Exploiting Isospin Symmetry to Study the Role of Isomers in Stellar Environments.

Proton capture on the excited isomeric state of ^{26}Al strongly influences the abundance of ^{26}Mg ejected in explosive astronomical events and, as such, plays a critical role in determining the initial content of radiogenic ^{26}Al in presolar grains. This reaction also affects the temperature range for thermal equilibrium between the ground and isomeric levels. We present a novel technique, which exploits the isospin symmetry of the nuclear force, to address the long-standing challenge of determining proton-capture rates on excited nuclear levels. Such a technique has in-built tests that strongly support its veracity and, for the first time, we have experimentally constrained the strengths of resonances that dominate the astrophysical ^{26m}Al(p,γ)^{27}Si reaction. These constraints demonstrate that the rate is at least a factor ∼8 lower than previously expected, indicating an increase in the stellar production of ^{26}Mg and a possible need to reinvestigate sensitivity studies involving the thermal equilibration of ^{26}Al.

First Direct Measurement of an Astrophysical p-Process Reaction Cross Section Using a Radioactive Ion Beam.

We have performed the first direct measurement of the ^{83}Rb(p,γ) radiative capture reaction cross section in inverse kinematics using a radioactive beam of ^{83}Rb at incident energies of 2.4 and 2.7A MeV. The measured cross section at an effective relative kinetic energy of E_{cm}=2.393 MeV, which lies within the relevant energy window for core collapse supernovae, is smaller than the prediction of statistical model calculations. This leads to the abundance of ^{84}Sr produced in the astrophysical p process being higher than previously calculated. Moreover, the discrepancy of the present data with theoretical predictions indicates that further experimental investigation of p-process reactions involving unstable projectiles is clearly warranted.

Oncological outcomes and stoma-free survival following TaTME, a prospective cohort study.

BACKGROUND: Transanal TME (TaTME) was introduced to improve access to the pelvis in difficult cases (male sex, obesity and mid to low rectal cancers) and reduce the risk of anastomotic leak by avoiding cross stapling. In April 2018 the Norwegian hospital to whom all local; recurrences for rectal cancer are referred reported an unexpected rise in early multifocal local recurrences of 9.5% following TaTME compared with 3.4% following conventional TME leading to a nationwide moratorium on the procedure and ending, in an editorial published on the British Journal of Surgery in August 2020, by saying that other countries should consider the issue in the context of local practices and results. There are limited data concerning oncological outcomes of TaTME compared to conventional TME. The aim of this study was to report perioperative and oncological outcomes for patients with rectal cancer treated with TaTME in a high-volume, experienced UK centre. METHODS: From January 2015 to January 2020 consecutive patients with histologically confirmed rectal cancer having TaTME at Worcestershire Royal Hospital NHS were prospectively entered into an online international registry. Patients were followed according to local protocol with clinical examination, tumour markers, endoscopy and radiology. RESULTS: Seventy patients underwent TaTME for rectal cancer. The median distance of the tumour from the anorectal junction was 4 cm (IQR 2-5). The mesorectal margin was involved in 20 (1%) patients, all of whom received neoadjuvant chemoradiotherapy. Overall survival was 94% at a median follow-up of 15 months (IQR 9-31 months). Distant recurrence occurred in 12 (17%) of patients at a median of 14 months (IQR 10-17 months). The 18-month stoma-free survival rate was 66%. CONCLUSIONS: A local recurrence rate of 5.7% supports the oncological safety of TaTME for rectal cancer.

Search for Nova Presolar Grains: γ-Ray Spectroscopy of

The discovery of presolar grains in primitive meteorites has initiated a new era of research in the study of stellar nucleosynthesis. However, the accurate classification of presolar grains as being of specific stellar origins is particularly challenging. Recently, it has been suggested that sulfur isotopic abundances may hold the key to definitively identifying presolar grains with being of nova origins and, in this regard, the astrophysical ^{33}Cl(p,γ)^{34}Ar reaction is expected to play a decisive role. As such, we have performed a detailed γ-ray spectroscopy study of ^{34}Ar. Excitation energies have been measured with high precision and spin-parity assignments for resonant states, located above the proton threshold in ^{34}Ar, have been made for the first time. Uncertainties in the ^{33}Cl(p,γ) reaction have been dramatically reduced and the results indicate that a newly identified ℓ=0 resonance at E_{r}=396.9(13) keV dominates the entire rate for T=0.25-0.40 GK. Furthermore, nova hydrodynamic simulations based on the present work indicate an ejected ^{32}S/^{33}S abundance ratio distinctive from type-II supernovae and potentially compatible with recent measurements of a presolar grain.

