Difficulties using the Franco-Italian Glossary in assessing toxicity of cervical cancer treatment

Shakespeare TP, Ferrier AJ, Holecek MJ, Jagavkar RS, Stevens MJ. Difficulties using the Franco-Italian Glossary in assessing toxicity of cervical cancer treatment. Int J Gynecol Cancer 1998; 8: 51–55
We assessed the toxicities of patients treated for cervical cancer using the revised Franco-Italian Glossary (FIG). A total of 69 separate complications were appraised in 47 patients; however, only 43.5% of these side-effects could be accurately graded. In all, 56.5% of toxicities could not be scored for a variety of reasons: (1) the FIG does not account for all possible complications of cervical cancer treatment; (2) some important toxicities are regarded as too minor to be graded; (3) subjective assessment of some side-effects did not allow consensus to be reached when assigning a grade; (4) we could not accurately score toxicities using the FIG in a retrospective manner. Previous studies utilizing the FIG retrospectively have noted few problems with its use, with no indication of the number of toxicities unable to be graded. In view of the inability to grade the majority of complications in the present study in an accurate manner, we conclude that the revised FIG requires detailed data that are best collected prospectively and that several minor modifications of the glossary should be considered. Results of studies using the glossary retrospectively should be viewed with caution.     

Acute effects of phenylbutyrate on glutamine,branched‐chain amino acid and protein metabolism in skeletal muscles of rats

Phenylbutyrate (PB) acts as chemical chaperone and histone deacetylase inhibitor, which is used to decrease ammonia in urea cycle disorders and has been investigated for use in the treatment of a number of lethal illnesses. We performed in vivo and in vitro experiments to examine the effects of PB on glutamine (GLN), branched‐chain amino acid (BCAA; valine, leucine and isoleucine) and protein metabolism in rats. In the first study, animals were sacrificed one hour after three injections of PB (300mg/kg b.w.) or saline. In the second study, soleus (SOL, slow twitch) and extensor digitorum longus (EDL, fast twitch) muscles were incubated in a medium with or without PB (5 mM). L‐[1‐¹⁴C] leucine was used to estimate protein synthesis and leucine oxidation, and 3‐methylhistidine release was used to evaluate myofibrillar protein breakdown. PB treatment decreased GLN, BCAA and branched‐chain keto acids (BCKAs) in blood plasma, decreased BCAA and increased GLN concentrations in muscles, and increased GLN synthetase activities in muscles. Addition of PB to incubation medium increased leucine oxidation (55% in EDL, 29% in SOL), decreased BCKA and increased GLN in medium of both muscles, increased GLN in muscles, decreased protein synthesis in SOL and increased proteolysis in EDL. It is concluded that PB decreases BCAA, BCKA and GLN in blood plasma, activates BCAA catabolism and GLN synthesis in muscle and exerts adverse effects on protein metabolism. The results indicate that BCAA and GLN supplementation is needed when PB is used therapeutically and that PB may be a useful prospective agent which could be effective in management of maple syrup urine disease.     

Incidence of tick-borne encephalitis in the West Bohemia Region 1960-1999--evaluation of vaccination

In 1960-1999 in the West Bohemian region 1216 cases of tick-borne encephalitis were recorded, four were fatal. Since 1992 there was a marked increase in the number of these infections--in 1992-1999 the relative morbidity was 6.7 per 100,000 population per year, the highest specific morbidity shifted to the age group of 55-64 years. In the whole region changes occurred as to the probable transmission of infection. By the end of 1999 in western Bohemia the hygiene service immunized, by at least three doses against tick-borne encephalitis 23,225 subjects, i.e. 2.7% of the population. The negligible vaccination rate did not have so far an impact on the epidemiological characteristics of the infection. In view of the more frequent and clinically more severe affection in elderly subjects it is important to raise the vaccination rate in particular in more advanced age groups.     

Study of lung cancer and residential radon in the Czech Republic

Epidemiological evidence of lung cancer risk from radon is based mainly on studies of men employed underground in mines where exposures are relatively high in comparison to indoor exposure. Risk from residential radon can be estimated from occupational studies. Nevertheless, as such extrapolations depend on a number of assumptions, direct estimation of the risk is needed. The present study of lung cancer mortality was designed as a follow-up of a population (N = 12,004) in a radon prone area of the Czech Republic covering the period 1960-1999. Information on vital status and causes of death were obtained mostly from local authorities and from the national population registry. Exposure estimates were based on one year measurements of radon progeny in most houses of the study area (74%). Exposures outside the area (16%) were based on country radon mapping. Mean concentration of 509 Bq/m3 is higher than the country estimate by a factor of 5. By 1999, a total of 210 lung cancers were observed, somewhat more than the nationally expected number (O/E = 1.10) in comparison to generally low numbers corresponding to cancers other than lung (O/E = 0.81). The excess relative risk per standard radon concentration (100 Bq/m3) was 0.087 (90% CI: 0.017-0.208). This value is consistent with risk coefficients derived in other indoor studies. The present follow-up demonstrated that increased incidence of lung cancer depends linearly on exposure in terms of average radon concentration in the course of previous 5-34 years. Adjustment for smoking did not substantially change this estimate, although the risk coefficient for non-smokers (0.130) was higher in comparison to that for ever smokers (0.069), but not statistically different.     

