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Background & aims Upregulation of hepatic delta-aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta-aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims evaluate long-term efficacy and safety of givosiran in acute hepatic porphyria. Methods Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double-blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open-label extension (continuous givosiran, n = 47/48; placebo crossover, n = 46/46). Endpoints included annualized attack rate, urinary delta-aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events. Results Patients receiving continuous givosiran had sustained annualized attack rate reduction (median 1.0 in double-blind period, 0.0 in open-label extension); in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double-blind period) and 0.0 (open-label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long-term givosiran led to sustained lowering of delta-aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double-blind period. Conclusions Long-term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.

Author(s): Naik, Hetanshi; Overbey, Jessica R; Desnick, Robert J; Anderson, Karl E; Bissell, D Montgomery; Bloomer, Joseph; Bonkovsky, Herbert L; Phillips, John D; Wang, Bruce; Singal, Ashwani; Balwani, Manisha | Abstract: BackgroundErythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who treat EPP patients acknowledge their life-altering effects, tools that fully capture their impact on quality of life (QoL) are lacking.MethodsAdult patients with EPP/XLP were given four validated QoL tools: the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), the Hospital Anxiety and Depression Scale (HADS), the Illness Perception Questionnaire Revised (IPQR), and an EPP-Specific tool. All patients received the PROMIS-57 while the HADS, IPQR, and EPP-Specific tools were introduced at a later date. Associations between responses and clinical phenotypes were explored.ResultsTwo hundred and two patients were included; 193 completed PROMIS-57, 104 completed IPQR, 103 completed HADS, and 107 completed the EPP-Specific tool. The IPQR showed that patients strongly believed EPP/XLP had a negative impact on their lives. Mean scores in anxiety and depression domains of both HADS and PROMIS-57 were normal; however, anxiety scores from HADS were borderline/abnormal in 20% of patients. The EPP-Specific tool revealed a decreased QoL in most patients. The PROMIS-57 showed that 21.8% of patients have clinically significant pain interference. Several tool domains correlated with measures of disease severity, most being from the PROMIS-57.ConclusionsImpaired QoL is an important consequence of EPP/XLP. PROMIS-57 was most sensitive in evaluating impaired QoL in EPP/XLP. Further research is needed to compare the effectiveness of it for assessing response to treatment.

Research projects in translational science are increasingly complex and require interdisciplinary collaborations. In the context of training translational researchers, this suggests that multiple mentors may be needed in different content areas. This study explored mentoring structure as it relates to perceived mentoring effectiveness and other characteristics of master's-level trainees in clinical-translational research training programs. A cross-sectional online survey of recent graduates of clinical research master's program was conducted. Of 73 surveys distributed, 56.2% (n = 41) complete responses were analyzed. Trainees were overwhelmingly positive about participation in their master's programs and the impact it had on their professional development. Overall the majority (≥75%) of trainees perceived they had effective mentoring in terms of developing skills needed for conducting clinical-translational research. Fewer trainees perceived effective mentoring in career development and work-life balance. In all 15 areas of mentoring effectiveness assessed, higher rates of perceived mentor effectiveness was seen among trainees with ≥2 mentors compared to those with solo mentoring (SM). In addition, trainees with ≥2 mentors perceived having effective mentoring in more mentoring aspects (median: 14.0; IQR: 12.0-15.0) than trainees with SM (median: 10.5; IQR: 8.0-14.5). Results from this survey suggest having ≥2 mentors may be beneficial in fulfilling trainee expectations for mentoring in clinical-translational training.

