High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia

BACKGROUND: Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by a high degree of genomic instability and predisposition to cancer development. Recent evidence suggests that the incidence of head and neck squamous cell carcinoma (HNSCC) may be increased in patients with FA. OBJECTIVE: To determine the cumulative incidence, tumor distribution, and outcome of HNSCC in patients with FA. DESIGN AND SETTING: We analyzed data from 754 subjects from the International Fanconi Anemia Registry, a prospectively collected database of patients with FA. MAIN OUTCOME MEASURES: Cumulative incidence of HNSCC and 2-year overall, relapse-free and disease-specific survival. RESULTS: Of the 754 patients in the International Fanconi Anemia Registry, 19 (3%) had HNSCC. This is a significantly higher incidence of HNSCC compared with that observed in the general population (standardized incidence ratio, 500; 95% confidence interval, 300-781) (P<.001). The patients' age ranged from 15 to 49 years (median, 31 years), and there was a 2:1 female predominance. Surgical treatment was well tolerated (n = 17); however, radiation therapy and chemotherapy were associated with significant morbidity and mortality. Of the 19 patients, 10 (53%) developed locoregional recurrences within a median of 16 months from diagnosis. The median follow-up was 29 months. The 2-year disease-specific, overall, and relapse-free survival rates were 49%, 49%, and 42%, respectively. The cumulative incidence of relapse by the age of 40 years was 50%. CONCLUSIONS: In patients with FA, there is a high incidence of aggressive HNSCC at a young age. Surgery remains the mainstay of treatment because patients with FA tolerate radiation therapy and chemotherapy poorly, with significant morbidity. An increased understanding of FA-associated malignancies is not only important in the clinical management of patients with FA but can also elucidate the role of chromosomal instability in the development of HNSCC in general.     

The prophylactic effects of natural water-soluble antioxidant from spinach and apocynin in a rabbit model of lipopolysaccharide-induced endotoxemia

Radical-scavenging antioxidants, as part of the cellular defense system, function to inhibit the formation and propagation of free radicals and active oxygen species formation. In previous studies we demonstrated that endotoxin lipopolysaccharide (LPS) promotes oxidative stress and associated pathological changes in a rat model and that use of selected antioxidants was effective in reducing LPS-related lipid peroxidation product formation in the liver, as well as LPS-related pathological changes in different organs. In this study, several toxicological parameters (ie, clinical signs, blood chemistry, and histopathological changes) were compared among groups of male New Zealand rabbits injected with LPS following prophylactic pretreatment with either of 2 antioxidants, a group injected with LPS without pretreatment with antioxidants, groups injected with either of the 2 antioxidants only, and an untreated control group. The antioxidants used were a water-soluble natural antioxidant (NAO) from spinach and the NADPH oxidase inhibitor, apocynin. Exposure to LPS alone was associated clinically with depression, tachypnea, outer ear vasodilation, and iris congestion; biochemically with a significant increase in blood total bilirubin, transaminase activity, and glucose, total cholesterol, and triglyceride levels; macroscopically with multiple whitish areas in the liver; and histologically with hepatocellular focal necrosis and acute inflammation, thymic and splenic lymphoid necrosis and depletion, acute uveitis and hemorrhages in the ciliary processes, and decreased adrenal cortical cytoplasmic vacuolation considered consistent with depletion of steroidal hormone contents. The NAO had more effective prophylactic capacities than the apocynin. The protective effects were obvious in all investigated parameters. The results indicate the possible therapeutic efficacy of NAO in the treatment of clinical endotoxemia associated with gram-negative bacterial sepsis that is known to be associated with oxidative stress.     

Synthesis and antimicrobial properties of new cepham and penam derivatives with the carboxylic group in the “wrong” β-configuration

The cepham (9) and the penam (10) derivatives, with their carboxylic group in the “wrong” β-configuration, which is opposite to that exhibited by the common penicillins, were synthesized and assayed in vitro for antimicrobial properties. Compounds 9 and 10, tested on Gram-positive and Gram-negative bacteria, both sensitive and resistant to β-lactamase inactivation, exhibited a very poor activity, directed only against non-β-lactamase-producing Gram-positive bacteria. One of the possible explanations for these results may be found in unfavourable steric and electronic effects deriving from the α-oriented methoxy group which is adjacent to the pharmacophoric carboxylic function.     

