The complex and often confusing history, histology and histogenesis of mesonephric, STK11 adnexal tumour and mesonephric-like neoplasms of the upper female genital tract (including broad ligament).

Mesonephric lesions in the female genital tract are uncommon, with those arising from the upper tract being much less frequent than those developing in the lower tract (mesonephric hyperplasia and carcinoma). The most common upper tract lesions include rete cyst/cystadenoma and female adnexal tumour of Wolffian origin (FATWO). The integration of morphological, immunohistochemical and molecular studies on FATWOs has enabled recognition of a novel entity, the STK11 adnexal tumour, which is often associated with Peutz-Jeghers syndrome (~50%) and frequently has a salivary gland morphology but an unknown origin. Similarly, 'mesonephric-like' adenocarcinoma, an entity with striking similarities to mesonephric carcinoma but currently favoured to be of Müllerian derivation based on its association with other Müllerian tumours and molecular findings, has also been recently described, and may histologically mimic both FATWOs and STK11 adnexal tumours. In this review, we provide a historical overview of upper female genital tract mesonephric proliferations and discuss mesonephric lesions, STK11 adnexal tumour, mesonephric-like adenocarcinoma, and mimickers, the most common being endometrioid carcinoma.

Callosal disconnection and limb-kinetic apraxia.

According to Liepmann, patients with limb-kinetic apraxia (LKA) have a loss of upper limb deftness-dexterity. Prior studies have revealed in right-handed patients that, whereas injury of the left hemisphere induces an ipsilesional LKA, injury to the right hemisphere does not induce an ipsilesional LKA. There are at least two possible means by which the left hemisphere may influence the deftness of the left hand, either by callosal connections or by ipsilesional corticospinal projections. The purpose of this study was to learn whether a patient with a focal lesion of the corpus callosum had a callosal disconnection LKA. This 57-year-old right-handed man had a memory impairment, and upon brain imaging, was found to have a septum pellucidum cyst, which was causing mild ventricular obstruction to the occipital and temporal horns. He underwent an endoscopic-assisted fenestration of the septum pellucidum. Postoperative imaging revealed a lesion of the mesial portion of his corpus callosum and an assessment of praxis revealed that he had both a limb-kinetic and ideomotor apraxia of his left but not his right hand. The observation that this man had a callosal disconnection LKA of his left hand suggests that in some people it is the left hemisphere's premotor or motor cortex that enables the right hemisphere's motor system to program deft movements of the left hand.

Semi-hydrogenation of alkynes at single crystal, nanoparticle and biogenic nanoparticle surfaces: the role of defects in Lindlar-type catalysts and the origin of their selectivity.

For the first time, the method of shell-isolated nanoparticle Raman spectroscopy (SHINERS) is used in combination with cyclic voltammetry (CV) and reactivity studies to investigate the adsorption behaviour of a series of three alkynes undergoing hydrogenation on nanoparticle, single crystal and bacteria/graphite-supported platinum surfaces. It is found that a strong association of alkynes with defect sites to produce a long-lived di-sigma/pi-alkene surface complex allows for deep hydrogenation of this intermediate to the alkane product. In contrast, when platinum surface defect sites are blocked by either bismuth or polyvinylpyrrolidone (PVP) (and thus leaving behind only Pt{111} terrace adsorption sites), large increases in selectivity to the semi-hydrogenation product are observed for all three alkynes. This finding is consistent with SHINERS collected from both well-ordered and roughened Pt{111} electrodes which revealed that the di-sigma/pi-bonded surface intermediate is hardly formed at all on Pt{111} unless defect sites are introduced via electrochemical roughening. As a general method of producing selective catalysts, the elimination of toxic heavy metals from Lindlar-type catalyst, used commonly in organic chemistry, and their replacement by more benign, organic species adsorbed at defect sites is discussed.

Impact + resistance training improves bone health and body composition in prematurely menopausal breast cancer survivors: a randomized controlled trial.