Multiinstitutional research collaborations now form the most rapid and productive project execution structures in the health sciences. Effective adoption of a multidisciplinary team research approach is widely accepted as one mechanism enabling rapid translation of new discoveries into interventions in human health. Although the impact of successful team-based approaches facilitating innovation has been well-documented, its utility for training a new generation of scientists has not been thoroughly investigated. We describe the characteristics of how multidisciplinary translational teams (MTTs) promote career development of translational research scholars through competency building, interprofessional integration, and team-based mentoring approaches. Exploratory longitudinal and outcome assessments from our experience show that MTT membership had a positive effect on the development of translational research competencies, as determined by a self-report survey of 32 scholars. We also observed that all trainees produced a large number of collaborative publications that appeared to be associated with their CTSA association and participation with MTTs. We conclude that the MTT model provides a unique training environment for translational and team-based learning activities, for investigators at early stages of career development.

Translational science requires that scientists from multiple disciplines work together to improve the prevention, diagnosis, and treatment of human disease. Although a literature exists on the design and management of multidisciplinary teams, little has been written on multidisciplinary translational teams (MTTs). MTTs are distinct hybrid entities, with goals taken from both industry and academic models. We identified 30 design factors in 10 domains from a literature survey relevant to our MTT model: specific goals, structures, and processes. These dimensions were adapted to our own institutional environment in the selection and management of 11 MTTs that exploited resources of University of Texas Medical Branch (UTMB) Clinical and Translational Sciences Awards (CTSA). Case illustrations of two specific MTTs illustrate some of the challenges encountered and opportunities realized in terms of education and scientific advances. Network depiction of disciplinarity indicated that CTSA KRs and CTSA leadership contributed to discipline diversity especially in small (or nascent) MTTs. A separate depiction of MTT-KR utilization indicated that data analysis, translational technologies, and novel methods were heavily utilized by MTTs, whereas other KRs contributed significant effort to infrastructure development. We conclude that the CTSA can provide a rich infrastructural framework and scientific environment for the development of successful MTTs.

Summary 1. Geographic information systems (GIS) have recently proved useful for estimating the environmental niche of species across broad geographic regions. However, the application of these niche-based GIS techniques has yet to be extensively applied to local systems. The assumptions of the methods are transferable across scales: species exist across a range of habitats, and these habitats represent a gradient of suitability that can be characterized using multivariate environmental data in association with known species occurrences. 2. Habitat availability and species’ niche characteristics are often considered to be important predictors of population density. However, seasonal habitat variability and stochastic events have been hypothesized to limit interactions among species and confound the relationship between available habitat, species niche characteristics and community structure. This research examines the relationship between environmental niche breadth and niche position and population density among species of stream fishes in a seasonally variable environment using a novel application of fine-scale GIS data. 3. Niche breadth and niche position were estimated for 11 species in a local assemblage using five fine-scale (0·5 m) GIS-based environmental data sets collected during four different times of the year (July, October, January, April). We compared niche measures to variation in population density among species to determine whether environmental niche characteristics, in the context of available habitat, explain variation in numbers of individuals among species. 4. Variation in population density among species in the October sample was predicted by niche breadth measures (R2 = 0·752), while variation in population density among species in the January sample was predicted by a model incorporating measures of both niche breadth and niche position (R2 = 0·953). Measures of niche breadth and niche position were not correlated with variation in population density in the July and April samples. 5. Species presence and local abundance are often assumed to be predictable based on the availability of suitable habitat. However, little effort has been directed at understanding the influence of both niche breadth and niche position on local abundance. Our results suggest that the amount and distribution of available habitat can be a strong predictor of interspecific variation in population density, even in seasonally variable environments.

Background Some porphyrias are associated with cutaneous phototoxicity due to photoactivation of porphyrins, but whether ionizing radiation can have an additive effect is not clear. We report a case of severe radiation therapy-related toxicity in a patient with porphyria cutanea tarda and review the literature.

