Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS.

Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery, leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.

Supporting cystic fibrosis disease management during adolescence: the role of family and friends.

BACKGROUND: Successful management of a complex disease, such as cystic fibrosis (CF), requires support from family and friends; however, few studies have examined social support in adolescents with CF. METHODS: Twenty-four adolescents were interviewed about the support they receive from family and friends. Interviews were transcribed, coded and analysed to determine the types, frequency and perceived supportiveness of specific behaviours. RESULTS: Both family and friends provided treatment-related support to adolescents with CF. Family provided more tangible support and friends provided more relational support. Adolescents also reported that the manner, timing and context of support behaviours influenced their perceptions of the behaviours' supportiveness. A subset of adolescents (17%) chose not to disclose their diagnosis to their friends. CONCLUSIONS: The provision of support appears to be distinct from adolescent's perception of support and there may be some behaviours, such as treatment reminders, that are important to disease management but viewed as less supportive by adolescents. Facilitating increased social support holds the promise of improving disease management during adolescents, but more work is need to understand which aspects of support are related to management outcomes.

Galantamine in frontotemporal dementia and primary progressive aphasia.

BACKGROUND/AIMS: The treatment of frontotemporal dementia (FTD) has been mainly symptomatic. Small randomized or open-label case control studies of neurotransmitters have been inconclusive. We tried galantamine in the 2 most common varieties of FTD. METHOD: Thirty-six behavioral variety FTD and primary progressive aphasia (PPA) patients were treated in an open-label period of 18 weeks and a randomized, placebo-controlled phase for 8 weeks with galantamine. The primary efficacy measures were the Frontal Behavioral Inventory, the Aphasia Quotient of the Western Aphasia Battery, the Clinical Global Impression of Severity and the Clinical Global Impression of Improvement. RESULTS: No significant differences in behavior or language were found for the total group. A treatment effect (p = 0.009), in a subgroup of subjects with PPA in the global severity score, in favor of galantamine was detected in the placebo-controlled withdrawal phase but was not considered significant after correction for multiple comparisons. The language scores for the treated PPA group also remained stable compared to the placebo group, which showed deterioration. CONCLUSION: Galantamine is not effective in the behavioral variety of FTD, but a trend of efficacy is shown in the aphasic subgroup, which may be clinically significant. Galantamine appeared safe in FTD/PPA.

Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers.

There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.

Improving seedling vigour of indigenous medicinal plants with smoke.

The application of smoke and aqueous smoke solutions stimulates seed germination in a number of plant species. This study highlights the effects of aerosol smoke and smoke solutions on the germination and seedling vigour of three South African indigenous medicinal plants Albuca pachychlamys, Merwilla natalensis and Tulbaghia violacea. The vigour index of one-week-old seedlings of all three species examined was increased with the application of dry smoke and smoke extract dilutions, as compared to control treatments. Seedlings of A. pachychlamys germinated with smoke solutions showed a significant (p0.05) gain in bulb and leaf mass (27.9 and 197.6 mg respectively) compared to untreated seedlings (9.9 and 124.7 mg respectively) when grown in vitro for 75 days. The leaf mass of smoke solution-treated seedlings of T. violacea was significantly (p0.05) higher (120.4 mg) than that of untreated seedlings (47.6 mg). Subsequently, the height of seedlings in both species was also significantly (p0.05) greater. Seedlings germinated in water and then transferred to smoke solutions (1:2000) showed enhancement of some of the growth parameters studied. Albuca pachychlamys and T. violacea seeds exposed to aerosol smoke exhibited higher seedling survival percentages than from non-smoked seeds, while no significant effect was observed for M. natalensis seedlings. This investigation shows that the application of smoke technology can be adopted to produce high vigour seedlings.

Riding the wave: South Africa's contribution to ethnopharmacological research over the last 25 years.

South Africa is a country with both rich floral biodiversity and cultural diversity. Traditional herbal medicines form an important part of the healthcare of most South Africans, and relies heavily on the use of indigenous plants. This article briefly describes the role South Africa has played in recent years, in contributing to the worldwide increase in research in the field of ethnopharmacology.

Phytochemical and pharmacological screening of Sterculiaceae species and isolation of antibacterial compounds.

