Oncogenic targeting of BRM drives malignancy through C/EBPß-dependent induction of α5 integrin.

Integrin expression and activity are altered in tumors, and aberrant integrin signaling promotes malignancy. However, how integrins become altered in tumors remains poorly understood. We discovered that oncogenic activation of MEK signaling induces cell growth and survival, and promotes the malignant phenotype of mammary epithelial cells (MECs) by increasing α5 integrin expression. We determined that MEK activates c-Myc to reduce the transcription of the SWI/SNF chromatin remodeling enzyme Brahma (BRM). Our studies revealed that reduced BRM expression and/or activity drives the malignant behavior of MECs by epigenetically promoting C/EBPß expression to directly induce α5 integrin transcription. Consistently, we could show that restoring BRM levels normalized the malignant behavior of transformed MECs in culture and in vivo by preventing C/EBPß-dependent α5 integrin transcription. Our findings identify a novel mechanism whereby oncogenic signaling promotes malignant transformation by regulating transcription of a key chromatin remodeling molecule that regulates integrin-dependent stromal-epithelial interactions.

Multiple, unilateral lisch nodules in the absence of other manifestations of neurofibromatosis type 1.

Lisch nodules associated with Neurofibromatosis Type 1 (NF1) are usually multiple and bilateral in nature. Here, we report a 21-year-old healthy, Caucasian female who was diagnosed with multiple, unilateral Lisch nodules during routine eye examination. A thorough history and physical examination revealed no other signs of NF1. We diagnosed the rare occurrence of numerous, unilateral Lisch nodules in the absence of additional features of NF1 in our patient and provide a discussion concerning the differential diagnosis of Lisch nodules as well as the potential genetic explanation of this finding.

The African cherry (Prunus africana): can lessons be learned from an over-exploited medicinal tree?

For the last 35 years, the African cherry (Prunus africana (Hook. f.) Kalm.) has been used in the treatment of benign prostatic hyperplasia and other disorders. The bark, from which the treatment is derived, is entirely wild-collected. The major exporters of bark include Cameroon, Madagascar, Equatorial Guinea, and Kenya. Groupe Fournier of France and Indena of Italy produce 86% of the world's bark extract, both for their own products and for the free market. Worldwide exports of dried bark in 2000 have been estimated at 1350-1525 metric tons per year, down from its peak of 3225 tons in 1997. Bark extracts (6370-7225 kg per year) are worth an estimated $4.36 million US dollars per year. In 2000, Plantecam, the largest bark exporter in Africa, closed its extraction factory in Cameroon, due to complex ecological, social, and economic factors. Wild-collection is no longer sustainable (and probably never was) where harvest seriously affects morbidity and mortality rates of harvested populations. Since 1995, it has been included in CITES Appendix II as an endangered species. In this paper, alternatives to wild-collection to meet future market demand are investigated, including conservation practices, enrichment plantings, small- and large-scale production, and protection of genetic resources. The species is at the beginning of a transition from an exclusively wild-collected species to that of a cultivated medicinal tree.

Bradykinin analogues with beta-amino acid substitutions reveal subtle differences in substrate specificity between the endopeptidases EC 3.4.24.15 and EC 3.4.24.16.

The closely related zinc metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16) cleave many common substrates, including bradykinin (BK). As such, there are few substrate-based inhibitors which are sufficiently selective to distinguish their activities. We have used BK analogues with either alanine or beta-amino acid (containing an additional carbon within the peptide backbone) substitutions to elucidate subtle differences in substrate specificity between the enzymes. The cleavage of the analogues by recombinant EP24.15 and EP24.16 was assessed, as well as their ability to inhibit the two enzymes. Alanine-substituted analogues were generally better substrates than BK itself, although differences between the peptidases were observed. Similarly, substitution of the four N-terminal residues with beta-glycine enhanced cleavage in some cases, but not others. beta-Glycine substitution at or near the scissile bond (Phe5-Ser6) completely prevented cleavage by either enzyme: interestingly, these analogues still acted as inhibitors, although with very different affinities for the two enzymes. Also of interest, beta-Gly8-BK was neither a substrate nor an inhibitor of EP24.15, yet could still interact with EP24.16. Finally, while both enzymes could be similarly inhibited by the D-stereoisomer of beta-C3-Phe5-BK (IC50 approximately 20 microM, compared to 8 microM for BK), EP24.16 was relatively insensitive to the L-isomer (IC50 12 approximately microM for EP24.15, >40 microM for EP24.16). These studies indicate subtle differences in substrate specificity between EP24.15 and EP24.16, and suggest that beta-amino acid analogues may be useful as templates for the design of selective inhibitors.

Carpentier-Edwards standard and supraannular porcine bioprostheses: comparison of technology.

