Impact of different glycaemic treatment targets on pregnancy outcomes in gestational diabetes.

AIM: With no current randomized trials, we explored the impact of tight compared with standard treatment targets on pregnancy outcomes in gestational diabetes mellitus (GDM). METHODS: This cohort study of singleton births ≥ 28 weeks' gestation was conducted at two major Australian maternity services (2009-2013). Standardized maternal, neonatal and birth outcomes were examined using routine healthcare data and compared for women with GDM at Service One (n = 2885) and Service Two (n = 1887). Services applied different treatment targets: Service One (standard targets, reference group) fasting < 5.5 mmol/l, 2-h postprandial < 7.0 mmol/l; Service Two (tight targets) fasting < 5.0 mmol/l, 2-h postprandial < 6.7 mmol/l. Multivariable regression with propensity score adjustment was used to examine associations between targets and outcomes. RESULTS: GDM prevalence and insulin use were 7.9% and 31% at Service One, and 5.7% and 46% at Service Two. There were no differences in primary outcomes: birthweight > 90th centile [adjusted odds ratio (OR) 1.06, 95% confidence interval (CI) 0.87-1.30] and < 10th centile (OR 0.84, 95% CI 0.70-1.01), or secondary outcomes gestational hypertension, pre-eclampsia, shoulder dystocia or a perinatal composite. Service Two with tight targets had increased induction of labour (OR 3.63, 95% CI 3.17-4.16), elective Caesarean section (OR 1.75, 95% CI 1.37-2.23) and Apgar scores < 7 at 5 min (OR 1.54, 95% CI 1.05-2.25), decreased hypoglycaemia (OR 0.76, 95% CI 0.61-0.94]), jaundice (OR 0.47, 95% CI 0.35-0.63) and respiratory distress (OR 0.68, 95% CI 0.47-0.98). CONCLUSIONS: Tight GDM treatment targets were associated with greater insulin use and no difference in primary birthweight outcomes. The service with tight targets had higher obstetric intervention, lower rates of reported hypoglycaemia, jaundice, respiratory distress and lower Apgar scores. High-quality interventional data are required before tight treatment targets can be implemented.

Transducing properties of a pre-structured α-helical DPT-peptide containing a short canine adenovirus type 2 E4orf4 PP2A1-binding sequence.

BACKGROUND: Induction of the death pathway resulting from the specific interaction of the PP2A1 phosphatase with adenoviral E4orf4 protein is a promising approach for cancer therapy. With the aim of deregulating tumor pathways, and mimicking E4orf4 anti-cancer signal, we have previously proposed the DPT technology concept, based on design of specific PP1/PP2A interacting penetrating peptides. METHODS: Using biochemical, structural and cell survival experiments, we have characterized new DPT-peptides containing short PP2A binding sequences. RESULTS: We identified overlapping sequences, located within the N-terminal domain E4orf423-46 of canine adenoviral E4orf4 protein, that interact with the PP2A-Bα subunit of PP2A1 holoenzyme. We characterized DPT-E4orf44 and TAT-E4orf44, two bi-partite cell penetrating peptides containing the 12 PP2A1 binding residues of the canine type 2 E4orf427-38 sequence, respectively fused to the DPT-sh1 and TAT shuttle sequences. Surprisingly DPT-E4orf44, in contrast to inactive TAT-E4orf44, adopted a well defined α-helical structure and co-precipitated PP2A1 from HeLa cell extracts. DPT-E4orf44 also internalized streptavidin-HRP and inhibited survival of HeLa cells more efficiently than TAT, TAT-E4orf44 or the previously published anti-tumor TAT-derived peptide shepherdin. DPT-E4orf44 also efficiently inhibited the survival of human adherent transformed cells, including wild type and p53 mutated colonic HCT116 cells, without affecting survival of human non-transformed fibroblasts. CONCLUSIONS: We characterized the transducing properties of a new α-helical DPT-E4orf44 peptide containing a short PP2A-interacting sequence from canine Adenoviral E4orf4 protein. GENERAL SIGNIFICANCE: Our results suggest that α-helical structured DPT peptides specifically interacting with PP2A could be a valuable anti-cancer drug design scaffold.

The feasibility and impact of implementing a computer-guided consultation to target health inequality in Asthma.