A systematic review of local excision followed by adjuvant therapy in early rectal cancer: are pT1 tumours the limit?

AIM: Total mesorectal excision remains the cornerstone of treatment for rectal cancer. Significant morbidity means local excision may be more appropriate in selected patients. Adjuvant therapy reduces local recurrence and improves survival; however, there is a paucity of data on its impact following local excision, which this systematic review aims to address. METHODS: A systematic search of the MEDLINE, Embase and Cochrane databases using validated terms for rectal cancer, adjuvant therapy and local excision was performed. Included studies focused on local excision with adjuvant therapy for adenocarcinoma of the rectum. Primary outcome measures were local recurrence, survival and morbidity. Studies providing neoadjuvant therapy or local excision alone were excluded. RESULTS: Twenty-two studies described 804 patients. Indications for local excision included favourable histology, patient choice and comorbidities. T1, T2 and T3 tumours accounted for 35.1%, 58.0% and 6.9% of cases, respectively. The most frequent local excision technique was transanal excision (77.7%). Adjuvant therapy included long-course chemoradiation or radiotherapy. Median follow-up was 51 months (range 1-165). The pooled local recurrence was 5.8% (95% CI 3.0-9.5) for pT1, 13.8% (95% CI 10.1-17.9) for pT2 and 33.7% (95% CI 19.2-50.1) for pT3 tumours. The overall median disease-free survival was 88% (range 50%-100%) with a pooled overall morbidity of 15.1% (95% CI 11.0-18.7). CONCLUSIONS: This area remains highly relevant to modern clinical practice. The data suggest that local excision followed by adjuvant therapy can achieve acceptable long-term outcomes in high-risk pT1 tumours, but not in T2 tumours and above in whom radical surgery should be offered.

Does declared surgeon specialist interest influence the outcome of emergency laparotomy?

INTRODUCTION: In the UK, general surgeons must demonstrate competency in emergency general surgery before obtaining a certificate of completion of training. Subsequently, many consultants develop focused elective specialist interests which may not mirror the breadth of procedures encountered during emergency practice. Recent National Emergency Laparotomy Audit analysis found that declared surgeon special interest impacted emergency laparotomy outcomes, which has implications for emergency general surgery service configuration. We sought to establish whether local declared surgeon special interest impacts emergency laparotomy outcomes. METHODS: Adult patients having emergency laparotomy were identified from our prospective National Emergency Laparotomy Audit database from May 2016 to May 2019 and categorised as colorectal or oesophagogastric according to operative procedure. Outcomes included 30-day mortality, return to theatre and length of stay. Binomial logistic regression was used to identify any association between declared consultant specialist interest and outcomes. RESULTS: Of 600 laparotomies, 358 (58.6%) were classifiable as specialist procedures: 287 (80%) colorectal and 71 (20%) oesophagogastric. Discordance between declared specialty and operation undertaken occurred in 25% of procedures. For colorectal emergency laparotomy, there was an increased risk of 30-day mortality when performed by a non-colorectal consultant (unadjusted odds ratio 2.34; 95% confidence interval 1.10-5.00; p = 0.003); however, when adjusted for confounders within multivariate analysis declared surgeon specialty had no impact on mortality, return to theatre or length of stay. CONCLUSION: Surgeon-declared specialty does not impact emergency laparotomy outcomes in this cohort of undifferentiated emergency laparotomies. This may reflect the on-call structure at Birmingham Heartlands Hospital, where a colorectal and oesophagogastric consultant are paired on call and provide cross-cover when needed.

Meta-analysis of prognostic factors for patients with colorectal peritoneal metastasis undergoing cytoreductive surgery and heated intraperitoneal chemotherapy.

