Bladder endometriosis: conservative management

PURPOSE: We evaluate the characteristics of women with bladder endometriosis successfully treated with hormonal therapy. MATERIALS AND METHODS: The records of 14 patients with a mean age of 48.7 years (range 26 to 71) diagnosed with bladder endometriosis on cystoscopic evaluation were reviewed for presenting complaints, findings and response to therapy. RESULTS: The most frequent presenting complaints were urgency (78%), frequency (71%), suprapubic pain (43%), urge incontinence (21%) and dyspareunia (21%). Of the patients 86% did not have a history of recurrent urinary tract infections, 6 (42%) had a history of endometriosis, including 3 who were previously treated with hysterectomy/oophorectomy and 8 (57%) were on some form of therapy for estrogen deficiency. In all patients endometrial implants were identified on cystoscopic examination. In 2 patients the endometrioma correlated to lesions on the serosal surface of the bladder during laparoscopic evaluation. Of the patients 13 were treated either with low dose oral contraceptives, decrease or elimination of the estrogen component of the present regimen or addition of progesterone to therapy, and 12 (92%) reported sustained improvement of symptoms at a mean of 18.6 months (range 8 to 24). CONCLUSIONS: In more than 70% of cases the presenting symptoms of bladder endometriosis are identical to those of interstitial cystitis. Therefore, endometriosis should always be considered in the patient referred for frequency, urgency and pain with no documented infection. Hormonal therapy is reasonable and effective management for bladder endometriosis. This option preserves fertility, making it especially attractive to younger women.     

Dietary intake of conjugated linoleic acids and risk of premenopausal and postmenopausal breast cancer, Western New York Exposures and Breast Cancer Study (WEB Study).

Specific fatty acids may have differential effects on breast cancer etiology. Animal studies have suggested that conjugated linoleic acids (CLA), a group of fatty acids found predominantly in dairy products and the meat of ruminants, have potent anticarcinogenic properties. We examined breast cancer risk and dietary CLA intake among 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases by age, race, and county of residence. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. We examined risk with intake of total CLAs and the 9c,11t-18:2 isomer of CLA (9,11 CLA). Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression, adjusting for age, the residual of fat adjusted for energy, and other breast cancer risk factors. No association was observed between intakes of total CLA or 9,11 CLA and overall risk of premenopausal or postmenopausal breast cancer. We observed little association between CLA intakes and risk of estrogen receptor (ER)-negative or ER-positive tumors, although, compared with premenopausal women in the lowest quartile of 9,11 CLA intake, those in the highest quartile had a marginally significant reduction in risk of having an ER-negative tumor (odds ratio, 0.40; 95% confidence interval, 0.16-1.01). Our findings suggest that, although CLA intake was not related to overall breast cancer risk, there may be associations with tumor biology at least among premenopausal women.     

STK15 polymorphisms and association with risk of invasive ovarian cancer.

STK15 is a putative oncogene that codes for a centrosome-associated, serine/threonine kinase, the normal function of which is to ensure accurate segregation of chromosomes during mitosis. Amplification of STK15 has been reported in ovarian tumors, suggesting a role in ovarian cancer pathology. STK15 is polymorphic with two single nucleotide substitutions (449t/a and 527g/a) in evolutionarily conserved regions causing amino acid changes (F31I and V57I). Two other nucleotide substitutions (287c/g and 1891g/c) of unknown significance are in 5' and 3' untranslated regions (UTR), respectively. To learn more about the involvement of STK15 in ovarian cancer, we genotyped and haplotyped these polymorphisms in three population-based ovarian cancer case-control studies from the United Kingdom, United States, and Denmark with 1,821 combined cases and 2,467 combined controls and calculated risks for developing ovarian cancer. Genotypes of individual polymorphisms in control groups of the United Kingdom, United States, and Denmark conformed to Hardy-Weinberg equilibrium. In combined cases and combined controls, rare allele frequencies were 0.23 and 0.21 for I31, 0.16 and 0.17 for I57, 0.08 and 0.07 for 5' UTR g, and 0.25 and 0.24 for 3' UTR c, respectively. Using FF common homozygotes of F31I as comparator, there was increased ovarian cancer risk to FI heterozygotes (odds ratio, 1.18; 95% confidence interval, 1.01-1.36), II homozygotes (odds ratio, 1.25; 95% confidence interval, 0.89-1.75), and I31 allele carriers (odds ratio, 1.17; 95% confidence interval, 1.02-1.35) in the combined group data. For either V57I, 5' UTR C/G, or 3' UTR G/C, all genotypic ovarian cancer risks were essentially in unity relative to their respective common homozygotes, VV, cc, or gg. Haplotype analysis of combined group data revealed seven haplotypes with frequencies between 0.02 and 0.5, with c-F-V-g the most common. None of the haplotype-specific risks significantly differed from unity relative to c-F-V-g. These results suggest a model of dominant inheritance of ovarian cancer risk by the I31 allele of F31I and that the I31 allele may be a common ovarian cancer susceptibility allele of low penetrance.     