Greater Manchester has a greater prevalence and worse asthma outcomes than the national average. This study aims to evaluate a digital approach to primary care asthma management and in particular the initial impact of implementing Clinical Decision Support System software in the form of a computer-guided consultation (CGC) in the setting of primary care asthma reviews in deprived areas of Greater Manchester. The CGC (LungHealth Ltd) is an intelligent decision support system ensuring accurate guideline-based staging of asthma and assessment of asthma control with the software subsequently prompting guideline-standard management. Patients on asthma registers in Greater Manchester Primary Care Networks were identified and underwent remote review by nursing staff using the CGC linked directly to the GP clinical system. Three-hundred thirty-eight patients (mean age 59 (SD 17) years; 60% Female) were reviewed. The CGC reported the patient's asthma control to be "Good" in 22%, "Partial" in 6% and "Poor" in 72%. ACT scores were significantly higher in those patients exhibiting "Good" and "Partial" control when compared to those with "Poor" control. The number of steroid courses and hospital admissions in the previous 12 months was significantly lower in those patients exhibiting "Good" and "Partial" control when compared to those with "Poor" control. Nineteen percent were found not to have a personalised asthma management plan during CGC review, which was alerted by the CGC and subsequently, all but 3 patients had this created on review completion (McNemar's test; p < 0.001). 5% were found not to have been prescribed regular inhaled steroid therapy resulting in the operator being alerted by the CGC in all cases. Overall, 44% underwent alteration in asthma therapy following the CGC review with 82% of these representing treatment escalation. An end-to-end digital service solution is feasible for Asthma within primary care and the utilisation of a CGC when conducting primary care asthma reviews increases implementation of guideline-level management thus addressing healthcare inequality while enabling identification of "high risk" asthma patients and guiding appropriate therapy escalation and de-escalation.

New insight into flavivirus maturation from structure/function studies of the yellow fever virus envelope protein complex.

IMPORTANCE: All enveloped viruses enter cells by fusing their envelope with a target cell membrane while avoiding premature fusion with membranes of the producer cell-the latter being particularly important for viruses that bud at internal membranes. Flaviviruses bud in the endoplasmic reticulum, are transported through the TGN to reach the external milieu, and enter other cells via receptor-mediated endocytosis. The trigger for membrane fusion is the acidic environment of early endosomes, which has a similar pH to the TGN of the producer cell. The viral particles therefore become activated to react to mildly acidic pH only after their release into the neutral pH extracellular environment. Our study shows that for yellow fever virus (YFV), the mechanism of activation involves actively knocking out the fusion brake (protein pr) through a localized conformational change of the envelope protein upon exposure to the neutral pH external environment. Our study has important implications for understanding the molecular mechanism of flavivirus fusion activation in general and points to an alternative way of interfering with this process as an antiviral treatment.

Flash decaging of tyrosine sidechains in an ion channel.

A nonsense codon suppression technique was employed to incorporate ortho-nitrobenzyl tyrosine, "caged tyrosine," in place of tyrosine at any of three positions (93, 127, or 198) in the alpha subunit of the muscle nicotinic ACh receptor (nAChR) expressed in Xenopus oocytes. The ortho-nitrobenzyl group was then removed by 1 ms flashes at 300-350 nm to yield tyrosine itself while macroscopic currents were recorded during steady ACh exposure. Responses to multiple flashes showed (1) that each flash decages up to 17% of the tyrosines and (2) that two tyrosines must be decaged per receptor for a response. The conductance relaxations showed multiple kinetic components; rate constants (<0.1 s(-1) to 10(3) s(-1)) depended on pH and the site of incorporation, and relative amplitudes depended on the number of prior flashes. This method, which is potentially quite general, (1) provides a time-resolved assay for the behavior of a protein when a mutant sidechain is abruptly changed to the wild-type residue and (2) will also allow for selective decaging of sidechains that are candidates for covalent modification (such as phosphorylation) in specific proteins in intact cells.

Some insights about 1,6-diphenyl-1,3,5-hexatriene-lipid supramolecular assemblies by steady-state fluorescence measurements.