BACKGROUND: Performance with regard to structural valve deterioration (SVD) with the Carpentier-Edwards standard (CE-S) and supraannular (CE-SAV) (Baxter Healthcare Corp, Irvine, CA) porcine bioprostheses was evaluated to determine whether progress in reduction of structural failure has been achieved with technological changes. METHODS: The CE-S was implanted during 567 aortic valve replacement (AVR) and 486 mitral valve replacement (MVR) procedures, and the CE-SAV was implanted during 1,670 AVR and 1,096 MVR procedures. The failure mode of early stent dehiscence with the CE-SAV prosthesis, thought to be controlled by manufacturing changes in 1986 and 1987, supported comparison of the CE-SAV with censored cases of stent dehiscence. Stent dehiscence accounted for only 1.2% (1 of 81) and 14.1% (29 of 205) of AVR and MVR CE-SAV failures, respectively. RESULTS: The only difference for AVR for freedom from SVD occurred in the 21- to 40-year age group at 15 years and was 68% for the CE-SAV and 31% for the CE-S (p<0.05). In the 61- to 70-year age group, freedom from SVD at 15 years was 76% for the CE-S and 84% for the CE-SAV; for the 71-year or higher age group, freedom from SVD was 89% and 95%, respectively (p = NS). For MVR freedom from SVD was different only in the 71-year or higher age group and was 90% for the CE-S and 59% for the CE-SAV (p<0.05). Freedom from SVD was reduced but was similar (p = NS) for the other age groups. For AVR the actual freedom from SVD at 15 years for the CE-S and CE-SAV was, respectively, 79% and 72% for the 51- to 60-year age group, 86% and 91% for the 61- to 70-year age group, and 98% and 98% for the 71-year or higher age group. For MVR, these rates were, respectively, 69% and 75% for the 61- to 70-year age group and 96% and 89% for the 71-year and higher age group. CONCLUSIONS: The technologic advancements made in the second-generation CE-SAV bioprosthesis to reduce the incidence of structural failure have not uniformly been successful. The actual freedom from SVD provides evidence for implantation of porcine bioprostheses for AVR in age groups 61 to 70 years and 71 years or higher and for MVR in the age group 71 years or higher.

Resting systolic blood pressure, parental history of hypertension, and sensitivity to noxious stimuli.

Increased nociceptive thresholds have been reported in hypertensive rats and humans, and also in normotensive humans at risk for developing hypertension by virtue of elevated resting blood pressure levels or a family history of hypertension. Because risk for hypertension may be more accurately predicted by a combination of risk factors, the present study examined the pain sensitivity of young adult males as a function of resting systolic blood pressure and family history of hypertension. Cold pressor and forearm ischemia tasks were administered in a counterbalanced order. Pain was assessed using numerical rating scales of intensity and unpleasantness during the tasks and the McGill Pain Questionnaire immediately following the tasks. Individuals with a parental history of hypertension obtained significantly lower Pain Rating Index scores on the McGill Pain Questionnaire for both tasks, and also reported significantly lower pain on both numerical rating scales during the ischemic task. No significant relationship was observed between resting systolic blood pressure and measures of pain sensitivity.

Exteroceptive suppression of temporalis and masseter muscle activity is enhanced in offspring of hypertensives.

Exteroceptive suppression of temporalis and masseter muscle activity was examined in young men with and without a parental history of hypertension. Recent clinical studies suggest that the second exteroceptive suppression period is attenuated in several chronic pain disorders and that this brainstem reflex may serve as a noninvasive index of endogenous pain control. In the present study, offspring of hypertensives exhibited a significant protraction of the late exteroceptive suppression period for both muscle sites, suggesting that the decreased pain sensitivity previously observed in individuals at risk for hypertension may be related to enhanced central pain modulation.

Multipin solid-phase synthesis of acyl 2, 3-diaminopropionic acid oligomers.

A modular approach for the synthesis of sets of diverse organic molecules is described. N-alpha-Fmoc-N-beta-Alloc-D-2,3-diaminopropionic acid (Fmoc-D-Dpr(Alloc)-OH) was prepared in four steps from Boc-D-asparagine and used as a scaffold for attachment of sidechains. Using the Multipin approach, a number of model acyl trimers were rapidly prepared by sequential coupling of Fmoc-D-Dpr(Alloc)-OH and acylation of the beta-amino group with a range of activated carboxylic acids.

Parental history of hypertension and enhanced cardiovascular reactivity are associated with decreased pain ratings.