UNLABELLED: Our randomized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for >1 year. INTRODUCTION: Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors (BCS). We investigated whether impact + resistance training could improve bone mineral density (BMD), reduce bone turnover, build muscle, and decrease fat mass in BCS with premature menopause. METHODS: We conducted a randomized controlled trial in 71 BCS (mean age, 46.5 years) within 5 years of treatment-related menopause. Women were randomly assigned to one of two groups: (1) impact + resistance training (prevent osteoporosis with impact + resistance (POWIR)) or (2) exercise placebo (FLEX) 3×/week for 1 year. Outcomes were hip and spine BMD (in grams per square centimeter) and body composition (percent body fat (%BF) and lean and fat mass (in kilograms)) by DXA and bone turnover markers (serum osteocalcin (in nanograms per milliliter) and urinary deoxypryrodinoline (in nanomoles per milliliter). RESULTS: There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample. In analyses restricted to BCS who were menopausal for ≥1 year, POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX (femoral neck-POWIR, 0.004 ± 0.093 g/cm(2) vs. FLEX, -0.010 ± 0.089 g/cm(2); p < 0.01; spine-POWIR, -0.003 ± 0.114 g/cm(2) vs. FLEX, -0.020 ± 0.110 g/cm(2); p = 0.03). POWIR prevented increases in %BF (POWIR, 0.01 % vs. FLEX, 1.3 %; p < 0.04). Women with attendance to POWIR at ≥64 % had better improvements in %BF than women attending less often (p < 0.03). CONCLUSION: Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS.

New insight into transient contrast enhancement on computed tomography after endovascular treatment of stroke.

Transient contrast enhancement on computed tomography following endovascular treatment of stroke is a recognized entity that has been previously reported. Technological advances in brain imaging now have the potential to explore and refine its proposed etiology. We describe three patients in whom the location of contrast enhancement correlates with decreased cerebral blood volume on pre-therapeutic CT perfusion studies and with restricted diffusion on MRI. In this regard, contrast enhancement demarcated areas of completed cerebral infarction. The diagnostic and etiological implications are discussed.

Endobronchial ultrasound guided transbronchial needle aspiration.

Staging for non-small cell lung cancer (NSCLC) requires accurate assessment of the mediastinal lymph nodes which determines treatment and outcome. As radiological staging is limited by its specificity and sensitivity, it is necessary to sample the mediastinal nodes. Traditionally, mediastinoscopy has been used for evaluation of the mediastinum especially when radical treatment is contemplated, although conventional transbronchial needle aspiration (TBNA) has also been used in other situations for staging and diagnostic purposes. Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) offers a minimally invasive alternative to mediastinoscopy with additional access to the hilar nodes, a better safety profile, and it removes the costs and hazards of theatre time and general anaesthesia with comparable sensitivity, although the negative predictive value of mediastinoscopy (and sample size) is greater. EBUS-TBNA also obtains larger samples than conventional TBNA, has superior performance and theoretically is safer, allowing real-time sampling under direct vision. It can also have predictive value both in sonographic appearance of the nodes and histological characteristics. EBUS-TBNA is therefore indicated for NSCLC staging, diagnosis of lung cancer when there is no endobronchial lesion, and diagnosis of both benign (especially tuberculosis and sarcoidosis) and malignant mediastinal lesions. The procedure is different than for flexible bronchoscopy, takes longer, and requires more training. EBUS-TBNA is more expensive than conventional TBNA but can save costs by reducing the number of more costly mediastinoscopies. Revenue based tariff systems have been slow to reflect the innovation of techniques such as EBUS-TBNA. In the future, endobronchial ultrasound may have applications in airways disease and pulmonary vascular disease.

A prospective study of conventional transbronchial needle aspiration: performance and cost utility.

BACKGROUND: Conventional transbronchial needle aspiration (TBNA) is a cheap, minimally invasive tool for lung cancer staging and diagnosis. Endobronchial ultrasound-guided TBNA (EBUS-TBNA) is more sensitive but is more expensive and less widely available. We describe a prospective analysis of TBNA diagnostic, staging and cost utility in a centre in the UK. OBJECTIVES: To illustrate the potential diagnostic, staging and cost utility of a low cost conventional TBNA service. METHODS: A prospective analysis of 79 TBNA procedures over a 2-year period was performed looking at performance and cost utility in a 'mixed' cohort with variable pre-test probability of malignancy (year 1) followed by a high probability cohort (year 2). RESULTS: TBNA avoided mediastinoscopy in 25% of the cases overall (37% in high probability vs. 13% in the 'mixed' cohort, p = 0.03). The overall prevalence of malignancy was 84%, sensitivity 79%, negative predictive value 58% and accuracy 85%. Diagnostic utility varied with pre-test probability and nodal station. TBNA down-staged 8% of lung cancer patients to receive surgery and confirmed the pre-treatment stage (inoperability) in 74%. TBNA led to theoretical cost savings of GBP 560 per patient. CONCLUSIONS: TBNA can achieve a high diagnostic sensitivity for cancer in high probability patients and stage the majority appropriately, thereby avoiding unnecessary mediastinoscopies and reducing costs. It may also down-stage a minority to have surgery. TBNA is cheap, routinely available and learnable. As EBUS-TBNA will take time to develop due to its costs, all respiratory centres should perform TBNA at flexible bronchoscopy in suspected lung cancer with accessible mediastinal adenopathy.

