Fluoropyrimidine chemotherapy in a rat model: comparison of fluorouracil metabolite profiles determined by high-field 19F-NMR spectroscopy of tissues ex vivo with therapy response and toxicity for locoregional vs systemic infusion protocols

A Sprague-Dawley rat model with DS sarcoma transplanted in the thigh was used to compare transcatheter locoregional i.a. and systemic i.v. administration of 5-fluorouracil (FU) at 12 dose-rate schedules: 25, 50 and 100 mg/kg; bolus, 1, 5 and 24 h infusions. In experiment A tumor (62/67 animals) as well as liver and kidney (56/67 animals) were excised 1 h after a single bolus or 1 h infusion or at the end of 5 and 24 h infusions. (19)F-NMR spectroscopy at 11.7 T was used to quantitate FU and its metabolites in ca. 1 g of tissue at 4 degrees C. In experiment B analogous FU treatments were repeated for 5 days (rats 80+11 controls). Tumor volumes vs time, various blood parameters and survival times were recorded, and a log growth rate parameter log GR, a response index RI, and a toxicity index TI were calculated. The i.a. vs i.v. ratios for tumor concentrations of FU and total anabolites (F-Nucl) were >1 for nearly all treatments and increased with infusion time at the higher doses. F-Nucl in tumor correlated linearly with total fluorine concentration (Tot. F range 30-1100 nmol/g) over all treatments (r=0.92, slope=0.45, p<0.0001). For non-bolus i.v. treatments [FU+F-Nucl] decreased linearly with decreasing FU dose rate (r(2)=0.74, zero intercept), while i.a. treatments showed non-linear behavior. For non-bolus treatments the mean log GR per treatment group showed a negative correlation (r=-0.87) with log[F-Nucl]. The most effective non-toxic treatments were 25 mg/kg over 5 or 24 h; the i.a. route was superior to i.v. on the basis of [FU+F-Nucl], RI, the reduction in log GR, and Kaplan-Meier survival statistics. For liver and kidney Tot. F (>83% FU catabolites) reached ca. 3-4 and 6-7 micromol/g, respectively, at the highest dose rates for either route; F-Nucl were detected only for Tot. F>500 nmol/g and increased exponentially as Tot. F increased (toxic treatments). The concentrations of the main catabolite (alpha-fluoro-beta-alanine, FBAL) in tumor did not correlate with Tot. F but rather with FBAL levels in kidney (r=0.90, all treatments), indicating that uptake of liver-derived FBAL from the circulation is the major source of FBAL in tumor.     

Treatment advances for CMV retinitis

For many years the clinician's arsenal for managing cytomegalovirus (CMV) retinitis included only systematic therapies that required daily infusions via a central venous catheter. The introduction of cidofovir has permitted biweekly maintenance therapy by peripheral IV. Local therapies, such as the ganciclovir intraocular device and intravitreal injections of cidofovir, fomavirsen, or ganciclovir, have reduced toxicity while increasing absorption of drug in the eye. At the same time, due to highly active antiretroviral therapy (HAART), the incidence of CMV retinitis is dropping. Current investigation into the natural history of CMV retinitis in the era of HAART may ultimately result in new management strategies.     

British Association of Urological Surgeons (BAUS) consensus document: management of bladder and ureteric injury

Injuries to the bladder and ureter are uncommon but usually require prompt urological management. Due to their infrequent nature, Urologists maybe unfamiliar with managing these acute problems and may not work in specialist centres with readily available expertise in open and abdominal surgery. We aim to provide advice in the form of a consensus statement led by the Female, Neurological and Urodynamic Urology (FNUU) Section of the British Association of Urological Surgeons (BAUS), in consultation with BAUS members and consultants working in units throughout the UK, to create a comprehensive management pathway and a series of statements to aid clinicians.     

Toll- like receptor 2 polymorphism and IL-6 profile in relation to disease progression in chronic HBV infection: a case control study in Egyptian patients

Chronic hepatitis B (CHB) has a wide range of outcomes depending on host immune responses mainly Toll-like receptors (TLRs) signaling and released cytokines. Toll-like receptor 2 (TLR2) single nucleotide polymorphisms (SNPs) and interleukin 6 (IL-6) may influence the course of CHB. We aimed to elucidate the relation between TLR-2 polymorphism, IL-6 profile, and CHB progression. We analyzed TLR-2 polymorphism (SNP; rs3804099) in 185 CHB patients and 60 controls using TaqMan allelic discrimination assay. Serum IL-6 levels were assessed by ELISA. IL-6 levels were considerably higher in active CHB and cirrhotic patients compared with inactive carriers and controls (P < 0.001). IL-6 showed positive correlation with ALT and advanced fibrosis in active CHB patients (r = 0.31, P = 0.02). A significant positive correlation was noticed between IL-6 and HBV DNA PCR in all CHB groups. TT genotype of rs3804099/TLR-2 was significantly more prevalent in inactive carriers compared to active hepatitis patients (P = 0.04, OR = 0.39 and 95% CI: 0.16–0.95). Both heterozygous CT and mutant TT genotypes were significantly more frequent among inactive carriers compared to cirrhotic patients (P = 0.01, OR = 0.33, 95% CI: 0.13–0.81 and P = 0.009, OR = 0.32, 95% CI: 0.13–0.77). TT genotype was significantly related to lower IL-6 levels in active hepatitis and cirrhotic groups (P = 0.005 and P = 0.001, respectively) showing that TLR mutations would be associated with milder hepatitis activity and lower possibility for disease progression. There may be a positive association between TLR2 rs3804099 polymorphism and hepatitis B activity. IL-6 is a good indicator of CHB disease progression.

     

The nasal: paranasal block technique. Preparation and uses.

A new technique for removing nasal: paranasal blocks at autopsy is described. The technique allows the removal of these cavities without disfigurement of the head after the brain has been removed. The importance of the technique in relation to training on endo-nasal micro-surgery, and histopathological study of nasal and paranasal disorders is emphasized.     

Intrafamilial phenotypic variability of Hallervorden-Spätz syndrome in a Tunisian family

We report clinical features, CT-scan and MRI findings of three siblings with Hallervorden-Sp?tz disease, one of them followed for more than 20years. Patient 1 presented at age 10 with progressive generalized dystonia. Five years later she had violent dystonic spasms with opisthotonos and marked oro-mandibular involvement. Later, dystonia stabilized and examination showed dysarthria, multiple deformities related to dystonic posturing, retinal degeneration and no cognitive impairment. Cerebral CT-scan showed bilateral pallidal lucencies and T2 cerebral MRI showed the "eye of the tiger" sign.Patient 2 developed delusions and hallucinations at age 18 with acute phases of hetero-aggressivity diagnosed as "schizophrenic" in a psychiatric hospital. At age 20, he developed oromandibular dystonia, severe dysarthria and epilepsy. Cerebral MRI showed the same "eye of the tiger" sign.Patient 3 presented at age 37 with isolated psychiatric features similar to those of patient 2, also diagnosed "schizophrenic" in a psychiatric hospital. Neurological examination showed mild postural tremor of the hands and intermittent cervical dystonia. He was stabilized with neuroleptic treatment.This family shows marked intrafamilial variability of age at onset, symptom at onset (with "schizophrenic" features unusually described and leading to misdiagnosis), clinical presentation (almost entirely dystonic in one patient and almost entirely psychiatric in two others) and course of the disease (slowly progressive in one sibling, rapidly deteriorating in the second and stabilization in the third). Classification and nosology of subtypes of HSD are discussed.