Absence Of Long-term Studies Research Articles

Risk Assessment of "Other Substances" – L-Glutamine and L-glutamic Acid

Risk Assessment of "Other Substances" – L-Glutamine and L-glutamic Acid

Risk Assessment of "Other Substances" – L-Tyrosine

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis for regulating the addition of "other substances" to food supplements and other foods.
 "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. VKM has not in this series of risk assessments of "other substances" evaluated any claimed beneficial effects from these substances, only possible adverse effects.
 The present report is limited to the use of L-tyrosine in food supplements. Risks related to tyrosine added to food and drinks, protein hydrolysates or high dietary protein intake are outside the scope of the opinion. The report is based on previous risk assessments of tyrosine and scientific papers retrieved from a comprehensive literature search.
 L-tyrosine, an aromatic amino acid, is considered a conditionally indispensable amino acid because it can be synthesised from L-phenylalanine in the liver. The magnitude of endogenous synthesis of L-tyrosine is not known, but is related to the intake of phenylalanine.
 L-tyrosine is a precursor of several biologically active substances, including catecholamine neurotransmitters, thyroid hormones and melanin skin pigments. L-tyrosine is available from all protein-containing foods such as meat, eggs, fish, dairy products, grains and pulses. According to information from the NFSA, L-tyrosine is an ingredient in food supplements sold in Norway. The NFSA has requested a risk assessment of the following doses of L-tyrosine food supplements: 1250 mg/day, 1500 mg/day, 1750 mg/day, and 2000 mg/day. Dietary intake of tyrosine in Norway is not known, but data from NHANES III (USA) suggest a mean dietary intake of about 2.8 g per day.
 In phase 1 seven previous reports that assessed the safety of L-tyrosine supplementation in humans were identified. For the present report, a literature search was performed to retrieve relevant human or animal studies on the safety of L-tyrosine. One relevant animal study assessing the toxicity of tyrosine by feeding rats different doses of tyrosine daily by oral gavage for 13 weeks was identified. No human studies have been identified.
 No major specific issues related to adverse effects from L-tyrosine used as food supplements were identified in previous reports. However, a lack of studies in healthy adult individuals as well as in children was pointed out, and in particular the absence of long-term studies in healthy individuals. 
 A lowest observed adverse effect level (LOAEL) and a no observed adverse effect level (NOAEL) of 2000 and 600 mg/kg bw per day, respectively, for tyrosine have been identified in a 90-day toxicological study in rats. At 2000 mg/kg bw per day, significant increases, were found in weights of livers and kidneys in addition to increased plasma lipids and hypertrophy of centrilobular hepatocytes in both sexes.
 The NOAEL at 600 mg/kg per day was used to calculate the margin of exposure (MOE), the ratio of the NOAEL to the specified doses of 1250, 1500, 1750 and 2000 mg/day of Ltyrosine in food supplements. The MOE-values range from 13 for the highest supplement dose in children to 34 for the lowest supplement dose in adults.
 Given the low MOE-values (range 13-34), and the severity of the adverse effects at the LOAEL (3.3 times the NOAEL), VKM concludes that all the specified doses may represent a risk of adverse effects. No evidence was found to assume specific tolerance levels for L-tyrosine for children or adolescents. Therefore, a similar tolerance as for adults relative to body weight was assumed for these age groups. 
 Based on these data, the Norwegian Scientific Committee for Food Safety (VKM) concludes that:
 
 In adults (≥18 years), the specified doses of 1250, 1500, 1750, and 2000 mg/day Ltyrosine in food supplements may represent a risk of adverse health effects.
 In adolescents (14 to <18 years), the specified doses of 1250, 1500, 1750, and 2000 mg/day L-tyrosine in food supplements may represent a risk of adverse health effects.
 In children (10 to <14 years), the specified doses of 1250, 1500, 1750, and 2000 mg/day L-tyrosine in food supplements may represent a risk of adverse health effects.
 
 Children below 10 years were not included in the terms of reference.