A phase I and pharmacokinetic study of pegylated camptothecin as a 1-hour infusion every 3 weeks in patients with advanced solid malignancies.

PURPOSE: To assess the feasibility of administering camptothecin (CPT), the prototypic topoisomerase I inhibitor, as polyethylene glycol (PEG)-CPT, a macromolecule consisting of CPT conjugated to chemically modified PEG. The study also sought to determine the maximum-tolerated dose (MTD) of PEG-CPT, characterize its pharmacokinetic behavior, and seek preliminary evidence of anticancer activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of PEG-CPT as a 1-hour intravenous (IV) infusion every 3 weeks. A modified continual reassessment method was used for dose-level assignment to determine the MTD, which was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. RESULTS: Thirty-seven patients were treated with 144 courses of PEG-CPT at seven dose levels ranging from 600 to 8,750 mg/m(2). Severe myelosuppression was consistently experienced by heavily pretreated (HP) and minimally pretreated (MP) patients at the highest dose level evaluated, 8,750 mg/m(2), whereas both HP and MP patients tolerated repetitive treatment at 7,000 mg/m(2). Cystitis, nausea, vomiting, and diarrhea were also observed but were rarely severe. A partial response was noted in a patient with platinum- and etoposide-resistant small-cell lung carcinoma, and minor responses were noted in one patient each with adenocarcinoma of unknown primary type and osteosarcoma. The pharmacokinetics of free CPT were dose proportional. Free CPT accumulated slowly in plasma, with maximal plasma concentrations achieved at 23 +/- 12.3 hours; the harmonic mean half-life (t(1/2)) of free CPT was long (t(1/2), 77.46 +/- 36.77 hours). CONCLUSION: Clinically relevant doses of CPT can be delivered by administering PEG-CPT. The recommended dose for phase II studies in both MP and HP patients is 7,000 mg/m(2) as 1-hour IV every 3 weeks. The characteristics of the myelosuppressive effects of PEG-CPT, the paucity of severe nonhematologic toxicities with repetitive treatment, the preliminary antitumor activity noted, and the slow clearance of CPT enabling simulation of desirable pharmacokinetic parameters with a convenient single-dosing regimen warrant further disease-directed evaluations.     

Bronchoalveolar lavage: Comparison of nucleopore filters and direct smear preparations

To determine whether cytopreparation affects the diagnostic yield of bronchoalveolar lavage specimens, we compared 50 lavage samples by using two methods. One nucleopore filter preparation and four direct slides were prepared on each sample submitted. All slides were stained by the Papanicolaou method. Assessment of cellularity, cellular preservation, and an independent diagnosis were rendered on each sample for both preparatory methods. Statistical analysis showed no difference in cellularity between the two methods (P = .06). The degree of nuclear and cytoplasmic preservation was higher using the direct method, although this did not appear to affect diagnosis in this study. One major discrepancy in diagnosis was observed between the two methods. By prospectively comparing nucleopore filter and direct preparation of bronchoalveolar lavages, we found that there was minimal affect on either cellularity or diagnosis. We conclude that either method delivers reliable cytologic results. Diagn. Cytopathol. 17:160–164, 1997. © 1997 Wiley-Liss, Inc.     

Bicarbonate-controlled reduction of oxygen by the QA semiquinone in Photosystem II in membranes

Photosystem II (PSII), the water/plastoquinone photo-oxidoreductase, plays a key energy input role in the biosphere. QA•−, the reduced semiquinone form of the nonexchangeable quinone, is often considered capable of a side reaction with O₂, forming superoxide, but this reaction has not yet been demonstrated experimentally. Here, using chlorophyll fluorescence in plant PSII membranes, we show that O₂ does oxidize QA•− at physiological O₂ concentrations with a t_1/2 of 10 s. Superoxide is formed stoichiometrically, and the reaction kinetics are controlled by the accessibility of O₂ to a binding site near QA•−, with an apparent dissociation constant of 70 ± 20 µM. Unexpectedly, QA•− could only reduce O₂ when bicarbonate was absent from its binding site on the nonheme iron (Fe²⁺) and the addition of bicarbonate or formate blocked the O₂-dependant decay of QA•−. These results, together with molecular dynamics simulations and hybrid quantum mechanics/molecular mechanics calculations, indicate that electron transfer from QA•− to O₂ occurs when the O₂ is bound to the empty bicarbonate site on Fe²⁺. A protective role for bicarbonate in PSII was recently reported, involving long-lived QA•− triggering bicarbonate dissociation from Fe²⁺ [Brinkert et al., Proc. Natl. Acad. Sci. U.S.A. 113, 12144–12149 (2016)]. The present findings extend this mechanism by showing that bicarbonate release allows O₂ to bind to Fe²⁺ and to oxidize QA•−. This could be beneficial by oxidizing QA•− and by producing superoxide, a chemical signal for the overreduced state of the electron transfer chain.