Background: Up to 15 per cent of colorectal cancers present with peritoneal metastases (CPM). Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS + HIPEC) aims to achieve macroscopic tumour resection combined with HIPEC to destroy microscopic disease. CRS + HIPEC is a major operation with significant morbidity and effects on quality of life (QoL). Improving patient selection is crucial to maximize patient outcomes while minimizing morbidity and mortality. The aim of this study was to identify prognostic factors for patients with CPM undergoing CRS + HIPEC. Methods: A systematic search of MEDLINE, Embase and Cochrane Library electronic databases was performed using terms for colorectal cancer, peritoneal metastasis and CRS + HIPEC. Included studies focused on the impact of prognostic factors on overall survival following CRS + HIPEC in patients with CPM. Results: Twenty-four studies described 3128 patients. Obstruction or perforation of the primary tumour (hazard ratio (HR) 2·91, 95 per cent c.i. 1·5 to 5·65), extent of peritoneal metastasis as described by the Peritoneal Carcinomatosis Index (PCI) (per increase of 1 PCI point: HR 1·07, 1·02 to 1·12) and the completeness of cytoreduction (CC score above zero: HR 1·75, 1·18 to 2·59) were associated with reduced overall survival after CRS + HIPEC. Conclusion: Primary tumour obstruction or perforation, PCI score and CC score are valuable prognostic factors in the selection of patients with CPM for CRS + HIPEC.

Hartmann's procedure, reversal and rate of stoma-free survival.

Background Hartmann's procedure is a commonly performed operation for complicated left colon diverticulitis or malignancy. The timing for reversal of Hartmann's is not well defined as it is technically challenging and carries a high complication rate. Methods This study is a retrospective audit of all patients who underwent Hartmann's procedure between 2008 and 2014. Reversal of Hartmann's rate, timing, American Society of Anesthesiologists grade, length of stay and complications (Clavien-Dindo) including 30-day mortality were recorded. Results Hartmann's procedure (n = 228) indications were complicated diverticular disease 44% (n = 100), malignancy 32% (n = 74) and other causes 24%, (n = 56). Reversal of Hartmann's rate was 47% (n = 108). Median age of patients was 58 years (range 21-84 years), American Society of Anesthesiologists grade 2 (range 1-4), length of stay was eight days (range 2-42 days). Median time to reversal of Hartmann's was 11 months (range 4-96 months). The overall complication rate from reversal of Hartmann's was 21%; 3.7% had a major complication of IIIa or above including three anastomotic leaks and one deep wound dehiscence. Failure of reversal and permanent stoma was less than 1% (n = 2). Thirty-day mortality following Hartmann's procedure was 7% (n = 15). Where Hartmann's procedure wass not reversed, for 30% (n = 31) this was the patient's choice and 70% (n = 74) were either high risk or unfit. Conclusions Hartmann's procedure is reversed less frequently than thought and consented for. Only 46% of Hartmann's procedures were stoma free at the end of the audit period. The anastomotic complication rate of 1% is also low for reversal of Hartmann's procedure in this study.

Compliance with enhanced recovery protocols in elderly patients undergoing colorectal resection.

Introduction Enhanced recovery after surgery (ERAS) is associated with reduced length of stay (LOS) and improved outcomes in colorectal surgery. It is unclear whether ERAS can be safely implemented in elderly patients undergoing complex colorectal resections. The aim of this study was to evaluate the feasibility of ERAS in patients of all ages undergoing colorectal surgery. Methods A prospective database of a consecutive series of patients undergoing colorectal resections with ERAS between August 2012 and December 2014 was evaluated. Patients were divided into four age groups. Outcomes studied were compliance with ERAS elements, LOS, morbidity and mortality. Results Of the 294 patients in the study cohort, 79 were <60 years, 81 were 60-69 years, 86 were 70-79 years and 48 were ≥80 years of age. There was no significant difference between age groups in compliance with ERAS elements. Age was not predictive of delayed discharge (LOS >6 days) or morbidity. Factors that were predictive of delayed discharge on multivariate analysis were open surgery (odds ratio [OR]: 2.23, p=0.003), conversion to open surgery (OR: 3.23, p=0.017), stoma formation (OR: 2.10, p=0.019) and chronic obstructive pulmonary disease (OR: 4.12, p=0.038). Factors predictive of morbidity on multivariate analysis comprised conversion to open surgery (OR: 7.72, p=0.004), high creatinine (OR: 1.03 per unit increase in creatinine, p=0.008) and stoma education (OR: 0.31, p=0.030). Conclusions ERAS can be successfully implemented in older patients. There was equal compliance with the ERAS programme across the four age groups and no significant effect of age on LOS or morbidity.

Constitutive expression of cellular retinoic acid binding protein II and lack of correlation with sensitivity to all-trans retinoic acid in acute promyelocytic leukemia cells.

