Association between ischaemic heart disease and interstitial lung disease: a case-control study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is increasing in incidence. One of the authors noted that many of his patients with IPF were taking statins, and suspected an association. A case-control study was undertaken to investigate the association of statins with interstitial lung disease. METHODS: The study population comprised patients attending the respiratory outpatients diagnosed with IPF between the beginning of 1999 and the beginning of July 2004, and 50 cases were identified. Data regarding the age, sex, smoking habits, occupational histories, exposure to birds, co-morbidity (ischaemic heart disease, diabetes, atrial fibrillation, and hyperlipidaemia), biopsy evidence for IPF, and use of beta blockers, statins, aspirin, NSAIDS, loop diuretics and proton pump inhibitors were recorded. Two age and sex-matched controls were obtained for each case from patients attending a general gastroenterology clinic within 3 months of attendance of the case, and thus 100 controls were obtained. Data on the controls were collected as for the cases. RESULTS: Of the cases, 12 of 50 were taking statins compared with 20 of 100 controls (matched OR 1.13, CI 0.30-4.24, NS). Coronary artery disease was seen in 20 of 50 cases and 20 of 100 controls (matched OR 5.37, CI 1.52-19.0, p<0.01). CONCLUSIONS: There was no statistically significant association between the use of statins and the diagnosis of interstitial lung disease. However there was a statistically significant association between ischaemic heart disease and the diagnosis of ILD.

Stability of supershort single-walled carbon nanotubes.

How short can single-walled carbon nanotubes (SWNTs) be? How stable are such supershort SWNTs (ss-SWNTs)? This work is the first to address these questions. On the basis of binding energy (E(B)), standard heats of formation , and strain energy (E(S)), we found that SWNTs with only one benzene ring in the axial direction, which we refer to as supershort SWNTs (ss-SWNTs), can be thermodynamically stable. On the basis of the data of E(B), , and E(S), the relative stabilities of ss-SWNTs, fullerenes, polycyclic aromatic hydrocarbons, and butadiyne are discussed. This study has laid a theoretical foundation for the possible synthesis of ss-SWNTs.

Regional population structure of a widely introduced estuarine invertebrate: Nematostella vectensis Stephenson in New England.

Nematostella vectensis is an infaunal anemone occurring in salt marshes, lagoons and other estuarine habitats in North America and the United Kingdom. Although it is considered rare and receives protection in England, it is widely distributed and abundant in the United States, particularly along the Atlantic coast. Recent studies suggest that both anthropogenic dispersal and reproductive plasticity may significantly influence the genetic structure of N. vectensis populations. Amplified fragment length polymorphism (AFLP) fingerprinting of individuals from nine populations in the northeastern United States indicates that stable populations are maintained by both asexual and sexual reproduction; in some cases asexually reproducing lineages exist within sexually reproducing populations. F statistics reveal extraordinarily high degrees of genetic differentiation between populations, even those separated by very short distances (less than 100 m). Genetic distances show little to no correlation with geographical distances, consistent with a role for sporadic, geographically discontinuous dispersal coupled with limited gene flow. No single genotype was found at more than one site, despite apparent homogeneity of habitat. In contrast with reported genotypic distributions for Nematostella in the United Kingdom, where a single clonal genotype dominates at multiple sites through southern England, our data thus fail to support the hypothesis of a general-purpose genotype in the northeastern United States. However, they are consistent with important roles for reproductive plasticity, sporadic introductions and complex local population dynamics in determining the global and regional distribution of this species.

Gamete retrieval in terminal conditions.

There has been a growing interest and requests by patients facing intensive chemotherapy or surgically ablative procedures for gamete retrieval and preservation for future procreative efforts. There are technical difficulties in this area but little ethical discomfort. More troubling are the issues that arise with a terminally ill, incapable patient-one who is in a persistent vegetative state or who is declared brain dead or who is neurologically devastated with no hope for recovery, but not yet in either of the above states-or with a person who has suddenly died. In these cases, the surviving spouse, partner, or family members may request gamete retrieval for future reproductive efforts. Discussion of this topic within the Ethics Consultation Service at the University of Virginia demonstrated a need for development of insight derived from facts and ethical deliberation to help formulate a policy that would apply to such cases. A group was assembled with the expertise to explore the issue and to help formulate a policy that could be suggested for adoption by the hospital administration. The group consisted of a urologist with experience in sperm retrieval from terminally ill patients; the director of the laboratory supporting the assisted reproductive facility in the Department of Obstetrics and Gynecology; the chairperson of the Ethics Consultation Service (who is also a neonatologist); and 2 members of the Ethics Consultation Service, one a genetic counselor and the other an obstetrician-gynecologist with a master's degree in biomedical ethics. Current literature was reviewed, the expertise of the urological member and the reproductive laboratory director was explored, and the insight of the members of the Ethics Consultation Service was added. We explored the technical aspects of both male and female gamete retrieval and preservation and the reproductive potential of these stored gametes. We present a review of the current literature on both the technical and ethical aspects of the topic. Finally, we present a policy that we deem acceptable for adoption and that should be of value to other practitioners and facilities as they contemplate facing requests for gamete retrieval.