Photosystem II (PSII) is the water/plastoquinone photo-oxidoreductase that uses the energy of red light to drive the oxidation of water and the reduction of plastoquinone (PQ). This process leads to the formation of a radical pair on the chlorophyll P_D1^•+ and pheophytin Pheo_D1^•−. The electron hole is transferred from the chlorophyll cation radical, P_D1^•+, via a redox-active tyrosine (Tyr_Z) to the Mn₄O₅Ca cluster, where, after four sequential photochemical turnovers, two water molecules are oxidized on the luminal side of the membrane. The electron is transferred from the pheophytin anion radical (Pheo_D1^•−) via a nonexchangeable plastoquinone (Q_A), which acts as a one-electron relay, to an exchangeable plastoquinone (Q_B), the terminal electron acceptor (1–3). Q_B accepts two electrons and takes up two protons from the aqueous phase to form Q_BH₂ before it is released as a PQH₂ into the PQ/PQH₂ pool in the membrane (4). From here, the PQH₂ delivers electrons to cytochrome b₆f complex, the subsequent enzyme of the photosynthetic electron transfer chain.As photochemical charge separation is intrinsically a one-photon-per-electron process, two photochemical turnovers are required to form PQH₂, with the one-electron reduced semiquinone, QB•−_, formed as an intermediate. Semiquinones can be very reactive, but QB•− is rendered thermodynamically stable by the environment provided by its binding site on the D1 protein (4). The electron on QB•− is still able to back-react via QA•− with the S₂ and S₃ states, the two semistable intermediates of the water oxidizing enzyme (5). This back-reaction occurs by thermal repopulation of the intermediate radical pairs between S2/3QB•− and PD1•+PheoD1•−. PD1•+PheoD1•− can either repopulate P*, which can decay radiatively (5, 6), or it undergoes direct charge recombination, forming the chlorophyll triplet state, ³P₆₈₀ (7–9). As expected for a long-lived chlorophyll triplet state, it reacts with dioxygen to form a highly reactive singlet oxygen species, ¹O₂, which causes photodamage (10, 11).On the electron acceptor-side of PSII (Fig. 1), the reduced forms of the electron transfer cofactors can potentially reduce oxygen, forming superoxide radical (O2•−) by a one-electron transfer to O₂. This would be a wasteful leak of electrons, and the O2•− formed could be damaging and act as redox signal within the cell. During forward electron transfer, QA•− has a half-time of ∼1 ms (1) and is unlikely to react with O₂. However, when, for example, Q_B and the PQ pool are reduced, QA•− is longer lived, and it is then more likely to reduce oxygen. Oxygen reduction by QA•− is often discussed in the literature (12–16), but clear experimental evidence for this reaction has not been reported. Here, using PSII membranes, we have directly tested for electron transfer from QA− to O₂ and for formation of superoxide. We show the reaction does occur, and we characterized the reaction in terms of the O₂ binding site using biochemical and computational approaches. The results indicate the reaction constitutes an unexpected regulatory mechanism involving bicarbonate.Open in a separate windowFig. 1.The quinone-iron complex in PSII. The nonheme iron shown as a red sphere and the bicarbonate in pink. The amino acid side chains involved in the hydrogen-bonding network are shown, green if belonging to D1 and cyan if belonging to D2. Data from the 1.9-Å crystal structure (PDB ID: 3WU2) (41).     

B cell receptor isotypes differentially associate with cell signaling,kinetics, and outcome in chronic lymphocytic leukemia

In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events. Since both IgM and IgD carry the same antigen-binding domains, the divergent actions of the receptors are attributed to differences in immunoglobulin (Ig) structure or the outcome of signal transduction. We showed that IgM, not IgD, level and organization associated with CLL-cell birth rate and the type and consequences of BCR signaling in humans and mice. The latter IgM-driven effects were abrogated when BCR signaling was inhibited. Collectively, these studies demonstrated a critical, selective role for IgM in BCR signaling and B cell fate decisions, possibly opening new avenues for CLL therapy.     

Older Americans Act: implications for nursing.

The Older Americans Act is the most comprehensive legislation concerning the aged and provides programs, services, and administration of elderly services nationwide. It is important that nurses understand the role this act plays in the health and well-being of elders as we deal with the everchanging health care delivery and payment system.