Changes in lung cancer incidence in South Asians in Leicester, 1990-2005.

BACKGROUND: A previous study showed that lung cancer incidence in Leicester's South Asian (SA) population had increased between 1990 and 1999. We expanded the original data set to determine if this increase had continued in recent years. METHODS: All patients diagnosed with lung cancer in Leicester between 1990 and 2005 were identified. Ethnicity was assigned using Nam Pechan software, deprivation by Townsend score. Using Poisson regression, incidence rate ratios (IRRs) were calculated to assess variations in incidence by ethnicity, deprivation and period of diagnosis. RESULTS: Comparing patients diagnosed in 2000-2005 with those in 1990-1994, the risk of lung cancer increased in the SA men (IRR: 1.67 (95% CI: 0.99, 2.78)) whereas in the non-South Asian (NSA) men, it had fallen (IRR: 0.84 (95% CI: 0.76, 0.94)). Comparing patients diagnosed in 2000-2005 with those in 1995-1999 an increase continued in the SA men (IRR: 1.11 (95% CI: 0.71-1.74)). A significant rise was observed in the NSA women comparing those diagnosed from 2000-2005 to 1995-1999 (IRR: 1.16 (95% CI: 1.01, 1.33)). CONCLUSION: Lung cancer is an important public health issue amongst SAs in Leicester and has increased significantly since the early 1990s, with rates sustained in the more recent years of 2000-2005. Changes in the rates of lung cancer in SA and NSA populations are likely to be due to changing smoking habits.

A performance and theoretical cost analysis of endobronchial ultrasound-guided transbronchial needle aspiration in a UK tertiary respiratory centre.

BACKGROUND: New innovative techniques can improve patient care but may not be appropriately funded. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS) offers a minimally invasive mediastinal staging and diagnostic method for suspected lung cancer. AIM: We report the performance and cost analysis of a newly established EBUS service in a prospective real world cohort of patients to assess the impact of Payment by Results (PbR). DESIGN: Prospective cohort study. METHODS: Fifty-four patients between June 2008 and April 2009 underwent EBUS for evaluation of unexplained mediastinal lymphadenopathy on CT. Cost analysis was performed from local Trust financial data and 2008-09 tariffs. RESULTS: EBUS had an 89% sensitivity, 75% negative predictive value and 92% accuracy for malignancy. EBUS coding was inaccurate in 15.6% of cases. The actual cost of an EBUS is 1252-1433 pounds but is coded as a standard bronchoscopy (561 pounds). EBUS reduces health community costs by 107824 pounds/year, as a result of a Primary Care Trust cost saving of 113968 pounds/year and a Trust cost deficit of 6144 pounds/year. Coding inaccuracies further alter the Primary Care Trust costs. CONCLUSION: Medical innovation is fundamental to improved patient care. EBUS can potentially reduce morbidity for lung cancer patients and save health community costs. However, with PbR the service provider delivers this at a loss as the tariffs do not reflect innovation and because of coding inaccuracies. We suggest tariffs for innovative procedures need to reflect the true cost.

A local anaesthetic video-assisted thoracoscopy service: prospective performance analysis in a UK tertiary respiratory centre.

INTRODUCTION: Local anaesthetic video-assisted thoracoscopy (LAVAT) is a safe, reliable and therapeutic procedure used by respiratory physicians in the management of pleural disease, especially pleural malignancy. We describe a prospective analysis of a UK LAVAT service set up in a tertiary respiratory centre to complement an existing large surgical video-assisted thoracic surgery (VATS) service. METHODS: A prospective analysis of 125 LAVAT procedures over a 34-month period was performed looking at a variety of quality control endpoints comparing them to national thoracic surgical VATS standards. RESULTS: Talc pleurodesis was effective in over 86% of cases and this did not significantly lengthen bed stay (median 4.5 days). Bed stay was also unchanged between the ages of 60-89 years. Over 77% of the 48 patients with proven metastatic pleural lung malignancy or mesothelioma received either surgical decortication or oncological treatment (palliative chemotherapy in 57%). In only 6% were biopsies not possible because of technical factors. LAVAT biopsies had a diagnostic accuracy of 97.4%, sensitivity 95.4%, specificity 100%, positive predictive value 100%, and negative predictive value 94.7%. Our complication rate was 4% and mortality rate 0.8%. DISCUSSION: Our LAVAT service meets surgical VATS standards for diagnosis and safety with a good pleurodesis efficacy rate. It complements our surgical VATS service, offering a pleural diagnostic service for patients with non-complex pleural exudates or too frail for VATS. Our data demonstrate there is a demand and potential for respiratory physicians dealing with pleural malignancy to develop LAVAT and enhance their local lung cancer and pleural diagnostic pathway.