Aims To assess whether renal impairment influences the pharmacokinetics of ziprasidone, and to determine whether ziprasidone is cleared via haemodialysis. Methods Thirty-nine subjects with varying degrees of renal impairment were enrolled into an open-label, multicentre, multiple-dose study and assigned to four groups according to their renal function: normal (group 1, creatinine clearance > 70 ml min− 1); mildly impaired (group 2, creatinine clearance 30–60 ml min− 1); moderately impaired (group 3, creatinine clearance 10–29 ml min− 1), and severely impaired (group 4, requiring haemodialysis three times-a-week). Subjects received ziprasidone 40 mg day− 1, given orally with food, as two divided daily doses for 7 days and a single 20 mg dose on the morning of day 8. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 8 (haemodialysis day for subjects with severe renal impairment). Additional samples were collected from subjects with severe renal impairment on day 7 (nonhaemodialysis day). Results On day 1 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax) of ziprasidone among subjects with normal renal function and those with mild, moderate and severe renal impairment. The AUC(0,12 h) and Cmax in subjects with mildly impaired renal function were statistically significantly greater than in those with moderately impaired renal function (P= 0.0163–0.0385). The mean AUC(0,12 h) was 272, 370, 250 and 297 ng ml−1 h in groups 1, 2, 3 and 4, respectively. Corresponding mean Cmax values were 47, 61, 41 and 50 ng ml− 1 and corresponding mean tmax values were 5, 6, 5 and 5 h. On day 8 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax, λz, Fb) of ziprasidone among subjects with normal renal function and those with moderate or severe renal impairment. The AUC(0,12 h) in subjects with mild renal impairment was statistically significantly greater than those in the other three groups (P=0.0025–0.0221), but this was not considered clinically significant. The mean AUC(0,12 h) were 446, 650, 389 and 427 ng ml − 1h in groups 1, 2, 3 and 4, respectively. Corresponding mean Cmax values were 68, 93, 54 and 70 ng ml− 1, corresponding mean tmax values were 4, 5, 4 and 5 h and corresponding mean λz were 0.14, 0.11, 0.14 and 0.17 h− 1. The mean percentage Fb was 99.84–99.88% across all groups and the mean t½,z ranged from 4.2 to 6.4 h. Comparison of the mean AUC(0,12 h) and Cmax values in subjects with severe renal impairment on day 7 with those on day 8 suggested that haemodialysis does not have a clinically significant effect on the pharmacokinetics of ziprasidone. Conclusions The findings of this study indicate that mild-to-moderate impairment of renal function does not result in clinically significant alteration of ziprasidone pharmacokinetics and therefore does not necessitate dose adjustment.

Congenital erythropoietic porphyria (Gunther's disease) is one of the least common porphyrias. This article describes the life and career of Hans Gunther (after whom the disease is named), his contributions to the field of porphyrias and the current understanding of Gunther's disease.

Coumarin (1,2-benzopyrone), a natural food constituent, prevents polycyclic aromatic hydrocarbon-induced neoplasms in rats and mice, but has not been studied with other chemical carcinogens. We examined coumarin chemoprotection against aflatoxin B1 using the 6-thioguanine resistance mutation assay in two different Chinese hamster ovary cell lines (K1BH4 and AS52) with liver S9 from rats and 19-day-old chick embryos for aflatoxin B1 bioactivation. Laboratory rodents metabolize coumarin through 3-hydroxylation, whereas 7-hydroxylation predominates in chick embryos and humans. Chick embryo liver S9 was approximately 25-fold more effective in activating aflatoxin B1 to the mutagenic and cytotoxic metabolite(s) than rat liver S9. Coumarin added at 50 and 500 microM with chick embryo liver S9 reduced the mutant frequency of 1 microM aflatoxin B1 by 40 and 85%, respectively. Coumarin up to 500 microM had no effect on aflatoxin B1 mutagenicity with rat liver S9. When liver S9 from chick embryos pretreated with coumarin was used for aflatoxin B1 bioactivation, mutant frequency and cytotoxicity were decreased compared to liver S9 from vehicle-treated controls. Liver S9 from coumarin-treated rats did not significantly affect mutant frequency or cytotoxicity. HPLC analysis of chick embryo liver S9 incubated with 1 microM aflatoxin B1 showed a dose-dependent decrease by coumarin of aflatoxin B1 activation to the 8,9-epoxide ranging from 70% of controls at 5 microM coumarin to 4% of controls at 500 microM coumarin. In contrast, coumarin produced a dose-dependent increase in 20 microM aflatoxin B1 activation by rat liver S9, reaching twice the control levels at 500 microM coumarin. These findings, using a mammalian cell system as a mutagenic endpoint, demonstrate marked species differences in chemoprotection by coumarin.