1,6-Diphenyl-1,3,5-hexatriene (DPH) is the most widely proposed molecular probe for the post-column fluorescence derivatization of lipids after liquid chromatography separation. This kind of detection consists of a supramolecular combination of DPH and eluted lipids. The detection is optimally performed in a mainly aqueous environment (over 80% v/v) because the weak fluorescence of DPH in water is drastically enhanced upon formation of supramolecular assemblies with lipids. In the present study, and in order to obtain better spectroscopic insights into the nature of these supramolecular assemblies, two different lipids were tested, 1,2,3-tridodecanoylglycerol (LLL) as a model triglyceride (nonpolar lipid) and dimyristoylphosphatidylcholine (DMPC) as a model phosphatidylcholine (charged amphiphilic lipid). Stoichiometry and association constants were determined on the basis of the variation of fluorescence intensity in the presence of various concentrations of lipids. LLL(60)-DPH(2) and DMPC(200)-DPH(2) complexes were identified with association constants as high as K(2) = (5.8 +/- 0.5) x 10(13) M(-2) and (17.3 +/- 2.0) x 10(13) M(-2) for LLL and DMPC, respectively. The fluorescence intensity of DPH in the presence of LLL is greater than in the presence of DMPC. An attempt to characterize the insertion mode of DPH in the lipidic supramolecular assemblies is also made.

A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion.

The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

Proteomic identification of M. tuberculosis protein kinase substrates: PknB recruits GarA, a FHA domain-containing protein, through activation loop-mediated interactions.

Genes for functional Ser/Thr protein kinases (STPKs) are ubiquitous in prokaryotic genomes, but little is known about their physiological substrates and their actual involvement in bacterial signal transduction pathways. We report here the identification of GarA (Rv1827), a Forkhead-associated (FHA) domain-containing protein, as a putative physiological substrate of PknB, an essential Ser/Thr protein kinase from Mycobacterium tuberculosis. Using a global proteomic approach, GarA was found to be the best detectable substrate of the PknB catalytic domain in non-denatured whole-cell protein extracts from M. tuberculosis and the saprophyte Mycobacterium smegmatis. Enzymological and binding studies of the recombinant proteins demonstrate that docking interactions between the activation loop of PknB and the C-terminal FHA domain of GarA are required to enable efficient phosphorylation at a single N-terminal threonine residue, Thr22, of the substrate. The predicted amino acid sequence of the garA gene, including both the N-terminal phosphorylation motif and the FHA domain, is strongly conserved in mycobacteria and other related actinomycetes, suggesting a functional role of GarA in putative STPK-mediated signal transduction pathways. The ensuing model of PknB-GarA interactions suggests a substrate recruitment mechanism that might apply to other mycobacterial kinases bearing multiple phosphorylation sites in their activation loops.

Assessment of population structure by single nucleotide polymorphisms (SNPs) in goat breeds.

Single nucleotide polymorphisms (SNPs) may be used in biodiversity studies and commercial tasks like traceability, paternity testing and selection for suitable genotypes. Twenty-seven SNPs were characterized and genotyped on 250 individuals belonging to eight Italian goat breeds. Multilocus genotype data were used to infer population structure and assign individuals to populations. To estimate the number of groups (K) to test in population structure analysis we used likelihood values and variance of the bootstrap samples, deriving optimal K from a drop in the likelihood and a rise in the variance plots against K.

Sudden unexplained infant death in 20 regions in Europe: case control study.

BACKGROUND: After striking changes in rates of sudden unexplained infant death (SIDS) around 1990, four large case-control studies were set up to re-examine the epidemiology of this syndrome. The European Concerted Action on SIDS (ECAS) investigation was planned to bring together data from these and new studies to give an overview of risk factors for the syndrome in Europe. METHODS: We undertook case-control studies in 20 regions. Data for more than 60 variables were extracted from anonymised records of 745 SIDS cases and 2411 live controls. Logistic regression was used to calculate odds ratios (ORs) for every factor in isolation, and to construct multivariate models. FINDINGS: Principal risk factors were largely independent. Multivariately significant ORs showed little evidence of intercentre heterogeneity apart from four outliers, which were eliminated. Highly significant risks were associated with prone sleeping (OR 13.1 [95% CI 8.51-20.2]) and with turning from the side to the prone position (45.4 [23.4-87.9]). About 48% of cases were attributable to sleeping in the side or prone position. If the mother smoked, significant risks were associated with bed-sharing, especially during the first weeks of life (at 2 weeks 27.0 [13.3-54.9]). This OR was partly attributable to mother's consumption of alcohol. Mother's alcohol consumption was significant only when baby bed-shared all night (OR increased by 1.66 [1.16-2.38] per drink). For mothers who did not smoke during pregnancy, OR for bed-sharing was very small (at 2 weeks 2.4 [1.2-4.6]) and only significant during the first 8 weeks of life. About 16% of cases were attributable to bed-sharing and roughly 36% to the baby sleeping in a separate room. INTERPRETATION: Avoidable risk factors such as those associated with inappropriate infants' sleeping position, type of bedding used, and sleeping arrangements strongly suggest a basis for further substantial reductions in SIDS incidence rates.