Little previous phytochemical investigation has been conducted on South African Sterculiaceae species used in traditional medicine. In this study, five species, varying in growth type (small herbs, shrubs and large trees) and traditional usage were investigated. The species screened were Cola greenwayi Brenan, Cola natalensis Oliv., Dombeya burgessiae Gerr. ex Harv., Dombeya cymosa Harv. and Hermannia depressa N.E.Br. Extracts were screened for alkaloids, cardiac glycosides, cyanogenic glycosides, saponins and tannins. The probable presence of bufadienolides in the leaf material of Dombeya burgessiae and Dombeya cymosa was determined. Alkaloids, cyanogenic glycosides and saponins were absent in all the plant material investigated. Tannins were detected in the leaf extract of Cola greenwayi and in the leaves, stems and roots of Hermannia depressa. Extracts were screened for anti-inflammatory and antibacterial activity using the cyclooxygenase-1 (COX-1) inhibition assay and the microdilution antibacterial assay. The ethanol and dichloromethane extracts of Cola greenwayi, Dombeya burgessiae and Dombeya cymosa, and the dichloromethane extracts of Hermannia depressa showed the highest levels of COX-1 inhibition. It is possible that the high levels observed may be due to the presence of tannins in some of the extracts. Generally, all the aqueous extracts exhibited low activity. Similarly, no antibacterial activity was observed with the aqueous extracts, although some mild activity was exhibited with some of the ethanol and ethyl acetate extracts. Following the general phytochemical and pharmacological screening, extracts showing antibacterial activity were further purified using bioassay-guided fractionation. Dombeya rotundifolia (Hochst.) Planch., which was screened in a previous study, was also included in the isolation of active compounds. A bioautographic assay, using Staphylococcus aureus, was used to detect the presence of the antibacterial compounds. These were isolated and identified as fatty acids.

The time course of metabolic changes induced by dietary cholesterol in guinea pigs.

The time course of the effects of dietary cholesterol on the lipid composition of liver, plasma and red cells of guinea pigs, of the pathological changes of tissues and of hematological parameters was studied. The purpose was to identify the primary injury and so to contribute to the eludication of the mechanism(s) for the development of the hemolytic anemia observed in this species after long-term cholesterol supplementation. The results showed that the initial effects observed within 1 week occur in the liver lipids and histology accompanied by changes in plasma and RBC lipids. These events were followed by further, slower increases of tissue lipids without major qualitative changes. The earliest signs of an anemia were observed between weeks 5 and 7. We conclude that the primary insult of cholesterol is liver damage leading to the production of abnormal plasma lipoproteins which in turn cause a net increase of RBC-cholesterol that is accompanied by their morphological abnormalities. The hemolytic anemia does not seem to be caused directly by either the altered composition of RBC nor their altered morphology.

Allergic bronchopulmonary aspergillosis in cystic fibrosis: reported prevalence, regional distribution, and patient characteristics. Scientific Advisory Group, Investigators, and Coordinators of the Epidemiologic Study of Cystic Fibrosis.

OBJECTIVES: Using the large database from the Epidemiologic Study of Cystic Fibrosis (ESCF), the objectives of this study were to (1) estimate the reported prevalence of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF); (2) compare reported prevalence rates across geographic regions; (3) compare reported prevalence rates between patient subgroups based on demographic and disease characteristics; and (4) describe the ABPA group with regard to their sex, age, and disease severity. STUDY DESIGN: All patients > or = 5 years of age enrolled in ESCF between December 1993 and May 1996 were eligible. Criteria for the diagnosis of ABPA were defined by the ESCF guidelines. Prevalence rates for ABPA were calculated, and potential risk factors for the diagnosis of ABPA were analyzed, including sex, age, pulmonary function, diagnosis of asthma, presence of wheeze, and positive respiratory culture for Pseudomonas. RESULTS: There were 14,210 eligible patients enrolled in ESCF during this period, and ABPA was diagnosed in 281 patients (2%). Regional prevalence varied from 0.9% in the Southwest to 4.0% in the West. Increased prevalence rates occurred in female patients, the adolescent age group, and subjects with lower lung function, wheeze, asthma, and positive Pseudomonas cultures. Although most ABPA patients had evidence of airway obstruction, 10% had an FEV1 of > 100% of predicted. The rates of wheeze (17%) and asthma (30%) were lower than expected in the ABPA group. CONCLUSIONS: This observational study found a reported prevalence rate of ABPA of 2% of CF patients in a large database. This rate was lower than the 5 to 15% rate reported in smaller studies, suggesting that ABPA is underdiagnosed in the CF population. There was wide regional variation in reported prevalence rates, which is unexplained at this time. The characteristics of the patients with ABPA and the epidemiologic risk factors for diagnosis of ABPA were described. Simplified diagnostic criteria were adapted for ESCF with the intent of increasing awareness of ABPA among the participants in this study.

