Endometriosis: current and future medical therapies

Endometriosis is a chronic inflammatory disease that responds to steroidal manipulation. Creation of a steady hormonal environment with inhibition of ovulation temporarily suppresses the ectopic implants and reduces the inflammatory status as well as the associated pain symptoms. Pharmacological management of endometriosis must be set within the framework of long-term therapeutic strategies. As the available drugs are not curative, treatments will need to be administered for years or until women desire a pregnancy. The various therapies studied have shown similar efficacy. Consequently, based on a more favourable profile in terms of safety, tolerability and cost, combined oral contraceptives and progestins should be considered as the first-line option, both as an alternative to surgery and as a postoperative adjuvant measure. Gonadotrophin-releasing hormone analogues, danazol and gestrinone should be used when progestins and oral contraceptives fail, are not tolerated or are contra-indicated. Future therapies for endometriosis must compare favourably with existing drugs before hypothesizing their implementation in current practice. Medical treatment is not indicated in women seeking conception because reproductive prognosis is not ameliorated.     

Mutation spectra analysis suggests that N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea-induced lesions are subject to transcription-coupled repair in Escherichia coli

To determine the influence of some bacterial DNA report pathways on the mutagenic and the lethal effects of N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea (CCNU), pZ189 plasmids treated in vitro with 2 mM CCNU were transfected into Escherichia coli strains with different repair capacities (uvr⁺ada⁺ogt⁺, uvr⁻ada⁺ogt⁺, and uvr⁻ada⁻ogt⁻). Despite the differences in repair capacities, no statistically significant difference in survival and mutability was observed among the tested strains. One hundred and sixty-six CCNU-induced supF mutants were isolated and sequenced. All mutants were characterized by single base-pair substitutions, most of which (more than 96%) were GC→AT transitions (the mutated G being almost exclusively preceded 5′ by a purine). Mutation distribution was not random. Position 160 (5′-GGT-3′, nontranscribed (NT) strand) was a uvr⁺ada⁺ogt⁺-specific hot-spot. Position 123 (5′-GGG-3′, NT strand) was a common hot-spot but significantly more mutable in repair-proficient strains than in repair-deficient strains. Conversely, position 168 (5′-GGA-3′, transcribed (T) strand) was significantly more mutable in repair-deficient strains than in repair-proficient strains. By applying a computer program for comparison of mutational spectra, we found that the uvr⁺ mutational spectrum was significantly different from those obtained in uvr⁻ strains, whereas in the uvr⁻ background, no difference was observed between mutation spectra in ada⁺ogt⁺ versus ada⁻ogt⁻ strains. Our results are consistent with the hypothesis that O⁶-alkylguanine is responsible for most mutations observed in all strains. The results also indicate that excision repair modulates the distribution of GC→AT transitions. The fact that mutations at G lesions on the T strand were significantly less frequent in uvr⁺ than in uvr⁻ strains suggests that CCNU-induced premutational lesions are susceptible to strand-preferential repair in E. coli. Mol. Carcinog. 19:39–45, 1997. © 1997 Wiley-Liss, Inc.     

Bacterial toxins and enteral feeding of premature infants at risk for necrotizing enterocolitis

Bacterial translocation and enteral feeding are factors implicated in neonatal necrotizing enterocolitis (NEC) in the preterm infant. A cohort of 60 preterm low birth-weight (LBW) infants (600–1,600 g at birth) consecutively admitted to the neonatal intensive care unit (NICU; N = 183) were prospectively followed to evaluate the role of bacterial endotoxins (lipopolysaccharides) and enteral feeding in the development of NEC. Stage I NEC was identified in 14/60 (23%) infants. In all, 15% (9/60) of infants followed, which represented roughly 5% of higher risk, LBW infants admitted to the NICU, progressed to Stage II or III NEC disease. Infants not enterally fed (nothing by mouth [NPO]) were at greatest risk of developing NEC. No infant who was breast milk fed progressed to Stage II or III NEC. The protective effect of breast milk was most evident when compared with the combined group of NPO or formula-feeding infants per person-week at risk (RR = .15, P < .04). Toxin-producing bacteria and endotoxin levels in stool filtrates predicted early and advanced stages of NEC disease. Cytokine concentrations (interleukin-6 [IL-6]) in stool appeared of limited value in reflecting mucosally limited disease in the gastrointestinal tract. Overgrowth of toxin-producing bacteria and their toxin products may adversely affect gut barrier function; monitoring endotoxin concentrations in stool filtrates may be most clinically useful in NPO and formula-fed infants identified at risk of developing NEC. Am. J. Hum. Biol. 10:211–219, 1998. © 1998 Wiley-Liss, Inc.     

New perspectives on techniques for the clinical psychiatrist: Brain stimulation,chronobiology and psychiatric brain imaging

This review summarizes a scientific dialogue between representatives in non‐pharmacological treatment options of affective disorders. Among the recently introduced somatic treatments for depression those with most evidenced efficacy will be discussed. The first part of this article presents current opinions about the clinical applications of transcranial magnetic stimulation in the treatment of depression. The second part explains the most relevant uses of chronobiology in mood disorders, while the last part deals with the main perspectives on brain imaging techniques in psychiatry. The aim was to bridge gaps between the research evidence and clinical decisions, and reach an agreement on several key points of chronobiological and brain stimulation techniques, as well as on relevant objectives for future research.     

Short‐ and intermediate‐term efficacy of buprenorphine TDS in chronic painful neuropathies

Abstract Buprenorphine is a potent opioid available as a transdermal delivery system (TDS) formulation. This open‐label study investigated its safety, tolerability, and efficacy in 30 patients with chronic painful neuropathy. Subjects with visual analogue scale (VAS) score ≥5 under stable analgesic treatment were entered. The starting dosage of 35 μg/h was increased up to 70.0 μg/h in case of unsatisfactory pain control as assessed by fortnightly visits. The primary endpoint was the number of patients achieving at least 30% pain relief at day 42 visit. Treatment was safe over the study period. Nine patients dropped out for side effects, mostly nausea and daily sleepiness. Buprenorphine TDS was well tolerated in 21 patients. Thirteen patients achieved >30% of pain relief at day 42 visit. Five patients needed to increase the dosage to 52.5 μg/h. Eight patients did not meet the primary outcome, but none allowed increasing the dosage to 70 μg/h, and four patients withdrew consent to continue the study before day 42 visit because of a ‘fear to become addicted,’ although 40% had obtained VAS reduction. In our study, which needs to be confirmed by a controlled trial, buprenorphine TDS induced clinically meaningful pain relief in about 40% of patients with chronic painful neuropathy, suggesting its use as a third‐line treatment.