Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: an open-label, randomized study.

BACKGROUND: Sevelamer hydrochloride was recently proposed as a phosphate binder to prevent hypercalcaemia in place of calcium alkaline salts in dialysis patients. So far, it has been evaluated only in patients receiving calcitriol, without comparison with CaCO(3) alone, although the latter was found to be as effective as the combination of calcitriol and Al(OH)(3) in suppressing parathyroid hormone (PTH) without inducing hypercalcaemia and to have a better lowering effect on serum phosphate. Moreover, this bile salt binder may decrease serum 25-OH vitamin D. Therefore, we compared for 5 months two strategies for controlling moderate hyperparathyroidism: CaCO(3) alone vs sevelamer in conjunction with measures to increase calcium balance. METHODS: Forty-two patients were randomized: 21 continued their treatment with 4.8 g/day CaCO(3) and 21 were switched to sevelamer (initial dose: 2.4 g/day, increased to 4.4 g/day). Each month, when serum-corrected calcium decreased below 2.30 mmol/l, dialysate calcium was increased or alphacalcidol was given at each dialysis session, according to serum PO(4) levels. The following parameters were monitored: serum Ca, PO(4), bicarbonate and protein, weekly; and serum PTH, 25-OH vitamin D and total, LDL and HDL cholesterol monthly. RESULTS: Except for higher serum phosphate at month 1, lower serum bicarbonate at month 2 and lower LDL cholesterol at month 5 in the sevelamer group, no difference was found between the two groups. Compared with baseline levels, PTH increased and 25-OH vitamin D decreased significantly in both groups, these two parameters being inversely correlated. CONCLUSIONS: Given comparable control of plasma calcium, phosphate and 25-OH vitamin D, PTH control is comparable in both strategies. Sevelamer does not induce greater vitamin D depletion than CaCO(3). The transient decrease of serum bicarbonate after discontinuation of CaCO(3) in the sevelamer group suggests a less optimal prevention of acidosis. The sevelamer-induced decrease in LDL cholesterol gives this drug a potential advantage in cardiovascular prevention.     

A reassessment of the risk of multiple sclerosis developing in patients with optic neuritis after extended follow-up.

One hundred and one of 146 patients presenting with isolated idiopathic optic neuritis, previously reviewed in 1978, were reassessed clinically, and retyped for HLA antigens and Factor B alleles, after a mean follow-up of 11.6 years. Fifty eight patients (57%) had developed multiple sclerosis at the time of reassessment in the present study, of whom 51 (88%) had clinically definite disease. This compared with 40% of the original group, in 1978, of whom 62% then had clinically definite multiple sclerosis. When the life-table method of analysis was used, the probability of developing multiple sclerosis was 75%, 15 years after the initial episode of optic neuritis. The frequencies of HLA-DR2 and the recently defined D-region antigen, DQw1, were significantly increased in patients with isolated optic neuritis and those who subsequently developed multiple sclerosis compared with normal controls, but neither allele appears to influence progression from optic neuritis to multiple sclerosis. Patients with optic neuritis who were HLA-DR3 positive had an increased risk for the development of multiple sclerosis (RR = 2.8) and this risk was further enhanced when DR3 occurred in combination with DR2 (RR = 6.7). The overall increased risk of developing multiple sclerosis for patients with this combination was 26 times that for the normal population. When the patients' original tissue-typing was considered BT 101 no longer influenced conversion of optic neuritis to multiple sclerosis. This may partly be explained by improved methods of tissue-typing, since not all BT 101 patients were subsequently found to be positive for HLA-DR2 or HLA-DQw1 and vice versa and by extended follow-up as multiple sclerosis conversion in HLA-DR2 negative individuals increased with time. All 101 patients were typed for Factor B alleles. No significant differences in frequencies were found between individuals with isolated optic neuritis or those who progressed to multiple sclerosis compared with the control population. Recurrent episodes of optic neuritis were associated with an increased risk for the development of multiple sclerosis in this study.     

Multiple Implants for First Molar Prosthodontics

Problems that can occur when single implants are utilized to restore first molar teeth include the frequent loosening of screws, as well as screws and/or implant breakage. These may result from torquing and rotational movements of the prosthesis during masticatory and parafunctional mandibular movements. When sufficient bone and mesio-distal restorative space is present, the placement of two implants should be considered.     

Practical guidelines for action regarding application of CPR/DNR

Technological advances in the field of medicine have resulted in the prolongation of lives that under ordinary conditions would have terminated. Such advances, though calling attention to the wonders of modern technology, are not without significant complications. The injudicious application of extraordinary procedures for extending life highlights problems that affect medical, social, and psychological as well as moral and ethical realms. The complexity of the problems has long since perplexed health/human service practitioners charged with effecting and/or assisting in the implementation of the critical life-death decisions on which this paper focuses.

A systematic strategy is outlined to guide human service providers in making decisions regarding the application or withholding of life-sustaining procedures. Emphasis is placed upon the integrity of self-determination as it relates to competency. Procedures for the incompetent patient are recommended.     

New evidence for a gating action of norepinephrine in central neuronal circuits of mammalian brain

Many previous studies have examined the effects of norepinephrine (NE) on neuronal responsiveness to synaptic inputs and putative transmitter substances and have described differential depressant actions of NE on stimulus evoked versus spontaneous discharge such that the "signal to noise" ratio of threshold responses was increased. In the present studies, similar experimental strategies employing a combination of microiontophoresis, single unit recording and afferent pathway stimulation in intact anesthetized and brain tissue slice preparations have revealed noradrenergic "gating" actions whereby weak or subthreshold synaptic stimuli can evoke threshold neuronal responses in the presence of iontophoretically applied NE or following electrical stimulation of the locus coeruleus. Overall, these results suggest that potentially threshold excitatory and inhibitory synaptic inputs may normally arrive at central neurons but appear weak or absent except during behavioral conditions favoring the synaptic release of NE. As such, these findings provide evidence that signal to noise ratio may not be the only potential modulatory action expressed by NE in noradrenergic target circuits of the mammalian brain.     