The effectiveness of outpatient pulmonary rehabilitation in chronic lung disease: a randomized controlled trial.

BACKGROUND: Patients with chronic pulmonary disease have been shown to benefit from pulmonary rehabilitation programs. Published work has often been from specialized teaching centers and has involved inpatient stay. We assessed an entirely outpatient-based program of pulmonary rehabilitation in patients with chronic lung disease, using the St. George's Respiratory Questionnaire (SGRQ) (which measures health-related quality of life) as the primary outcome measure. METHODS: We undertook a randomized, prospective, parallel-group controlled study of an outpatient rehabilitation program in 65 patients with COPD (44 men and 21 women; mean age, 69.5 years [SD, 9.2 years]; FEV(1), 41% predicted [SD, 18.5%]). The active group (n = 36) took part in a 6-week program of education (2 h weekly) and exercise (1 h weekly). The control group (n = 29) were reviewed routinely as medical outpatients. The SGRQ was administered under supervision by a blinded observer at study entry, 12 weeks, and 24 weeks. RESULTS: The SGRQ in the active group was 59.9 (SE, 2.0) at study entry (n = 36), 47.4 (SE, 2.3) at 12 weeks (n = 32), and 50.6 (SE, 2.5) at 24 weeks (n = 24). The SGRQ in the control group was 59.3 (SE, 2.5) at study entry and did not change significantly over 24 weeks. There was a difference of 10.4 points (confidence interval [CI], 3.6 to 17.3) between the two groups at 12 weeks (p < 0.001) and of 8.1 points (CI, 1.4 to 14.9) at 24 weeks (p = 0.02) in favor of the active group. CONCLUSIONS: A 6-week outpatient-based program significantly improved quality of life in patients with moderate-to-severe COPD. Benefit was still evident after 24 weeks.

The prohormone convertase enzyme 2 (PC2) is essential for processing pro-islet amyloid polypeptide at the NH2-terminal cleavage site.

Impaired processing of pro-islet amyloid polypeptide (proIAPP), the precursor of the beta-cell peptide islet amyloid polypeptide (IAPP) (amylin), has been implicated in islet amyloid formation in type 2 diabetes. The prohormone convertase enzymes PC3 (also known as PC1) and PC2 are localized to beta-cell secretory granules with proIAPP and proinsulin and are responsible for proinsulin processing. To determine whether PC2 might be essential for proIAPP processing, we performed Western blot analysis of freshly isolated islets from normal mice and mice lacking active PC2. As expected, the primary species of IAPP immunoreactivity in islets from wild-type mice was fully processed (4-kDa) IAPP, with only small amounts of the 8-kDa precursor (unprocessed proIAPP) present. Islets from heterozygous PC2 null mice were identical to wild-type animals, suggesting that half the normal complement of PC2 is sufficient for normal proIAPP processing. By contrast, in islets from homozygous PC2 null mice, the predominant IAPP-immunoreactive form was of intermediate size (approximately 6 kDa), with no detectable mature IAPP and slightly elevated amounts of the 8-kDa precursor form present. Thus, in the absence of PC2, proIAPP processing appears to be blocked at the level of a proIAPP conversion intermediate. Immunofluorescence of pancreas sections and immunoblotting using antisera raised to the NH2- and COOH-terminal flanking regions of mouse proIAPP demonstrated that the 6-kDa intermediate form was an NH2-terminally extended proIAPP conversion intermediate (processed only at the COOH-terminus). These data indicate that PC2 is essential for processing of proIAPP at the NH2-terminal cleavage site in vivo and that PC3 is likely only capable of processing proIAPP at the COOH-terminal cleavage site.

Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA.

Two small RNAs regulate the timing of Caenorhabditis elegans development. Transition from the first to the second larval stage fates requires the 22-nucleotide lin-4 RNA, and transition from late larval to adult cell fates requires the 21-nucleotide let-7 RNA. The lin-4 and let-7 RNA genes are not homologous to each other, but are each complementary to sequences in the 3' untranslated regions of a set of protein-coding target genes that are normally negatively regulated by the RNAs. Here we have detected let-7 RNAs of approximately 21 nucleotides in samples from a wide range of animal species, including vertebrate, ascidian, hemichordate, mollusc, annelid and arthropod, but not in RNAs from several cnidarian and poriferan species, Saccharomyces cerevisiae, Escherichia coli or Arabidopsis. We did not detect lin-4 RNA in these species. We found that let-7 temporal regulation is also conserved: let-7 RNA expression is first detected at late larval stages in C. elegans and Drosophila, at 48 hours after fertilization in zebrafish, and in adult stages of annelids and molluscs. The let-7 regulatory RNA may control late temporal transitions during development across animal phylogeny.