Linear distortion of octahedral metal centres by multiple hydrogen bonds in modular ML(4) systems.

A series of compounds of the type [M(1)(4)(H(2)O)(2)]SO(4)[middle dot]2H(2)O containing a simple urea-based pyridyl ligand have been synthesised and characterised by X-ray crystallography. The enclathrated water exists within discrete linearly stacked cavities and causes significant distortions in the M-OH(2) bonds due to the presence of a strongly hydrogen bonded water square.

Perfluoroaryl boryl complexes: synthesis, spectroscopic and structural characterisation of a complex containing the bis(pentafluorophenyl)boryl ligand.

The synthesis, spectroscopic and structural characterisation of the bis(pentafluorophenyl)boryl derivative CpFe-(CO)2B(C6F5)2 are reported.

Radiation therapy and clinical physics practices in the midwest (1982-1986).

As a part of an on-site physics review procedure, the Midwest Center for Radiological Physics (MWCRP) interviewed midwest clinical radiotherapy physicists and radiation therapists in institutions that participated in federally funded Cancer Control Programs. Information from 77 institutions was compiled regarding types of megavoltage units, daily patient load, radiotherapy personnel, treatment planning responsibilities, dosimetric practices, and treatment planning computers. Even though some practices, such as frequency of patient charge checks, were consistent throughout the midwest, other practices varied considerably such as patient load with the number of megavoltage units. This information may be useful either for planning a new facility, considering the needs for staff, or for comparing existing practices and responsibilities.

Epidemiologic study of cystic fibrosis: design and implementation of a prospective, multicenter, observational study of patients with cystic fibrosis in the U.S. and Canada.

Cystic fibrosis (CF) is a complex illness characterized by chronic lung infection leading to deterioration in function and respiratory failure in over 85% of patients. An understanding of the risk factors for that progression and the interaction of these factors with current therapeutic strategies should materially improve the prevention of this progressive lung disease. The Epidemiologic Study of Cystic Fibrosis (ESCF) was therefore designed as a multicenter, longitudinal, observational study to prospectively collect detailed clinical, therapeutic, microbiologic, and lung function data from a large number of CF treatment sites in the U.S. and Canada. The ESCF also serves an important role as a phase-IV study of dornase alfa. To be eligible for enrollment, subjects must have the diagnosis of CF and receive the majority of their care at an ESCF site. In this paper, the authors present the ESCF study design in detail. Further, enrollment data collected at 194 study sites in 18,411 subjects enrolled from December 1, 1993 to December 31, 1995 are presented in summary form. This comprehensive study is unique in the detail of clinical data collected regarding patient monitoring and therapeutic practices in CF care. Two companion articles present data regarding practice patterns in cystic fibrosis care, including data on resource utilization and prescribing practices.

Cystic fibrosis, nutrition, and the health care team.

Because of the multiple systems involved in cystic fibrosis, the variability and chronicity of the disease, and the increased survival of this population, a specialty team of experts for care has evolved. A multidisciplinary approach is essential to assist patients and their families in adjusting to the disease and to optimize treatment interventions. The dietitian is responsible for assessment of nutritional status, including the determination of energy requirements and eating habits, interpretation of anthropometric data, and evaluation of nutritional adequacy. The nutrition care plan forms an integral part of the overall treatment objectives and is reported to other team members as it is devised, implemented, and monitored. A consensus report issued in April 1990 by the Cystic Fibrosis Foundation includes both general nutrition guidelines and detailed recommended treatment standards aimed at providing optimal nutrition care.

Management of chronic sinusitis in cystic fibrosis.