The up-regulation of cellular retinoic acid binding protein-II (CRABP-II) has been invoked as an important mechanism of clinically acquired resistance to all-trans retinoic acid (RA) therapy in acute promyelocytic leukemia (APL). To test this hypothesis, we used quantitative reverse transcription-PCR and fast performance liquid chromatography procedures to examine the levels of CRABP-II mRNA and RA binding activity in APL patient samples. We found that CRABP-II mRNA in APL cells from pretreatment patients (n = 36) was constitutively expressed at relatively high levels (median, 0.92; range, 0.16-4.13) relative to the level in CRABP-H protein-expressing NB4 cells (arbitrarily set at 1.0 unit). Consistent with this finding, the RA binding activity of CRABP in APL cells from three pretreatment cases (range, 27.2-53.2 fmol/mg protein) was similar to that of NB4 cells (22.6 +/- 5.4 fmol/mg protein). Furthermore, in the pretreatment samples, there was no association between CRABP-H mRNA expression level and APL cellular sensitivity to RA-induced differentiation in vitro. After 45 days of remission induction therapy on Eastern Cooperative Oncology Group protocol E2491, CRABP-II mRNA was modestly increased from day 0 values in patients treated with either RA (median increase, 0.41) or chemotherapy (median increase, 0.56), and there was no significant difference between the two treatment groups (P = 0.91). In patients studied after relapse from RA therapy (n = 7), there was a significant decline in APL cell sensitivity to RA-induced differentiation in vitro compared with patients after relapse from chemotherapy (n = 5; P = 0.015-0.055 at three RA concentrations tested), but in the RA relapse cases, there was no change from pretreatment levels of CRABP-II mRNA (median, 0.98) or, in three relapse cases studied, of RA protein binding activity (range, 22.1-70.7 fmol/mg protein). Taken together, our data strongly imply that variations in CRABP-II expression and RA binding activity are not causally related to the development of clinically acquired APL cellular RA resistance, but rather, they suggest that constitutive expression of CRABP-II could have a facilitative role in the response of APL cells to RA.

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen.

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.

BRCA1/2 Mutation-associated Breast Cancer, Wide Local Excision and Radiotherapy or Unilateral Mastectomy: A Systematic Review.

AIMS: BRCA1/2 mutation carriers show reduced apoptotic response to ionising radiation leading to recent debate about the safety of wide local excision and radiotherapy. The aim of the current study was to determine if BRCA1/2 mutation carriers with breast cancer undergoing wide local excision and radiotherapy show increased ipsilateral and contralateral breast tumour recurrence and reduced survival compared with unilateral mastectomy. MATERIALS AND METHODS: Following a detailed literature search, the methodology, populations, biases and outcomes of ipsilateral breast tumour recurrence, contralateral breast tumour recurrence and survival were evaluated for 25 articles. RESULTS: No differences in outcomes were found between wide local excision and mastectomy. BRCA1/2 mutation status was predictive of contralateral breast cancer only. Radiotherapy reduces the risk of ipsilateral recurrence and confers no increase in contralateral recurrence. CONCLUSION: BRCA1/2 mutation status does not preclude treatment with wide local excision and radiotherapy. Given the retrospective studies with inherent flaws and small patient numbers, further large prospective trials are required.

Improving postoperative pain management in subpectoral tissue expander implant reconstruction of the breast using an elastomeric pump.

INTRODUCTION: Postoperative pain after breast surgery is one of the major factors contributing to delay in mobilisation and prolonged hospital stay. A retrospective analysis was performed of patients undergoing skin sparing mastectomy and insertion of a subpectoral implant. The aim was to determine whether the use of an elastomeric local anaesthetic pump improved pain control and length of stay. METHODS: Twenty-five consecutive patients undergoing the above procedure were sited with an elastomeric local anaesthetic infusion pump intraoperatively, in addition to standard regular and pro re nata analgesia. The control group comprised 25 patients undergoing the same procedure in the same year who received standard analgesia alone. Visual analogue scale scores were recorded for the duration of inpatient stay, as was any further analgesic requirement. RESULTS: The median age was 51 years (range: 26-75 years) in the intervention group and 50 years (range: 28-70 years) in the control group. The mean visual analogue scale score was 0.28 (standard deviation [SD]: 0.61) at 24 hours for the intervention group and 1.84 (SD: 0.37) for the control group (p<0.0001). The mean length of stay was 1.8 days (SD: 0.71 days) for the intervention group and 2.28 days (SD: 0.94 days) for the control group (p=0.15). There were no complications involving catheter placement, leakage or toxicity relating to use of the local anaesthetic. CONCLUSIONS: There was significantly reduced pain with the use of the local anaesthetic infusion pump. The elastomeric pump is a step towards enhanced patient recovery after breast surgery in the case of skin sparing mastectomy and subpectoral tissue expander reconstruction.