Central effects of tetanus and botulinum neurotoxins

Tetanus neurotoxin (TeNT) and botulinum neurotoxins (BoNTs; from A to G) are metalloproteases that act on nerve terminals to prevent exocytosis. They are extensively exploited for the study of cellular physiology. Moreover, BoNTs are also employed in clinical neurology for the treatment of several disorders characterized by hyperexcitability of peripheral nerve terminals. This review summarizes recent studies that have provided a deeper understanding of the mode of action of TeNT and BoNTs. TeNT and BoNTs bind with extreme specificity and are internalized at the neuromuscular junction. We first examine the retrograde transport mechanisms by which TeNT gains access to the central nervous system. We also discuss recent findings indicating that, besides their well known local actions at the neuromuscular junction, BoNTs can also affect central circuits.     

Randomized Trial of Trimethoprim-Sulfamethoxazole versus Pyrimethamine-Sulfadiazine for Therapy of Toxoplasmic Encephalitis in Patients with AIDS

The aim of the present pilot study was to compare the efficacy and safety of trimethoprim (TMP) and sulfamethoxazole (SMX) with those of the standard therapy pyrimethamine (P)-sulfadiazine (S) for the treatment of toxoplasmic encephalitis in patients with AIDS. This was a pilot, multicenter, randomized, and prospective study. Patients were randomly assigned to receive TMP (10 mg/kg of body weight/day) and SMX (50 mg/kg/day) or P (50 mg daily) and S (60 mg/kg/day) as acute therapy (for 4 weeks) and then as maintenance therapy for 3 months at half of the original dosage. Seventy-seven patients were enrolled and randomized to the study: 40 patients were treated with TMP-SMX and 37 were treated with P-S. There was no statistically significant difference in clinical efficacy during acute therapy. In contrast, patients randomized to TMP-SMX appeared more likely to achieve a complete radiologic response after acute therapy. Adverse reactions were significantly more frequent in patients treated with P-S, and skin rash was the most common adverse event noted in these patients. In conclusion, the results of the study suggest that TMP-SMX appears to be a valuable alternative to P-S, in particular in patients with opportunistic bacterial infections.     

Nonenzymatic glycation of human platelet membrane proteins in vitro and in vivo

Human platelet membrane proteins (PMP), incubated in vitro in the presence of various concentrations of glucose, undergo nonenzymatic glycation, as evidenced by incorporation of [3-3H]glucose radioactivity into the acid-precipitable fraction. The time course of the reaction is linear for the first hours, and the rate of glycation depends on the glucose concentration in the medium: at a glucose concentration of 80 mmol/L, up to 60 nmol of glucose is bound per milligram of PMP. The ketoaminic nature of the glucose/protein linkages was demonstrated by the finding of 5-hydroxymethylfurfuraldehyde by liquid-chromatographic analysis of acid hydrolysates of PMP. We analyzed PMP from 13 subjects with type I poorly controlled diabetes and from 10 nondiabetics. Nonenzymatic glycation, evaluated as nanomoles of the aldehyde per milligram of protein, was much greater in diabetic patients than in nondiabetics: 1.58 +/- 0.70 vs 0.37 +/- 0.18 (mean +/- SD).     

Fructosamine, glycated hemoglobin, and dietary carbohydrates

Background: Glycated hemoglobin (HbA_1c), a marker of glycemia in the previous 3 months, was found to be associated with dietary saturated, fat but not with carbohydrates, in recent population surveys. Another nonenzymatically glycated substance in the blood, fructosamine, a marker of glycemia in the previous 3 weeks, is poorly correlated with HbA_1c in nondiabetic subjects. The aim of this study is to compare the correlation of glycated hemoglobin and fructosamine with dietary carbohydrate intake in the same subjects. Subjects and methods: Seventy-one individuals from a cohort study on diet and cancer entered this study. Serum fructosamine was measured by a standard colorimetric method, and glycated hemoglobin by high-performance liquid chromatography (HPLC). Diet was measured by a validated semiquantitative food frequency questionnaire. The correlation of fructosamine and glycated hemoglobin with dietary variables, corrected for calories, was evaluated by multiple correlation. Results: Fructosamine was more strongly correlated with dietary sugar (r=0.26, p=0.05) than HbA_1c was (r=0.001, p=0.99). Fructosamine was also inversely correlated with energy, and glycated hemoglobin with vitamin C. Conclusions: Fructosamine appears to be more related to dietary sugar intake than glycated hemoglobin and may be a marker of exposure to dietary carbohydrates, particularly simple sugars, in epidemiological studies.