Microsatellite and chromosome evolution of parthenogenetic sitobion aphids in Australia.

Single-locus microsatellite variation correlated perfectly with chromosome number in Sitobion miscanthi aphids. The microsatellites were highly heterozygous, with up to 10 alleles per locus in this species. Despite this considerable allelic variation, only seven different S. miscanthi genotypes were discovered in 555 individuals collected from a wide range of locations, hosts and sampling periods. Relatedness between genotypes suggests only two successful colonizations of Australia. There was no evidence for genetic recombination in 555 S. miscanthi so the occurrence of recent sexual reproduction must be near zero. Thus diversification is by mutation and chromosomal rearrangement alone. Since the aphids showed no sexual recombination, microsatellites can mutate without meiosis. Five of seven microsatellite differences were a single repeat unit, and one larger jump is likely. The minimum numbers of changes between karyotypes corresponded roughly one-to-one with microsatellite allele changes, which suggests very rapid chromosomal evolution. A chromosomal fission occurred in a cultured line, and a previously unknown chromosomal race was detected. All 121 diverse S. near fragariae were heterozygous but revealed only one genotype. This species too must have a low rate of sexual reproduction and few colonizations of Australia.

Evidence for a phosphorylation-induced conformational change in phospholamban from the effects of three proteases.

The effect of the proteases trypsin, thermolysin and papain on the cardiac membrane protein phospholamban was examined before or after phosphorylating the protein with the catalytic subunit of cyclic AMP-dependent protein kinase. The sensitivity of phospholamban to digestion by trypsin and thermolysin was greatly reduced by phosphorylation, suggesting that phospholamban undergoes a conformational change upon phosphorylation. It is suggested that this change in conformation is the mechanism by which phospholamban phosphorylation relieves its inhibition of the sarcoplasmic reticulum Ca2+-ATPase pump.

Sarcolemmal phospholamban is phosphorylated in isolated rat hearts perfused with isoprenaline.

Phosphorylation of phospholamban in cardiac sarcolemma is implicated in the increased influx of Ca2+ through the slow calcium channel induced by catecholamines. A method is described for the preparation of highly purified sarcolemmal vesicles from rat heart, and this has been used to examine the phosphorylation of phospholamban in 32Pi-perfused rat hearts. Phospholamban phosphorylation is increased 3-fold after 30 s of perfusion with 0.1 microM isoprenaline. The time course of this increase precedes the inotropic response by 5-10 s.

The oxidation of naphthalene and pyrene by cytochrome P450cam.

Mutants of the heme monooxygenase cytochrome P450cam in which Y96 had been replaced with hydrophobic residues, have been shown to oxidise naphthalene and pyrene with rates one to two orders of magnitude faster than the wild-type. Naphthalene was oxidised to 1- and 2-naphthol, probably via the 1,2-oxide intermediate. In the case of the Y96F mutant, naphthalene was oxidised at a rate comparable to camphor. Pyrene oxidation gave 1,6- and 1,8-pyrenequinone with no evidence for attack at the K-region, in contrast to mammalian enzymes. The results show that the Y96 residue plays a key role in controlling the substrate range of P450cam.

Synthesis and binding affinities of cyclic and related linear analogues of CCK8 selective for central receptors.

To investigate the role of the sulfate group and the influence of cyclization on the biological properties of conformationally constrained CCK8 analogues, three series of compounds were synthesized: Boc-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (1), Boc-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (2), and Boc-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (3) (series A); Boc-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (4), Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (5), Boc-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (6), and Boc-D-Glu-Tyr(SO3H)-Nle-D-Nle-Trp-Asp-Phe-NH2 (7) (series B); and Boc-gamma-D-Glu-Tyr-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (8), Boc-gamma-D-Glu-Tyr(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (9), and Boc-gamma-D-Glu-Tyr-(SO3H)-Nle-D-Lys-Trp-Nle-Asp-Phe-NH2 (10) (series C). The selectivity of these peptides was studied by measuring their ability to displace [3H]propionyl-CCK8 from guinea pig brain and pancreatic membranes. All the peptides displayed low affinities (KI values around 10(-6) M) for the pancreatic receptors (A type). In contrast, both sulfated and nonsulfated cyclic analogues displayed high affinities for central-type binding sites (B type), especially compounds belonging to series C [KI(8) = 4.7 nM and KI(9) = 0.56 nM]. In all series the linear analogues had relatively poor affinities (KI approximately 300 nM) for B-type receptors. Compound 9 was the most potent (KI = 0.56 nM) and selective [KI(pancreas)/KI(brain) = 4464] for central-type CCK receptors of guinea pig. The cyclization of the N-terminal region of CCK8 permits one therefore to obtain probes for central receptors, and small changes directed toward the cyclic part modulate the affinity for these receptors.