Risk Assessment of "Other Substances" – L-serine

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements.
 "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and / or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" the VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects.
 The present report is a risk assessment of specified doses of L-serine in food supplements, and it is based on previously published risk assessments and scientific papers retrieved from a comprehensive literature search. 
 L-serine is a non-essential amino acid which is produced endogenously and is supplied from the diet. In addition to its role in protein synthesis, L-serine has an important role as a major contributor to the one-carbon pool and is involved in the metabolism of several key compounds, including glycine, cysteine, taurine, and phospholipids and of D-serine.
 According to information from NFSA, L-serine is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of 50, 500, 1000, 1250, 1500 and 1750 mg/day of L-serine from food supplements. Most dietary proteins contain about 4-5% L-serine. Rich sources of proteins are meat, dairy products, legumes, fish, nuts, seeds, eggs and whole grains. Dietary intake of L-serine in Norway is not known, but results show an overall mean intake of L-serine from food and food supplements of 3.5 g/day in the United States (NHANES III, USA).
 In the first phase of the present evaluation of "other substances", previous reports that have assessed the safety of L-serine supplementation in humans were identified. In the second phase, a systematic literature search was performed to retrieve scientific papers published before 11 May 2016 (human studies literature search) and before 28 July 2016 (animal studies literature search). Based on this search, we did not identify any long-term studies in healthy individuals that could be used for safety evaluations. On the other hand, three relevant animal studies were included in this report.
 The animal studies revealed no adverse health effects as a result of the tested doses of Lserine (840-3000 mg/kg bw per day). For the risk characterisation of L-serine, in the absence of long-term studies in healthy individuals, VKM based the value of comparison on the no observed adverse effect level (NOAEL), 3000 mg/kg bw per day which was the highest dose tested in a 90-days toxicological study in rats. This value was used to calculate the Margin of Exposure (MOE) values for daily intake of 50, 500, 1000, 1250, 1500 and 1750 mg L-serine in children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). The MOE-values ranged from 74 to 4200, which were considered acceptable since L-serine is a nutrient that does not cause any well documented adverse effects and because studies indicate a high endogenous production (Snell, 1986) and a high dietary intake of L-serine (NHANES III, USA) compared to the doses considered in the present risk assessment.
 Thus, VKM concludes that:
 
 In adults (≥18 years), the specified doses 50, 500, 1000, 1250, 1500 and 1750 mg/day L-serine in food supplements are unlikely to cause adverse health effects. 
 In adolescents (14 to <18 years), the specified doses 50, 500, 1000, 1250, 1500 and 1750 mg/day L-serine in food supplements are unlikely to cause adverse health effects.
 In children (10 to <14 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-serine in food supplements are unlikely to cause adverse health effects.
 
 Children younger than 10 years were not within the scope of the present risk assessment.

Personalized Drug Therapy in Cystic Fibrosis: From Fiction to Reality.

Personalized drug therapy for cystic fibrosis (CF) is a long-term dream for CF patients, caregivers, physicians and researchers. After years of study, the fiction of personalized treatment has turned to hope. Basic information about CFTR mutations classes and new treatments is needed if we are to deal properly with the new CF era. The problems involved in this issue, however, should be evaluated with greater care and attention. VX-770 is a new drug available to treat CF patients with some class III CFTR mutations and other drugs are being studied regarding other classes. The scientific literature has constantly given information about each therapy, both in vitro and in vivo. The hope is increasing. Nevertheless the "scientific world" still lacks information about patients' reality and daily health related practical needs. Clinical trials have showed good evaluation of some drugs so far, but clinical response is a wide spectrum yet to be analyzed: CFTR mutations spectrum, costs related to the treatment with new drugs (for VX-770 therapy), variability of CF clinical expression, limitations to test in vitro drugs, absence of good clinical markers to evaluate drug response, absence of long-term studies and with patients below six years old, multidrug treatment used to improve the expression response, and finally, the most important problem, who will benefit from the new drugs therapy, are issues that constitute a barrier that should be overcome. Personalized drug therapy may not be a fiction anymore, but it is not yet a reality for all CF patients.