Retrospective analysis of Healthcare Resource Group coding allocation for local anaesthetic video-assisted 'medical' thoracoscopy in a UK tertiary respiratory centre.

BACKGROUND: Correct service costing is essential but may not always be done accurately. AIM: To assess the accuracy of Healthcare Resource Group (HRG) coding allocation for patients undergoing local anaesthetic video-assisted thoracoscopy (LAVAT) against predicted codes under Payment by Results (PbR). DESIGN: Single centre retrospective study. Tertiary respiratory centre in Leicestershire. METHODS: One hundred twenty-five patients undergoing LAVAT from July 2005 to July 2008. MAIN OUTCOME MEASURES: Predicted and actual revenue per LAVAT episode based on predicted and actual HRG codes allocated. RESULTS: Among 125 patients undergoing LAVAT, the actual HRG code matched the predicted code in only 39 cases (31.2%), odds ratio (OR) 0.002, 95% confidence intervals (CIs) 0.0001-0.03, P < 0.0001. In 51 cases (40.8%), this resulted in a median (interquartile range) excess of PbR revenue of 574 pounds (574-1366) per episode; a total estimated overspend of 29,274 pounds. In 35 cases (28.0%), this resulted in a median underspend of --1093 pounds (-1285 to -851) per episode; a total estimated underspend of 38,529 pounds, with a total estimated financial error of 67,529 pounds. The net median (interquartile range) difference for PbR-related revenue was 0 pounds (-89 to + 574). Factors associated with coding discrepancy were longer length of stay (OR = 2.52, 95% CIs = 1.09-5.81, P = 0.03) and talc pleurodesis (OR = 2.25, 95% CI = 1.01-4.99, P = 0.06). CONCLUSION: HRG coding allocation errors occur frequently. The potential financial implications of this are significant for providers and commissioners. Future strategies are required at multiple levels (NHS Trust, Primary Care Trust and Department of Health) to minimize future discrepancies and financial error.

Investigating the diet of the omnivorous mirid Dicyphus hesperus using stable isotopes.

Omnivory involves numerous feeding relationships and a complex web of interactions. When using omnivores in biocontrol, these interactions need to be understood to maximize feeding on the target species and minimize non-target interactions. Dicyphus hesperus is used along with Encarsia formosa for biocontrol of whiteflies in greenhouse tomato crops. Dicyphus hesperus is a generalist omnivore which feeds on all components of the system. To quantify these interactions, stable isotope analysis was used to identify trophic position with nitrogen isotopes (delta15N) and plant sources with carbon isotopes (delta13C). Feeding trials were used to establish baseline isotopic data for D. hesperus and their diet, including Verbascum thapsus, an alternative plant food. Cage trials were used to monitor population abundances and the isotopic signature of D. hesperus. In feeding trials, D. hesperus were enriched relative to their food, suggesting an elevated trophic position. However, large amounts of isotopic variation were found within all diet components, with only V. thapsus exhibiting a distinct signature. In cage trials, the average delta15N and delta13C of the omnivore declined over time, coinciding with declines in total available prey, though it may be confounded by changes in temperature. The range of delta13C, but not the range of delta15N, also declined over time. This suggests a change in the plant source within the diet, but also some unquantified variability within the population. We suggest that diet variability exists within D. hesperus populations, declining as prey become less abundant.

An alpha-fetoprotein-derived peptide reduces the uterine hyperplasia and increases the antitumour effect of tamoxifen.