Structure-activity relationships for epidermal ornithine decarboxylase induction and skin tumor promotion by anthrones

The present study was designed to compare the skin tumor promotingand epidermal ornithine decarboxylase (ODC) inducing activitiesof various structural analogs of anthralin (1, 8-dihydroxy-9-anthrone)and chrysarobin (1, 8-dihydroxy-3- methyl-9-anthrone). Groupsof 30 SENCAR mice each were initiated with 7, 12-dimethylbenz[a]anthraceneand 2 weeks later promoted with once- or twice-weekly applicationsof various doses of these anthrone derivatives. Carbon-10 (C₁₀)-acylderivatives of anthralin were active skin tumor promoters inthe range of 25–440 nmol per mouse. 10-Acetylanthralinwas significantly more active than 10-myristoyl-anthralin atlow doses (e.g. 25 and 50 nmol per mouse) and nearly as potentas the unsubstituted compound. Higher doses ( 100 nmol per mouse)of this derivative were toxic, hence, reducing the final papillomaresponse. On a relative activity scale where anthralin is 1.0,these derivatives had activities that were 0.7 and 0.2, respectively.10, 10-Dipropylanthralin was totally inactive at the doses tested.C⁶-Substituted derivatives of chrysarobin demonstrated diversetumor promoting activities when tested in the range of 25–440nmol per mouse. On a relative activity scale where chrysarobinis 1.0, 6-methoxychrysarobin (physcion anthrone) was 0.9, whereas6-hydroxychrysarobin (emodin anthrone) had no activity. Chrysophanicacid (1, 8-dihydroxy-3-methyl-9, 10-anthraquinone) was alsoinactive as a tumor promoter at the doses tested. In general,the tumor promoting activities of these anthrone derivativescorrelated very well with their ability to induce epidermalODC after a single topical application indicating an importantrole for this enzyme in skin tumor promotion by anthones. Theability of C₁₀-substituted derivatives of anthralin to undergobase catalyzed oxidation in vitro correlated with both ODC inducingand tumor promoting activities. In addition, copper(II) bis(diisopropylsalicylate)was found to inhibit both ODC induction and skin tumor promotionby chrysarobin. These latter data, when taken together, suggesta role for oxidation at C₁₀ in skin tumor promotion by anthronederivatives.     

Regulatory developmental neurotoxicity and human risk assessment.

A number of efforts, in the last 15 years, have been directed at developing protocols to assess the potential developmental neurotoxicity (DN) of test agents. Japan and the United Kingdom have general protocols that describe the behavioral parameters that should be evaluated as part of other types of testing protocols, such as standard developmental and/or reproductive toxicity studies. In 1986, EPA published a proposed separate guideline for the testing of glycol ethers. Since then, this protocol has undergone extensive review and comment by an agency-wide workgroup, participants of a workshop sponsored by EPA and NIDA, EPA's Scientific Advisory Panel, and the public. Comments were taken into consideration and the final DN testing protocol has been published recently by EPA's Office of Pesticide Programs. This protocol provides specific guidance on issues of study design, aspects of CNS function to be evaluated and criteria for selection of testing procedures. It is designed to be a "generic" protocol could be applied to testing of pesticides and other chemicals and that could be modified on a case-by-case basis depending on the data available on a specific agent of concern. With the development of testing protocols for assessing DN, there comes a need for the development of guidance as to how the data should be interpreted and applied toward conducting a risk assessment for extrapolation to humans. Some guidance was developed at the EPA-NIDA Workshop. EPA has published specific risk assessment guidelines in the area of developmental toxicity that include a section on interpretation of data on functional deficits, including DN.(ABSTRACT TRUNCATED AT 250 WORDS)     

Seasonal prevalence of major congenital malformations in the Fylde of Lancashire 1957-1981.

The seasonal prevalence of major congenital malformations was studied in a prospective survey of 88,449 children born in the circumscribed Fylde of Lancashire to residents there over 25 years. Ascertainment was thought to be as complete as was practically possible because cases were recorded daily by one, and for 17 years the only, paediatrician and a very high rate of necropsies was maintained. The number of malformations were classified by month of maternal last menstrual period and seasonal variation was assessed by three statistical models. Neural tube defects showed a significant seasonal variation in month of last menstrual period but not in month of birth. From May 1956 to April 1968, when the prevalence of neural tube defects was high (5.5 per 1000 total births), conceptions were significantly more common in December to May. For anencephaly alone the figures were not significant, but spina bifida and cranium bifidum were more common in March to May. From May 1968 to April 1981, when the prevalence of neural tube defects fell below the national average, the significant variations disappeared. Seasonality for spina bifida and cranium bifidum was seen only in "singles" (cases with no other major lesion), but for anencephaly it was seen only in "multiples" (cases with other lesions). The three types of cardiac septal defect and persistent ductus each showed a higher prevalence of conceptions at some time during May to October. In contrast the commonest group of cyanotic cases showed no such pattern but with greater numbers in winter. There was evidence of a seasonal variation for bilateral renal agenesis and for vesicoureteric reflux as ascertained. Seasonal prevalence in an aetiological factor for certain malformations of the central nervous system, cardiac and urinary systems.