Ischemic pain was examined in adult males with and without a parental history of hypertension. Blood pressure and heart rate were recorded during baseline, cold pressor, and ischemia. Repeated pain ratings were obtained during cold pressor and ischemia, and the McGill Pain Questionnaire was completed after each stressor. A median split was used to identify high and low mean arterial pressure and heart rate reactors to cold pressor. Parental history of hypertension, high heart rate reactivity, and high mean arterial pressure reactivity were each associated with significantly lower ischemic pain ratings on the McGill Pain Questionnaire, suggesting that risk for hypertension is associated with hypoalgesia in normotensives.

Prenatal stress attenuates ulceration in the activity stress paradigm.

In the present study, 28 pregnant rats were subjected to either light-restraint stress or no manipulation for days 14-21 of the gestational period. At approx. 50 days of age, both male (n = 16) and female (n = 16) prenatally stressed (PS) and control offspring were subjected to the activity stress (AS) paradigm. During this subsequent stress experience, PS rats developed less ulceration than control rats. PS rats also displayed about half the activity of the control animals during the habituation phase of the AS paradigm, prior to the induction of stress. Given this decrease in baseline activity in PS animals, implications of using activity as a measure of emotionality in PS animals are discussed. Several sex differences were also observed; females differed from males in that they 1) exhibited higher activity levels in both the habituation and experimental phases of the AS procedure, 2) developed heavier relative adrenal weights, and 3) reached criteria for sacrifice in fewer days.

The cardiac surgery program at the Royal Columbian Hospital: review of the first fiscal year.

From a budgetary viewpoint, the authors summarize the operative experience of the cardiac surgery program at the Royal Columbian Hospital during its first fiscal year of operation. The program was funded for 250 cardiopulmonary bypass (CPB) procedures: $16,800 per CPB procedure ($4.2 million for the program). The 250 CPB procedures were performed on 248 patients. The 30-day operative mortality was 2%. Thirty patients (12.1%) underwent a second operation for complications or delayed primary closure of the sternum, or both; the complications included aortic prosthetic perivalvular leaks in 2 patients. Eight patients (3.2%) required insertion of an intra-aortic balloon pump preoperatively to stabilize their condition; 10 others (4.0%) required intra-aortic balloon pump insertion at surgery to correct low-cardiac-output syndrome. Blood products were needed for 149 (59.6%) of the 250 CPB procedures. The average hospital stay was 10.4 days for noncoronary procedures and 9.0 days for coronary procedures.

Alerting patients to the risk of radon.

The potential lung cancer risk from exposure to radon gas and the development of appropriate public health policy have been the subject of much discussion for several years. The American Lung Association has taken a leading role in educating the public on radon and other environmental hazards. This article presents background on radon, including the issues of risk assessment and policy development; reviews the current understanding of the hazards of exposure and the scope of the problem; describes how to test for radon; and discusses how to decrease radon levels.

The future of environmental health in Scotland.

This paper reviews the considerable progress which the environmental health profession has achieved, particularly during the course of the past 10-20 years. The future of the profession is considered particularly in relation to the development of higher degree opportunities and progress of research, the expanding use of support and associate specialist staff, and the thorny area of meat inspection. Further re-organisation of local government is inevitable and the paper suggests the development of a broader based environmental health and public safety service within local government, mirrored nationally by a similar department at the Scottish Office. The key roles of the Environmental Health (Scotland) Unit and the Royal Environmental Health Institute of Scotland in the future development of the profession are highlighted.

Review and comparison of current trends in the postoperative management of tendon repair.

The precision of the Evans/Burkhalter protocol and the work by Silverman and associates exemplify one of the most valuable of all current trends in rehabilitation of the healing tendon. Knowledge of tendon excursion at each level and throughout the range of motion in each joint gives us safe parameters for tendon mobilization. Hand rehabilitation is becoming more of a science while remaining an art. Research into tendon healing, nutrition, anatomy, biomechanics, and physiology gives us a solid basis for our treatment techniques. We now need to replicate studies already performed and quantify more precisely the data we have. Many questions remain unanswered. There is a wide variety in the position of splinting for flexor tendon mobilization under current protocols: What joint positions are optimal and why? The number and frequency of repetitions in early mobilization protocols varies greatly: What number and frequency is more appropriate for which patients? How much tendon excursion will control adhesions, promote healing, and avoid gap formation or elongation of the repair? How much force should we apply passively to maintain or increase joint motion? How soon should we start active motion, and how can we control the strength of those early muscle contractions? Do "place-hold" exercises truly place less tension on the repair site? How soon should we begin resisted exercise, and how much resistance are we applying with each type of exercise? Should blocking exercises be considered resistive? How should tendon management protocols be adapted in the presence of associated injuries? Lack of space has prevented discussion here of recent and needed research in a number of areas, such as the effectiveness and appropriate precautions for the use of ultrasound, iontophoresis, and neuromuscular electrical stimulation in tendon management. The evidence is growing, but we have a long way to go. To improve our clinical results, the trend toward precision must continue and grow.