Tamoxifen (Tam) is effective for the treatment and prevention of breast cancer. However, it has toxic drawbacks and has limited-duration utility because, over time, human tumours become refractory to Tam. Recently, a new nontoxic peptide, alpha-fetoprotein-derived peptide (AFPep) has been proposed for the treatment and prevention of breast cancer. The purpose of this paper is to determine whether combining AFPep with Tam would increase efficacy and reduce toxicity in experimental models of breast cancer. Low doses of AFPep and Tam were more effective in combination than either agent alone against breast cancer growth in cell culture, in tumour-xenografted mice, and in carcinogen-exposed rats. alpha-Fetoprotein-derived peptide interfered with Tam-induced uterine hyperplasia in immature mice, and showed no toxic effects. Unlike Tam, AFPep did not inhibit binding of oestradiol (E(2)) to oestrogen receptor (ER). Thus, these two agents utilise different mechanisms to interfere with ER functionality, yet work cooperatively to reduce breast cancer growth and alleviate Tam's troubling toxicity of uterine hyperplasia and appear to be a rational combination for the treatment of ER-positive breast cancer.

Synthetic peptide derived from alpha-fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization.

Asynthetic peptide that inhibits the growth of estrogen receptor positive (ER+) human breast cancers, growing as xenografts in mice, has been reported. The cyclic 9-mer peptide, cyclo[EMTOVNOGQ], is derived from alpha-fetoprotein (AFP), a safe, naturally occurring human protein produced during pregnancy, which itself has anti-estrogenic and anti-breast cancer activity. To determine the pharmacophore of the peptide, a series of analogs was prepared using solid-phase peptide synthesis. Analogs were screened in a 1-day bioassay, which assessed their ability to inhibit the estrogen-stimulated growth of uterus in immature mice. Deletion of glutamic acid, Glu1, abolished activity of the peptide, but glutamine (Gln) or asparagine (Asn) could be substituted for Glu1 without loss of activity. Methionine (Met2) was replaced with lysine (Lys) or tyrosine (Tyr) with retention of activity. Substitution of Lys for Met2 in the cyclic molecule resulted in a compound with activity comparable with the Met2-containing cyclic molecule, but with a greater than twofold increase in purity and corresponding increase in yield. This Lys analog demonstrated anti-breast cancer activity equivalent to that of the original Met-containing peptide. Therefore, Met2 is not essential for biologic activity and substitution of Lys is synthetically advantageous. Threonine (Thr3) is a nonessential site, and can be substituted with serine (Ser), valine (Val), or alanine (Ala) without significant loss of activity. Hydroxyproline (Hyp), substituted in place of the naturally occurring prolines (Pro4, Pro7), allowed retention of activity and increased stability of the peptide during storage. Replacement of the first Pro (Pro4) with Ser maintains the activity of the peptide, but substitution of Ser for the second Pro (Pro7) abolishes the activity of the peptide. This suggests that the imino acid at residue 7 is important for conformation of the peptide, and the backbone atoms are part of the pharmacophore, but Pro4 is not essential. Valine (Val5) can be substituted only with branched-chain amino acids (isoleucine, leucine or Thr); replacement by d-valine or Ala resulted in loss of biologic activity. Thus, for this site, the bulky branched side chain is essential. Asparagine (Asn6) is essential for activity. Substitution with Gln or aspartic acid (Asp), resulted in reduction of biologic activity. Removal of glycine (Gly8) resulted in a loss of activity but nonconservative substitutions can be made at this site without a loss of activity indicating that it is not part of the pharmacophore. Cyclization of the peptide is facilitated by addition of Gln9, but this residue does not occur in AFP nor is it necessary for activity. Gln9 can be replaced with Asn, resulting in a molecule with similar activity. These data indicate that the pharmacophore of the peptide includes side chains of Val5 and Asn6 and backbone atoms contributed by Thr3, Val5, Asn6, Hyp7 and Gly8. Met2 and Gln9 can be modified or replaced. Glu1 can be replaced with charged amino acids, and is not likely to be part of the binding site of the peptide. The results of this study provide information that will be helpful in the rational modification of cyclo[EMTOVNOGQ] to yield peptide analogs and peptidomimetics with advantages in synthesis, pharmacologic properties, and biologic activity.

Gene frequencies of human platelet antigens 1-5 in indigenous Australians in Western Australia.