Nucleotide sequence, transcription and deduced function of a gene involved in polyketide antibiotic synthesis in Streptomyces coelicolor.

The BamHI fragment containing the actIII gene, from the actinorhodin (Act) biosynthetic gene cluster of Streptomyces coelicolor A3(2), was sequenced. The derived amino acid sequence for the actIII gene shows homology to known oxidoreductases and the actIII product is believed to be responsible for catalysing a beta-keto reductive step during assembly of the Act polyketide chain. High resolution transcript mapping identified the transcription start point at 33 nucleotides upstream of the putative translation start codon. The transcript ends in a large invertedly repeated sequence. In vivo promoter-probe studies suggest that efficient transcription of the actIII gene requires the product of the actII gene.

Inhibition of all-trans-retinoic acid metabolism by fluconazole in vitro and in patients with acute promyelocytic leukemia.

All-trans-retinoic acid induces acute promyelocytic leukemia cell differentiation in vitro, and it produces greater than 90% complete remissions in patients with acute promyelocytic leukemia. Despite the high response rate, the majority of patients relapse with continued trans-retinoic acid therapy, and disease progression has been observed to be accompanied by an increase in the metabolism of trans-retinoic acid in the patients. In this study, the pharmacokinetic disposition of trans-retinoic acid was determined by HPLC in patients with acute promyelocytic leukemia before and after concurrent therapy with the triazole antimycotic agent fluconazole. Treatment with trans-retinoic acid for 1 week reduced the area under the plasma trans-retinoic acid concentration vs time curve in one patient by 67%, from 277 to 91 ng/mL/hr. Trans-retinoic acid pharmacokinetics were repeated after the second dose of fluconazole, administered 1 hour prior to the retinoid, and the AUC was found to be 401 ng/mL/hr, a greater than 4-fold increase from the pre-fluconazole level. A similar, though more modest, effect of fluconazole was seen in a second acute promyelocytic leukemia patient. The effect of fluconazole on trans-retinoic acid metabolism was examined in vitro using isolated human hepatic microsomes. Fluconazole inhibited the NADPH-dependent cytochrome P450-mediated catabolism of trans-retinoic acid in a concentration-dependent manner. Although fluconazole was approximately one-half as potent an inhibitor when compared with ketoconazole, a related antifungal drug, 60-90% inhibition was observed at the concentrations of fluconazole measured in the acute promyelocytic leukemia patients. Neither fluconazole nor ketoconazole inhibited lipid hydroperoxide-mediated metabolism of trans-retinoic acid. Since fluconazole is a well-tolerated agent frequently administered to leukemia patients, its use in combination with trans-retinoic acid merits further consideration.

Effect of retinoic acid and interferon alpha on granulocyte-macrophage colony forming cells in chronic myeloid leukemia: increased inhibition by all-trans- and 13-cis-retinoic acids in advanced stage disease.

Granulocyte-macrophage colony forming units (CFU-GM) from patients with advanced stage chronic myelogenous leukemia (CML), i.e. in blastic crisis (BC) or accelerated phase (AP), were inhibited by all-trans-retinoic acid (tRA) approximately 1000-fold more potently than those from chronic phase (CP) CML patients (median IC50 = 10(-9) M tRA for six CML-AP/BC cases vs > 10(-6) M tRA for seven CML-CP cases). A similar activity pattern was observed for the stereoisomer 13-cis-RA (cRA). There was no apparent correlation of CFU-GM retinoid sensitivity with cloning efficiency or other colony characteristics. Interferon alpha-2a (INF alpha) alone strongly inhibited CFU-GM growth in all four CML-AP/BC cases (IC50 < or = 250 IU/ml) and three out of seven CML-CP cases (IC50 < or = 500 IU/ml), but there was little or no interactive effect between various concentrations of tRA and INF alpha (50 IU/ml) on CFU-GM from either CML-AP/BC or CML-CP cases. These results suggest that CML-AP/BC CFU-GM have some intrinsic molecular alteration(s) which markedly enhances their responsiveness to tRA and cRA, which may be clinically exploitable.

Implications of a novel cryptic splice site in the BRCA1 gene.

