Effect of lanreotide, a somatostatin analogue, on urea synthesis in normal man

The aim was to investigate the effect of lanreotide (Angiopeptin) on urea synthesis. Lanreotide is a somatostatin analogue used in therapy trials of certain cancers. Cancer patients are often protein catabolic, thus the effect of lanreotide on whole body protein metabolism is of importance. We investigated the effect of lanreotide by measuring urea nitrogen synthesis rate (UNSR) and blood alpha-amino nitrogen levels before, during and after a 30 min iv infusion of 25 g of an electrolyte-free amino acid solution. 6 healthy male subjects were studied following, i) placebo (saline), ii) lanreotide 5 mug/kg, and iii) lanreotide 80 mug/kg. Lanreotide decreased urea nitrogen synthesis rate (mmol/h) during amino acid infusion significantly compared to saline, independent of dose of lanreotide (max +/- SE of urea nitrogen synthesis rate measurements in each study: 117 +/- 8 mmol/h (saline), 85 +/- 10 mmol/h (high dose) and 85 +/- 12 mmol/h (low dose)). This occurred in spite of significantly higher plasma alpha-amino nitrogen following lanreotide (peak +/- SE of alpha-amino nitrogen level in each study: 3.7 +/- 0.1 mmol/l placebo versus 4.8 +/- 0.2 mmol/l low dose and 4.7 +/- 0.4 mmol/l high dose (p < 0.01). We conclude that a single dose of lanreotide decreases whole body urea nitrogen synthesis rate thereby conserving body protein. The results indicate that long term lanreotide therapy may not lead to further protein catabolism in cancer patients.     

HPV testing can reduce the number of follow-up visits in women treated for cervical intraepithelial neoplasia grade 3

OBJECTIVE: We evaluated high-risk human papillomavirus (HPV) testing by Hybrid Capture II (HC II) in addition to cytology to predict recurrent/residual cervical intraepithelial neoplasia (CIN) 2/3 and cervical cancer in women treated for CIN 3. METHODS: Follow-up study of 108 women with histologically confirmed CIN 3. RESULTS: Pretreatment, in 96% (104/108) of the smears high-risk HPV DNA was present. Posttreatment, 71% (77/108) of the women had normal cytology and negative HC II test and none developed recurrent/residual disease during a median follow-up of 28.8 months with a range of 2.4-64.8 months. One of the 12% (13/108) of women with normal cytology and positive HC II test was diagnosed with cervical adenocarcinoma. One of the 7% (8/108) of women with abnormal cytology (borderline dyskaryosis or worse) and negative HC II test was diagnosed with CIN 2. Three of the 9% (10/108) of women with abnormal cytology and a positive HC II test were diagnosed with CIN 2/3. These results show an increased risk for recurrent/residual CIN 2/3 and cervical carcinoma when at least one posttreatment test is positive. The highest relative risk (72.9, 95% CI 25-210) was present in women with both tests positive. CONCLUSIONS: HPV testing with Hybrid Capture II in conjunction with cytology can be used as a tool to select women with an increased risk for recurrent/residual CIN 2/3 and cervical cancer. The standard policy in The Netherlands is cytology at 6, 12, and 24 months posttreatment. However, for women with both normal cytology and negative HC II test at 6 months the chance to develop recurrent/residual CIN 2/3 and cervical carcinoma is so low that retesting at 12 months can be omitted.     

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency

Background  

A potential role for muscle in glucose homeostasis was recently suggested based on characterization of extrahepatic and extrarenal glucose-6-phosphatase (glucose-6-phosphatase-β). To study the role of extrahepatic tissue in glucose homeostasis during fasting glucose kinetics were studied in two patients with a deficient hepatic and renal glycogenolysis and/or gluconeogenesis.     

Growth hormone and mild exercise in combination increases markedly muscle mass and tetanic tension in old rats

OBJECTIVE: A decline of skeletal muscle mass and strength is seen with aging and immobilization. Growth hormone (GH) has been shown to increase muscle mass. In the present study the effects of a combination of mild exercise and GH on skeletal musculature tetanic tension, dry defatted weight (DDW), volume, water, fat and collagen concentrations were investigated in old rats. DESIGN: Recombinant human GH (2.7mg/kg per day) was injected subcutaneously for 73 days in 21-month-old female rats. Exercised rats ran on a treadmill, 8 m/min for 1 h/day. The in vivo maximal tetanic tension of the calf musculature (m. soleus, m. plantaris, m. gastrocnemius together) was analysed in anaesthetized rats by stimulating the ischiadic nerve. RESULTS: The maximal tetanic tension was increased by 23% in GH-injected compared to saline-injected rats. Mild exercise + GH in combination resulted in a further 18% increase in maximal tetanic tension. The mild exercise by itself did not influence the maximal tetanic tension significantly when compared with saline injected rats. The GH administration and/or mild exercise did not change skeletal muscle endurance, measured as tetanic tension during 30s of stimulation. Serum IGF-I concentration was increased twofold in GH-injected rats. CONCLUSION: The increased muscle mass induced by GH + mild exercise was associated with a corresponding increase in maximal tetanic tension. Combination of GH + mild exercise resulted in a substantial further increase of muscle mass and maximal tension compared with GH injections alone in these old rats.     