The frequencies of human platelet antigen (HPA) systems vary between different racial groups; however, HPA frequency data for some racial groups are still incomplete. We report the distribution of HPA 1-5 systems in Australian Aborigines from a remote community in the north-west of Australia and compare our findings with HPA observed in a Western Australian blood donor population. Using a polymerase chain reaction (PCR) with sequence-specific primers, 185 indigenous Australians and 1000 Western Australian blood donors were genotyped for each of the HPA 1-5 systems. Comparison of gene frequencies of alleles from HPA-1, -2, -3 and -5 systems showed significant differences between Aboriginal people and Western Australian blood donors (P < 0.001). In particular, the frequency of HPA-3b (0.068) in the Australian Aboriginals, from this study, was one of the lowest reported, whilst the frequency of HPA-5b (0.246) was one of the highest for this allele. Gene frequencies were similar to those reported for central Australian Aborigines but with no other ethnic group. In conclusion, this study confirms significant differences in HPA distributions between indigenous Australians, Australian blood donors and other racial groups. These results indicate a higher potential risk of alloimmunization to HPA-1, -2 and -3 in Australian Aborigines receiving transfusion therapy from a Caucasian blood donor population, thereby having practical implications for transfusion and pregnancy risks in people of Aboriginal origin.

Reducing waiting times for sleep apnoea hypopnoea syndrome and snoring using a questionnaire and home oximetry: results of a second audit cycle.

As a result of a previous audit on the management of sleep apnoea hypopnoea syndrome (SAHS) which showed long waiting times that were primarily due to unnecessary interspecialty referrals, a change in practice was adopted. All referrals are now sent a questionnaire about symptoms suggestive of SAHS, the Epworth Sleepiness Scale score and their body mass index (BMI) which when returned are categorized into having a high, intermediate or low risk of SAHS. Those patients with a high probability have home overnight oximetry and those with intermediate probability have video oximetry. Those with a low probability are referred directly to ENT. We audited the first 100 patients referred. All were General Practitioner referrals to either ENT or respiratory medicine. Only two patients had a low probability score and were seen directly in ENT. Following sleep study analysis, 10 patients were referred directly to ENT with no respiratory medicine follow-up and nine were discharged back to the General Practitioner with no apnoea or snoring. Eighty-one patients were followed up by respiratory medicine. Of these, 49 received a trial of nasal continuous positive airway pressure (nCPAP) and six were referred to ENT. Therefore the majority justified an investigation to exclude SAHS in the first instance and an unnecessary initial ENT appointment was avoided. We have reduced the average waiting times to sleep study by approximately 90 days and to nCPAP trial by 32 days, mostly due to decreased delays in interspeciality referrrals. We have also demonstrated a greater than 50 per cent reduction in ENT clinic visits, a small increase in the number of sleep studies but no increase in respiratory clinic workload.

Development of a synthetic cyclized peptide derived from alpha-fetoprotein that prevents the growth of human breast cancer.

The peptide, EMTPVNPG, derived from alpha-fetoprotein, inhibits estrogen-stimulated growth of immature mouse uterus and estrogen-dependent proliferation of human breast cancer cells. However, the biological activities of the peptide diminish over time in storage, even when in the lyophilized state, probably because of peptide aggregation through hydrophobic interaction among monomers. Two analogs of EMTPVNPG were designed with the intent of minimizing aggregation and retaining biological activity during prolonged storage. EMTOVNOG, where O is 4-hydroxyproline, is a linear peptide generated by substituting 4-hydroxyproline for the two prolines, thereby increasing peptide hydrophilicity. This analog exhibited a dose-dependent inhibition of estrogen-stimulated growth of immature mouse uterus similar to that of EMTPVNPG (maximal activity at 1 microg/mouse). A second analog, cyclo-(EMTOVNOGQ), a hydrophilic, cyclic analog with increased conformational constraint, was as potent as the other peptides in its inhibition of estrogen-dependent growth of immature mouse uterus, and had an expanded effective dose range. Both linear and cyclized hydroxyproline-substituted analogs exhibited indefinite shelf-life. Furthermore, both analogs inhibited the estrogen-dependent growth of MCF-7 human breast cancer growing as a xenograft in SCID mice. These analogs may become significant, novel agents for the treatment of breast cancer.

Two new loci affecting cell division identified as suppressors of an ftsQ-null mutation in Streptomyces coelicolor A3(2).

Mutations in fts genes partially or completely block both vegetative cell division and sporulation septation in the filamentous bacterium Streptomyces coelicolor A3(2). Using a novel screen, we independently isolated two double-mutant strains, each containing a spontaneous suppressor mutation, which partially restores division to an ftsQ-null mutant. Genetic complementation experiments revealed that the suppressor mutations alone confer no observable defect in sporulation. The suppressor mutations were genetically mapped to regions of the chromosome, distinct from each other and the division and cell wall cluster containing ftsQ. Therefore, the genes identified by the suppressor mutations were named sqnA and sqnB (suppressor of ftsQ-null) and may be representatives of a novel class of genes involved in cell division or the regulation of cell division in this mycelial organism.