The effects of reported Ca2+ sensitisers on the rates of Ca2+ release from cardiac troponin C and the troponin-tropomyosin complex.

1. The calcium sensitivity of force production of cardiac muscle fibres is altered by certain drugs. The sites of action of three such compounds (pimobendan, sulmazole, isomazole) within the myofibril have been investigated. Calmodulin antagonists, perhexilene and bepridil, which have been shown to alter the calcium dependence of myofibrillar ATPase activity and oxmetidine, an H2-receptor antagonist which binds to calmodulin, were also studied. 2. The rates of dissociation of calcium from both the regulatory and high affinity sites on bovine isolated cardiac troponin C (cTnC) were measured in a stopped-flow fluorimeter. The rates of dissociation were found to be 136.5 +/- 16 s-1 and 1.3 +/- 0.20 s-1 (mean +/- s.e.mean, n = 11 determinations; conditions: 100 mM KCl, 10 mM MOPS, 3 mM MgCl2, 0.1 mM dithriothreitol, pH 7.0, 15 degrees C). Sulmazole, isomazole and perhexiline (final concentration of 50 microM) had no effect on the rate of Ca2+ dissociation from the regulatory Ca2+ site, indicating that these compounds do not act on cTnC directly. 3. The rate of dissociation of Ca2+ from the regulatory site was slightly reduced (approximately 20%) by pimobendan (50 and 100 microM) and was somewhat increased by oxmetidine (28% at 100 microM). 4. Bepridil (25 microM) reduced the rate of dissociation by 50%, indicating a direct effect of bepridil on TnC. 5. Sulmazole, isomazole, perhexiline, pimobendan (50 microM) and bepridil (25 microM) were without effect on the rate of dissociation of Ca2+ from the high affinity Ca2+/Mg2+ sites. Oxmetidine caused 24% decrease in the rate of Ca2+ dissociation from these sites. 6. The rate of dissociation of Ca2+ from the regulatory site on the complex of troponin-tropomyosin (TnTm) was measured. Sulmazole and pimobendan (50 microM) were without effect on the rate of dissociation of Ca2+ from the regulatory site in the protein complex, and isomazole (50 microM) caused only a slight reduction (23%). Perhexiline (50 microM) or bepridil (10 microM) reduced the rate of Ca2 dissociation by about 50%. The rate of dissociation of Ca2+ from the high affinity Ca2 +/Mg2 + sites was not altered by sulmazole, isomazole, or pimobendan (50 microM), but was decreased - 35% by perhexiline (50 microM) or bepridil (10 microM).

The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function.

1. The effects of siguazodan (SK&F 94836) a selective phosphodiesterase (PDE) inhibitor with inotropic and vasodilator activity, were studied on human platelets. 2. Siguazodan selectively inhibited the major cyclic AMP-hydrolysing PDE in human platelet supernatants. The inhibited enzyme has been variously termed cyclic GMP-inhibited PDE or PDE-III. 3. In platelet-rich plasma (PRP), siguazodan inhibited U46619-induced aggregation more potently than that induced by ADP and collagen. Treatment of the PRP with aspirin had no effect on the potency of siguazodan. 4. In washed platelets, siguazodan increased cyclic AMP levels and reduced cytoplasmic free calcium [( Ca2+]i). ADP decreased the ability of siguazodan to raise cyclic AMP and this may explain its lower potency in inhibiting responses to ADP. 5. Siguazodan has anti-platelet actions over the same concentration range that it is an inotrope and vasodilator.

Direct PCR sequencing of dystrophin polymorphic CACA alleles after purification to remove shadow bands.