Chronic rhinosinusitis is extremely common in patients with cystic fibrosis. It causes numerous problems in these patients and can put them at risk for life-threatening illness. Potential problems include nasal obstruction, congestion, sinus pain and pressure, infection (usually with Pseudomonas organisms), hyposmia or anosmia, and the seeding of bacteria into the lower respiratory tract. Cystic fibrosis patients with chronically infected sinuses are at increased risk for pneumonia following lung transplantation. A prophylactic protocol has been developed for the management of chronic sinusitis in patients with cystic fibrosis. These patients are fully evaluated at the Nasal Dysfunction Clinic of the University of California, San Diego (UCSD), Medical Center. Based on the results of the evaluation, they are treated with endoscopic sinus surgery, partial middle turbinectomy, septoplasty, and a large middle meatal maxillary antrostomy. Surgery is followed by a rigorous regimen of pulsatile hypotonic saline nasal irrigation to wash away tenacious cystic secretions. Tobramycin (Nebcin) is given once daily in the nasal irrigant to inhibit the growth of Pseudomonas organisms. At the USCD Nasal Dysfunction Clinic, this prepulmonary transplantation protocol is now used in all cystic fibrosis patients with chronic sinusitis.

Biological activities and distribution of plant saponins.

Plant saponins are widely distributed amongst plants and have a wide range of biological properties. The more recent investigations and findings into their biological activities were summarized. Isolation studies of saponins were examined to determine which are the more commonly studied plant families and in which families saponins have been identified.

Assessing African medicinal plants for efficacy and safety: agricultural and storage practices.

The paper reviews an important but little researched area of ethnopharmacology, namely, the effect of cultivation and post-harvest storage practices on levels of biological activity in traditionally used medicinal plants. Changes in COX-1 inhibition and antibacterial activity, for example, occur at the onset of senescence and, in some species, are influenced by plant age. Plants in cultivation were also shown to have reduced anthelmintic and antibacterial activity while hypoxoside production was affected by nitrogen and phosphorous. Irrigation treatments, however, increased anthelmintic activity and, therefore, could be applied to medicinal plants cultivated in low rainfall areas. Pesticides have also been implicated in the regulation of plant growth and secondary metabolite production in cultivated medicinal plants, but residue levels have, so far, not been monitored. Post harvest storage of medicinal plants has been poorly researched in southern Africa. Available data indicates that antibacterial and anti-inflammatory activity changes following storage and is both species and temperature dependent. Similar trends were noted for materials that had been rapidly aged. Fatty acids with antibacterial activity are stable in dry specimens and, as such, may account for the fact that activity is unaffected by storage in certain instances.

Munchausen syndrome by proxy and apnea (MBPA). A survey of apnea programs.

The authors sent questionnaires to 127 apnea monitoring programs asking whether they had treated patients whose apnea appeared to have been induced by a parent (Munchausen syndrome by proxy-apnea, or MBPA). Fifty-one programs (40%) reported 54 cases of this kind from among their 20,090 monitored patients (0.27%). The authors obtained further information on 32 of these patients, 83% of whom presented with infantile apnea before the third month of life. Although medical problems were documented, including apnea, the clinical condition of these infants was inconsistent with the multiple life-threatening episodes typically reported by parents. Twenty-one of the infants reportedly received cardiopulmonary resuscitation at home, 15 had ambulance calls to the home, and 24 were rehospitalized. Child Protective Service agencies were consulted for 12 patients, 5 of whom were placed in foster homes. Three index infants and five siblings are known to be dead, and one additional infant is severely brain damaged from abuse.

Elevated concentrations in serum immunoglobulins due to infection by ovine progressive pneumonia virus.

Sixty-seven serum samples were obtained from 2 sheep flocks. Agar gel immunodiffusion (AGID) was used to separate progressive pneumonia virus (PPV)-infected sheep from noninfected sheep by the presence of precipitating antibodies. Immunoglobulin (Ig), total protein, and albumin concentrations were then measured from all 67 sera to determine whether differences existed between PPV-infected and non-infected sheep. A significant difference (P less than 0.0005) was found in both total protein and Ig concentration between PPV-infected and noninfected sheep. This corresponding difference was absent in albumin measurements. The significant differences (P less than 0.0005) in Ig and total protein concentrations were then used to evaluate a field test for diagnosing progressive pneumonia. The possibility of using either total protein or Ig concentrations as a field test was found to be highly unlikely due to variation in individual values.