Protein metabolism in slow- and fast-twitch skeletal muscle during turpentine-induced inflammation

The aim of our study was to evaluate the differences in protein and amino acid metabolism after subcutaneous turpentine administration in the soleus muscle (SOL), predominantly composed of red fibres, and the extensor digitorum longus muscle (EDL) composed of white fibres. Young rats (40-60 g) were injected subcutaneously with 0.2 ml of turpentine oil/100 g body weight (inflammation) or with the same volume of saline solution (control). Twenty-four hours later SOL and EDL were dissected and incubated in modified Krebs-Heinseleit buffer to estimate total and myofibrillar proteolysis, chymotrypsin-like activity of proteasome (CHTLA), leucine oxidation, protein synthesis and amino acid release into the medium. The data obtained demonstrate that in intact rats, all parameters measured except protein synthesis are significantly higher in SOL than in EDL. In turpentine treated animals, CHTLA increased and protein synthesis decreased significantly more in EDL. Release of leucine was inhibited significantly more in SOL. We conclude that turpentine-induced inflammation affects more CHTLA, protein synthesis and leucine release in EDL compared to SOL.     

Muscle wasting in animal models of severe illness

Muscle wasting is a serious complication of various clinical conditions that significantly worsens the prognosis of the illnesses. Clinically relevant models of muscle wasting are essential for understanding its pathogenesis and for selective preclinical testing of potential therapeutic agents. The data presented here indicate that muscle wasting has been well characterized in rat models of sepsis (endotoxaemia, and caecal ligation and puncture), in rat models of chronic renal failure (partial nephrectomy), in animal models of intensive care unit patients (corticosteroid treatment combined with peripheral denervation or with administration of neuromuscular blocking drugs) and in murine and rat models of cancer (tumour cell transplantation). There is a need to explore genetically engineered mouse models of cancer. The degree of protein degradation in skeletal muscle is not well characterized in animal models of liver cirrhosis, chronic heart failure and chronic obstructive pulmonary disease. The major difficulties with all models are standardization and high variation in disease progression and a lack of reflection of clinical reality in some of the models. The translation of the information obtained by using these models to clinical practice may be problematic.     

Relation between glutamine, branched-chain amino acids, and protein metabolism

The branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) are the major nitrogen source for glutamine and alanine synthesis in muscle. Synthesis of glutamine, alanine, and BCAA use is activated in critical illnesses such as in sepsis, cancer, and trauma. The use of glutamine often exceeds its synthesis, resulting in the lack of glutamine in plasma and tissues. In critical illness, resynthesis of BCAA from branched-chain keto acids is activated, particularly in hepatic tissue. The BCAA released to circulation may be used for protein synthesis or synthesis of alanine and glutamine. Glutamine and/or alanine infusion has an inhibitory effect on the breakdown of body proteins and decreases BCAA catabolism in postabsorptive control, endotoxemic, and irradiated rats. Decreased protein breakdown also was observed when glutamine synthesis was activated by ammonia infusion. In conclusion some favorable effects of BCAA supply can be explained by its role in the synthesis of glutamine and some positive effects of glutamine exogenous supply can be explained by its effect on metabolism of BCAA.     

Indicators of oxidative stress in cardiovascular diseases. II. Nitrogenous substances, AGE-substances and antioxidants

By oxidation of nitrogen oxide nitrites and nitrates are formed which can be considered markers of inflammation. AGE-substances (products of advanced glycation) are formed not only from proteins (e.g. Hb-AGE) but also from lipids (AGE-LDL) and DNA (AGE-DNA) and lead to an increased number of mutations. They are toxic and are deposited in the vascular wall. They cause coagulopathy, stimulate cytokines and inactivate nitrogen oxide and thus prevent relaxation of the vascular wall. Extracellular superoxide dismutase (EC-SOD) has a variant (mutation Arg213Gly with a 4% incidence) which causes deterioration of the cardiac prognosis. Selenium deficiency leads also to an increased frequency of cardiovascular diseases.