A 23-year-old man with epilepsy and a past history of abdominal pain and ileus, developed hypertension and arm and bulbar weakness when valproic acid and carbarnazepine were reinitiated. Electrophysiologic studies demonstrated a peripheral neuropathy with features of axonal degeneration and demyelination. Axonal degeneration was documented by sural nerve biopsy. Markedly elevated urinary 8-aminolevulinic acid and porphobilinogen indicated a diagnosis of acute porphyria. Other laboratory studies were most consistent with hereditary coproporphyria. Motor function improved considerably but incompletely over 1 year. An acute, primarily motor neuropathy can occur in several forms of porphyria, including acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria, sometimes even in the absence of concomitant gastrointestinal symptoms. © 1994 John Wiley & Sons, Inc.

The mean plasma half-life (T1/2) of antipyrine was prolonged (21.69 +/- 1.92 hr) in a group of 10 patients with hereditary hepatic porphyria, 8 of whom had acute intermittent porphyria (AIP) confirmed by decreased erythrocyte uroporphyrinogen-1-synthetase (URO-S) activities and 2 of whom had mixed hepatic porphyria, in comparison to the mean of 20 normal control subjects (12.65 +/- 0.86 hr, p less than 0.01). Antipyrine T1/2 was especially prolonged in patients with a history of more severe symptoms, but there was no correlation with the degree of elevation in urinary excretion of the porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). In 7 completely latent carriers of the AIP gene defect who had normal urinary ALA and PBG levels, the elimination rates of antipyrine from plasma were entirely normal. Phenylbutazone T1/2s were normal in 10 porphyric patients tested. These results demonstrate that the cytochrome P-450-dependent enzyme system for oxidizing antipyrine, but not that for phenylbutazone, is impaired in some AIP individuals in whom the gene defect for the disorder is clinically expressed and that this impairment may be related to the severity of the disease. The partial decrease in URO-S activity characteristic of AIP does not result in a profound or generalized decrease in hepatic cytochrome P-450 function, however, even when there is sufficient derangement in the hepatic heme biosynthetic pathway to lead to excessive excretion of chemical intermediates in the pathway.

This study was undertaken to examine the influence of changes in dietary carbohydrate and protein content on the oxidation of antipyrine and theophylline in man. When the diets of 6 normal volunteers were changed from their usual home diets to low carbohydrate-high protein diets, the plasma half-life of antipyrine decreased from 16.2 hr to 9.5 hr, and the half-life of theophylline decreased from 8.1 hr to 5.2 hr. When the subjects' diets were changed from low carbohydrate-high protein diets to a high carbohydrate-low protein diets, the mean antipyrine half-life increased from 9.5 hr to 15.6 hr and the mean theophylline half-life increased from 5.2 hr to 7.6 hr. These changes in half-lives were accompanied by changes in metabolic clearance rates but not in the apparent volumes of distribution of the drugs tested. Qualitatively similar results were obtained when the subjects were placed on standard diets followed by the standard diets supplemented with carbohydrate or protein. Supplementing the standard diets with carbohydrate caused an increase in drug half-lives, whereas a protein supplement caused a decrease in the drug half-lives. These data demonstrate marked influences of nutritional factors on oxidative biotransformation of drugs in man.