Increased incidence of placenta praevia and accreta with previous caesareans – A hypothesis for causation

With the increasing numbers of caesareans, long-term complications, such as anterior placenta praevia-accreta are becoming important. Two case reports are presented here, leading to a hypothesis that the increasing incidence of anterior placenta praevia after prior caesareans may be a result of excessive differential development of the lower uterine segment. This could result from marked stretching of a poorly-healed myometrial area by the developing placenta. This would explain the lower incidence of ‘apparent’ migration of low placenta, as well as the higher likelihood of morbid adhesion. Although different operative techniques do not have a significant effect on short-term outcomes of caesareans, they are likely to impact the long-term complications. In the absence of long-term studies and good quality evidence, theoretical and logical analysis suggests that adherence to good surgical techniques, such as gentle tissue handling, haemostasis, good myometrial approximation without compromising blood supply and restoration of normal anatomy, may reduce long-term complications.

Evidence of large, local variations in recruitment and mortality in the small giant clam, Tridacna maxima, at Ningaloo Marine Park, Western Australia

Understanding variability of recruitment and mortality is essential for attempts to conserve populations or assessing changes resulting from perceived disturbances. In the absence of long-term studies, we examined population density and size-frequency distributions of the small giant clam, Tridacna maxima, at 20 sites in Ningaloo Marine Park, Western Australia, where the clams are abundant on discontinuous, intertidal rocky platforms attached to the shoreline. Density ranged over two orders of magnitude (0.04–8.27 m–2), and size ranged from 1.5 to 31.0 cm. The shapes of the size-frequency distributions varied substantially, indicating variability in recruitment and mortality, including failures of cohorts to recruit and catastrophic events of mortality. Consistency of recruitment, as indexed by the coefficient of variation of the size-frequency distribution, was greater towards the north of the Park, on intertidal platforms with greater complexity across their widths, and with smoother surfaces in the part of the platform occupied by the clams. The average turnover time was estimated at 5.4 years, giving a median age of 13 years. However, variation among sites was large, highlighting the importance of variability of the dynamics of local populations and the need for long-term studies to understand any particular population.

A Review of Arthroscopic Bone Marrow Stimulation Techniques of the Talus: The Good, the Bad, and the Causes for Concern.

Osteochondral lesions of the talus are common injuries following acute and chronic ankle sprains. Numerous surgical treatment strategies have been employed for treating these lesions; arthroscopic bone marrow stimulation is recognized as the first-line technique to provide fibrocartilage infill of the defect site. While the short- and medium-term outcomes of this technique are good, the long-term outcomes are not yet known. An increasing number of studies, however, show a cause for concern in employing this technique, including declining outcome scores over time. The current authors have therefore developed a treatment strategy based on previously established guidelines in addition to morphological cartilage-sensitive fast spin echo techniques and quantitative T2 mapping magnetic resonance imaging (MRI). Accordingly, the authors advocate arthroscopic bone marrow stimulation in lesion sizes up to 8 mm in diameter and osteochondral autograft transplant (OATS) in lesion sizes greater than 8 mm in diameter. In the absence of long-term studies, confining the use of arthroscopic bone marrow stimulation to smaller lesions may support prolonged joint life by decreasing the rate at which the fibrocartilage ultimately degenerates over time. Employing the OATS procedure in larger lesions has the advantage of replacing “like with like.” The current review examines the role of arthroscopic bone marrow stimulation techniques of the talus.

Effects of deforestation on grass biomass and soil nutrient status in miombo woodland, Zambia

There is a growing concern in central and southern Africa about the negative effects of deforestation caused by shifting cultivation and charcoal production. In the absence of long-term studies that document and assess impacts of tropical deforestation, it is difficult to evaluate the relevance of current policy interventions that address the negative effects of deforestation. To contribute to the knowledge about impacts of tropical deforestation, the effects of clearing Brachystegia– Julbernardia (miombo) woodland on grass biomass and soil nutrient status were assessed at four sites over a 10-years period, from 1991 to 2000 in central Zambia. Woodland clearing increased grass biomass by 20–50% and although its impacts on topsoil organic matter and available phosphorus were apparent, these were not statistically significant. Site and year had the most significant effects on soil nutrient stocks, regardless of the woodland clearing treatment. Generally, fire did not affect grass production but reduced topsoil organic matter and nitrogen at three of the study sites. Deforestation followed by cultivation significantly reduced soil organic matter in the study area. Based on these results, it is recommended that local cultivation practices should incorporate measures that minimize loss of soil organic matter in order to sustain long-term soil fertility.