This study was designed to determine the significance of a single intronic base change (IVS5-12 G-->A) found in a family with a history of breast cancer. This change is predicted to form a cryptic splice site resulting in the addition of 11 nucleotides to the BRCA1 transcript. The BRCA1 gene of the relatives and control individuals was sequenced and analyzed using RT-PCR, ASO hybridization, and size fractionation. All patients showed an 11 nucleotide insert at the intron 5/exon 6 boundary. This variant is likely to form a short protein product incapable of the hypothesized tumor suppressor functions of the BRCA1 gene. This information is important for providing counseling for families with this cryptic splice site and a family history of breast cancer.

Clinical manifestations in a large hereditary hemorrhagic telangiectasia (HHT) type 2 kindred.

HHT type 2 (HHT 2) is a multi-system vascular dysplasia caused by a mutation in the ALK-1 gene, but the phenotype has not been well defined. We report on 51 members of an HHT 2 kindred with an ALK-1 gene mutation shown to be associated with the disorder. This ALK-1 mutation was detected in 38 kindred members who were evaluated systematically for associated vascular abnormalities. Pulmonary arteriovenous malformations (AVMs) were found in 6% of those screened, cerebral AVM in 7%, hepatic AVM in 17%, and spinal AVM in 3%. We discuss these and other findings in the 38 affected kindred members, as well as findings in the 13 kindred members in whom the mutation was not detected. This study shows that pulmonary, cerebral, spinal, and hepatic AVMs can all occur in HHT 2. It also adds to the evidence suggesting that pulmonary AVMs are more common in HHT 1 than in HHT 2. We identify a higher prevalence of hepatic AVMs than previously reported in either HHT 1 or 2. This may be specific to the mutation in this kindred, but probably reflects the lack of routine screening for this manifestation. Even in this family in which all affected individuals have the same mutation, the clinical manifestations of HHT and their severity varied tremendously. Intrafamilial variation in expression of HHT is clearly significant, emphasizing the difficulty in establishing the diagnosis in individuals and in sub-typing families when DNA testing is not available.

Expression of retinoic acid receptor-beta 2 mRNA in normal cervical epithelium and cervical squamous cell carcinoma.

Retinoids have antiproliferative effects on epithelial cells and have been used as chemopreventive and chemotherapeutic agents for several human cancers. Retinoid/interferon combinations have demonstrated activity in advanced stage cervical cancer. The objective of this study was to quantify and localize the expression of RAR-beta 2, a retinoid inducible receptor, in normal cervix and cervical squamous cell carcinoma by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ RT-PCR. Specimens where obtained from 11 patients enrolled in a clinical trial to test all-trans retinoic acid (tRA) in combination with interferon-alpha 2a (IFN-alpha 2a) in the treatment of metastatic or recurrent cervical carcinoma. Expression of RAR-beta 2 in cervical carcinoma and normal cervix was measured by quantitative RT-PCR. DNA competitors were used to estimate the relative expression level of RAR-beta 2. Expression of RAR-beta 2 was examined in normal cervix by in situ RT-PCR. Expression of RAR-beta 2 in cervical carcinoma ranged from 0.33 to 1.40 with a mean of 0.89+/-0.13 vs. 1.0+/-0.13 for normal cervix (NS) with RAR-beta 2 reduced to less than or equal to 65% in five cases. Irt situ RT-PCR identified RAR-beta 2 most prominently in basal and para-basal epithelial cell layers of normal exocervix; stromal expression was markedly decreased. This is the first report to localize expression of RAR-beta 2 mRNA in normal cervical epithelium and quantify expression in normal cervix and cervical squamous cell carcinoma. Because retinoid receptors are the proximate mediators of retinoid action on gene expression, alteration of their expression or function could result in cancer development.

Associative structure of differential inhibition: implications for models of conditioned inhibition.

Following A+/X- training (with A, X, and + being a light, tone, and footshock, respectively), rats received extinction of A and the training context, extinction of the training context alone, or no extinction. The inhibitory potential of X was then assessed with conditioned lick suppression in a neutral context using both summation and retardation tests. Extinction of the training context alone and extinction of A and the training context reduced the inhibitory potential of X appreciably and equally. Hence, what is traditionally called differential inhibition appears to depend not on the excitatory value of A but on the excitatory value of the training context. In conjunction with what is known about other inhibitory training procedures, these results suggest that a conditioned inhibitor is a stimulus that has been paired with little or no reinforcement in the presence of an accompanying stimulus that predicts greater reinforcement.