Mise en place d'un nouveau modele a partir de ceux de la litterature qui permet la determination des profils de vitesse moyens dans le temps. Trois zones sont considerees: le cœur, le tampon et la couche laminaire claire a la paroi. Le modele prend en compte la viscosite du liquide

The purpose of this study was to evaluate the association between signs of trauma from occlusion, severity of periodontitis and radiographic record of bone support. The maxillary first molars of 300 individuals were independently evaluated by two examiners for signs of trauma from occlusion, pattern or occlusal contacts and severity of periodontitis. Each site was also evaluated radiographically by an independent third examiner. The results indicated that: teeth with either bidigital mobility, functional mobility, a widened periodontal ligament space or the presence of radiographically visible calculus had a deeper probing depth, more loss of clinical attachment and less radiographic osseous support than teeth without these findings, teeth with occlusal contacts in centric relation, working, nonworking or protrusive positions did not exhibit any greater severity of periodontitis than teeth without these contacts, teeth with both functional mobility and radiographically widened periodontal ligament space had deeper probing depth, more clinical attachment loss and less radiographic osseous support than teeth without these findings and given equal clinical attachment levels, teeth with evidence of functional mobility and a widened periodontal ligament space had less radiographic osseous support than teeth without these findings.

Administration of the polychlorinated biphenyls (PCRs) mixture, Aroclor 1016, to rats elicited a barbiturate type of inducing effeet on the hepatic microsomal oxidative enzyme system. Aroclor 1016 eaused significant increases in liver eytoehrome P-450 eontent, microsomal protein, and ethylmorphine N-demethylase activity; its effeet on benzoiaipyrene hydroxylase activity was minimal. Unlike the widely studied PCRs mixture, Aroclor 1254, Aroclor 1016 did not induce eytoehrome P-448 in liver microsomes. Five workers occupationally exposed to Aroclor 1016 in a capacitor-manufacturing plant showed a significantly lower mean antipyrine half-life (10.8 hr) than the mean half-life of 15.6 hr in non-PCRs--exposed normal subjeets. These differenees in half-life were aeeompanied by increased metabolie clearanee rates in workers exposed to the PCRs, whieh strongly suggests that PCRs accelerate the rate of drug metabolism in man. Dur studies show that Aroclor 10/6 elicits the barbiturate type of inducing effeets on drug metabolism in man as weil as animals.

Large interindividual differences occur in the in vivo metabolism of drugs due to genetic and environmental factors. Our studies show that intraindividual variabilities in rates of metabolism are relatively low for antipyrine and phenylbutazone, which are drugs that are primarily metabolized by the liver and have low hepatic extractions; whereas in the case of phenacetin, a drug that undergoes extensive metabolism in the gastrointestinal tract or during its first pass through the liver, or both, intraindividual variations in plasma half-lifes and areas under the plasma concentration-time curves are of much greater magnitude. In our studies, no effort was made to control the lifestyles of our subjects. The variations in rates of drug metabolism did not result from assay procedures, since there was little variation in measured concentrations when the drugs were added to plasma and assayed on multiple occasions. Intraindividual variation occurring in subjects given the drug on 5 different occasions may be due to changes in the external environment or changes in internal physiologic parameters or both. Our studies confirm the usefulness of antipyrine as a test drug in studying drug metabolism in man and also demonstrate that the antipyrine test may be able to detect those subjects whose environments are perturbed by unidentified factors.

Uterine hypercontractility is considered to be an important factor in primary dysmenorrhea. A survey is given on possible mechanisms controlling the cytoplasmic concentration of free calcium and thereby contractile activity in the myometrial smooth muscle cell. Probably acting by different modes of action, inhibitors of prostaglandin synthesis, calcium antagonists and beta 2 stimulators have all been shown to reduce myometrial activity and relieve dysmenorrheic pain. The possibility of achieving further uterine relaxation after initial treatment with prostaglandin inhibitors by adding a calcium antagonist such as nifedipine is discussed. It is also suggested that when utilizing a reliable pressure recording technique in the evaluation of dysmenorrheic patients, the pronounced myometrial relaxation obtained by such combined therapy may be of diagnostic value.