15 was related to rate of delivery of nicotine from the products – 2% for patch, 7% for gum and inhaler, 10% for spray (P<0.05 for linear association). Among those abstinent for 15 weeks, the figures were: 8%, 25% and 37%, respectively. Stopping NRT use between weeks 12 and 15 was not accompanied by withdrawal discomfort or increased frequency of urges to smoke although subjects stopping inhaler use experienced a mild increase in strength of urges to smoke. We conclude that abuse liability from all four NRT products was low. Subjective dependence was moderate and did not differ across products. Behavioural dependence was modest and was positively related to rate of nicotine delivery. Physicians can reassure their patients that most are able to come off NRT as recommended without discomfort. Received: 9 February 1999 / Final version: 4 January 2000     

Effect of transdermal nicotine patches on cigarette smoking: a double blind crossover study

The effect of transdermal nicotine patches on ad libitum cigarette smoking was examined in 30 subjects by measuring behavioural, biochemical and subjective aspects of smoking during a week of smoking without patches, and then a week each of nicotine and placebo patches in a randomised double blind crossover design. While wearing nicotine patches the subjects did not reduce the number of cigarettes smoked, but their expired carbon monoxide was reduced by 14%, they obtained less satisfaction from their cigarettes, and reported fewer and weaker urges to smoke. Down-regulation of nicotine intake from cigarettes was imprecise, such that when subjects wore nicotine patches their post-cigarette plasma nicotine concentration increased to an average of 45 ng/ml compared with 37 ng/ml in both no patch and placebo patch conditions. As the nicotine patches produced a plasma nicotine concentration of 15.9 ng/ml in abstinent subjects, this suggests a 22% reduction in nicotine intake from cigarettes while wearing nicotine patches. No serious symptoms of nicotine overdose were reported. It is suggested that the continuous absorption of nicotine from the patch may cause a build-up of acute tolerance to both toxic and pleasant subjective effects from smoking.