Acute gastroenteritis in children attending day-care centres with special reference to rotavirus infections. I. Aetiology and epidemiologic aspects

Acute gastroenteritis (GE) among 214 children (aged 6 months-7 years) attending day-care centres (DDCs) in the Copenhagen County was studied during a 12-month period. A total of 197 cases of GE was observed in 109 children (i.e. 51% of the participants). The aetiology was as follows: rotavirus (n = 48) (24%), pathogenic bacteria (n = 11) (6%), Giardia lamblia (n = 3) (2%), while the aetiology of 68% remains unknown. The pathogenic bacteria included Yersinia enterocolitica, thermophilic Campylobacter, Clostridium difficile (+/- toxin) and enteropathogenic E. coli. In 4% of the GE the infections were multiple and Cryptosporidium was seen in one of these cases. The rate of GE declined with age from 1.35 GE per child per year (age group 1.0- less than 2.0 years) to 0.36 (6.0- less than 8.0 years). Serum sampled at the start of the study period showed that the frequency of detectable rotavirus IgG increased with age from 48% in the 6 months- less than 1.0 year group to 96% in the 4.0- less than 7.0 year group. The highest rates of rotavirus GE occurred from January to April (i.e. the rotavirus season). Moreover, rotavirus GE was almost absent after the age of 4. Hence, the rates of rotavirus GE per rotavirus season per child were 0.80 (age group 6 months-less than 1.0 year), 0.32 (1.0-less than 2.0), 0.14 (2.0-less than 3.0), 0.16 (3.0-less than 4.0), 0.06 (4.0-less than 5.0) and 0.04 (5.0-less than 6.0). Only 2 out of the 48 rotavirus GE were reinfections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Targeting of doxorubicin to the urinary bladder of the rat shows increased cytotoxicity in the bladder urine combined with an absence of renal toxicity

Targeting of anti-tumor drugs to the urinary bladder for the treatment of bladder carcinoma may be useful, since these agents generally have a low degree of urinary excretion and are highly toxic elsewhere in the body. The anti-tumor drug doxorubicin was coupled to the low-molecular weight protein lysozyme via the acid-sensitive cis-aconityl linker. All free amino groups of the lysozyme were used for drug attachment to achieve intact excretion of the doxorubicin-aconityl-lysozyme conjugate into the bladder. In the bladder, the cytotoxic drug should be regenerated through acidification of the urine. First, the doxorubicin-aconityl-lysozyme conjugate was tested in rats for its target specificity and general toxicity. Wistar rats were injected intravenously with 2 mg/kg free doxorubicin or 10 mg/kg lysozyme-conjugated doxorubicin. Total urinary excretion of doxorubicin was about 10 times higher if the drug was coupled to lysozyme (39 +/- 3% versus 4.4 +/- 0.4%). Free doxorubicin had no detectable toxic effects on heart, liver and lung but caused severe renal damage (proteinuria, N-acetylglucosaminidase excretion and glomerulosclerosis). None of the rats injected with doxorubicin-lysozyme conjugate showed such renal toxicity. Second, we tested whether doxorubicin could be released from the conjugate in the bladder through acidification of the urine and if the released doxorubicin could still exert a cytotoxic effect. Doxorubicin-aconityl-lysozyme (2 mg/kg conjugated doxorubicin, i.v.) was administered in rats with acidified urine (pH 6.1 +/- 0.1) and in rats with a high urinary pH (8.2 +/- 0.4). Ten times more doxorubicin was released from the conjugate in the group with acidified urine (15 +/- 7% versus 1.7 +/- 0.1%). In agreement with this, cytotoxicity was also higher in the low pH group (IC50 of 255 +/- 47 nM versus 684 +/- 84 nM doxorubicin). In conclusion, a specific delivery of doxorubicin to the urinary bladder combined with a reduced toxicity of doxorubicin in the kidneys can be achieved by coupling this anti-tumor drug to the low-molecular weight protein lysozyme via an acid-labile linker. A release of cytotoxic doxorubicin in the urinary bladder can be achieved by acidification of the urine. This technology, after further optimization, may provide an interesting tool for the treatment of bladder carcinoma.