A method is described that allows the sequencing of polymerase chain reaction (PCR) products containing CACA repeats. The method was tested using a DNA polymorphism that exists at the 3' end of the dystrophin gene. This polymorphism consists of a variation in the length of a CACA dinucleotide repeat. Four alleles from a total of 16 individuals were sequenced at this locus after the DNA sequence had been amplified by the PCR. Five examples of each of the common alleles were sequenced. For each allele all five sequences were the same. The only example of a rare allele was also sequenced. The PCR products of DNA sequences containing dinucleotide repeats consist of a number of bands differing by 2 bp below the most intense main band. Previously, direct sequencing of the PCR products lead to ambiguities and smearing at and above the CACA repeat. In this paper, the main PCR band was cut out of a sequencing gel and directly sequenced to give a clear DNA sequence. Our results indicate that for a particular allele, all individuals had exactly the same DNA sequence. This implies that with the appropriate choice of oligonucleotide primers, polymorphisms could be detected without electrophoresis.

Antibiotic prophylaxis for patients undergoing transurethral resection of the prostate.

OBJECTIVES: To evaluate the prevention of urinary tract infections (UTIs) after transurethral resection of the prostate (TURP) in a prospective randomized study using a quinolone antibiotic (fleroxacin) to compare the efficacy of: (1) a single oral dose, (2) a single intravenous (IV) dose, and (3) an extended regimen consisting of an initial IV dose followed by oral therapy until removal of the urinary catheter, but for less than 6 days. METHODS: We excluded from study patients who received antimicrobial agents within 48 hours of surgery. Single-dose prophylaxis consisted of 400 mg of fleroxacin given either orally or intravenously. The extended regimen consisted of an initial 400 mg IV dose followed by 400 mg oral each day (patients older than 75 years, or with a creatinine clearance less than 40 mL/min, received 200 mg/day). UTI was defined as clinical evidence of infection plus the presence of more than 10 white blood cells (WBC)/mm3 in any urine specimen plus the presence of more than 10(4) cfu/mL in midstream urine specimens or more than 10(2) cfu/mL in catheter specimens. RESULTS: Prior to TURP, 30% (25/84) of the patients had a urethral catheter in situ and 12% (3/25) of these patients had bacteriuria. Only 1 patient developed a UTI and that was 22 days after a TURP (intergroup comparisons, Fisher's exact test greater than 0.05). There were no instances of urosepsis. CONCLUSIONS: A single oral dose of a fluoroquinolone agent provided optimum prophylaxis for patients undergoing TURP.

Management of vaginal intraepithelial neoplasia: A series of 132 cases with long-term follow-up.

A series of 132 cases of vaginal intraepithelial neoplasia (VAIN) is presented, including nine (6.8%) where early invasive carcinoma of the vagina was found in the course of initial management of the VAIN. The majority of patients (75%) had high-grade VAIN (two or three). Seventy-two (55%) had undergone a prior hysterectomy; 22 for preinvasive disease (CIN), 33 for invasive gynecological cancer, 13 for benign reasons, and in 4 the reason for the hysterectomy and/or the Pap smear history was not known. Twenty-one (16%) had received prior pelvic radiotherapy. VAIN was noted to involve either the vaginal vault (in the post-hysterectomy group) or the upper vagina (in the no hysterectomy group) in more than 80% cases. A variety of treatment modalities was used with varying degrees of success. For high-grade VAIN excisional treatments had an overall (first-line plus subsequent) cure rate of 69% (53/77). The state of the surgical margins did not correlate with the risk of residual disease. CO2 laser ablation was curative in 69% (18/26) of cases and was significantly better than electrocoagulation diathermy which was curative in only 25% (3/12) of cases (P = 0.013). Five-fluorouracil cream was curative in 46% (5/11) of cases, including four patients who had received prior radiotherapy. Radiotherapy was effective in eradicating VAIN in the two cases where it was used as the primary treatment modality. Progression of high-grade VAIN to invasive cancer occurred in eight (8%) cases; after no treatment in two cases, after treatment failure in five cases, and as a late recurrence in one case. For low-grade VAIN an observational approach after biopsy was initially adopted in eight patients and regression occurred in seven (88%) of these patients. Other miscellaneous treatments were also effective in low-grade VAIN. These data provide evidence that high-grade VAIN is a precursor to invasive cancer of the vagina and every attempt should be made to eradicate it. Based on our experience and a review of the literature we have proposed a plan for optimal management of this condition.