Ethical theory and principles: do they have any relevance to problems arising in everyday practice?

This review of ethical theories with application to two difficult obstetric cases will allow the practicing obstetrician and gynecologist to use these theories to help resolve difficult ethical dilemmas. In the first case a pregnant human immunodeficiency virus-infected woman refuses to take triple preventive therapy, with potential fetal harm. In the second case a couple with a quintuplet multifetal pregnancy needs assistance to decide about selective termination to effect fetal reduction.

Cerebral arteriovenous malformation in pregnancy: presentation and neurologic, obstetric, and ethical significance.

Cerebral arteriovenous malformations infrequently complicate pregnancy. We sought to determine the neurologic, obstetric, and ethical significance of such malformations. We present the clinical course of 2 pregnant women with arteriovenous malformations who experienced cerebral hemorrhage and a loss of capacity for decision making. We also review the neurologic and obstetric significance of arteriovenous malformations in pregnancy. Various treatment options with concern for pregnancy and the prognosis for arteriovenous malformations are outlined. The ethical issues involved for pregnant patients whose decisional capacity is compromised as a result of cerebral injury are explored. A review of persistent vegetative state and brain death (death by neurologic criteria) occurring in pregnancy allows us to explore many issues that are applicable to decisionally incapacitated but physiologically functioning pregnant women. We outline a document, the purpose of which is to obtain advance directives from pregnant women regarding end-of-life decisions and to appoint a surrogate decision maker. We believe that evaluation and treatment of the arteriovenous malformation may be undertaken without regard for the pregnancy and that the pregnancy should progress without concern for the arteriovenous malformation.

Ancient origins of axial patterning genes: Hox genes and ParaHox genes in the Cnidaria.

Among the bilaterally symmetrical, triploblastic animals (the Bilateria), a conserved set of developmental regulatory genes are known to function in patterning the anterior-posterior (AP) axis. This set includes the well-studied Hox cluster genes, and the recently described genes of the ParaHox cluster, which is believed to be the evolutionary sister of the Hox cluster (Brooke et al. 1998). The conserved role of these axial patterning genes in animals as diverse as frogs and flies is believed to reflect an underlying homology (i.e., all bilaterians derive from a common ancestor which possessed an AP axis and the developmental mechanisms responsible for patterning the axis). However, the origin and early evolution of Hox genes and ParaHox genes remain obscure. Repeated attempts have been made to reconstruct the early evolution of Hox genes by analyzing data from the triphoblastic animals, the Bilateria (Schubert et al. 1993; Zhang and Nei 1996). A more precise dating of Hox origins has been elusive due to a lack of sufficient information from outgroup taxa such as the phylum Cnidaria (corals, hydras, jellyfishes, and sea anemones). In combination with outgroup taxa, another potential source of information about Hox origins is outgroup genes (e.g., the genes of the ParaHox cluster). In this article, we present cDNA sequences of two Hox-like genes (anthox2 and anthox6) from the sea anemone, Nematostella vectensis. Phylogenetic analysis indicates that anthox2 (= Cnox2) is homologous to the GSX class of ParaHox genes, and anthox6 is homologous to the anterior class of Hox genes. Therefore, the origin of Hox genes and ParaHox genes occurred prior to the evolutionary split between the Cnidaria and the Bilateria and predated the evolution of the anterior-posterior axis of bilaterian animals. Our analysis also suggests that the central Hox class was invented in the bilaterian lineage, subsequent to their split from the Cnidaria.

Aspiration pneumonia secondary to giant cervical osteophyte formation (diffuse idiopathic skeletal hyperostosis or Forrestier's disease): a case report.

An 80-year-old man was admitted to the hospital with recurrent right-sided aspiration pneumonia, found on barium swallow to be due to diffuse idiopathic skeletal hyperostosis (Forrestier's disease) of the cervical spine, with the formation of a giant cervical osteophyte. He was treated conservatively with a feeding gastrostomy. The medical literature concerning this unusual cause of dysphagia and aspiration pneumonia is reviewed.

The fetal-pelvic index has minimal utility in predicting fetal-pelvic disproportion.

OBJECTIVE: Our purpose was to evaluate the fetal-pelvic index in our patient population and to determine whether it would be predictive of route of delivery. STUDY DESIGN: One hundred seventy-six patients with a previous history or clinical findings in the current pregnancy suggestive of fetal-pelvic disproportion participated in this Human Investigation Committee-approved study. All underwent fetal ultrasonographic examinations and modified digital radiography before labor. Fetal head and abdominal circumferences and maternal inlet and midpelvic circumferences were determined, and the fetal-pelvic index was calculated. RESULTS: Ninety-one patients fulfilled all aspects of the study, including rigorous criteria pertaining to labor management. Thirty of these patients underwent cesarean delivery and 61 were delivered vaginally. The fetal-pelvic index value for the vaginal delivery group was -5.4 +/- 5.3, as opposed to -2.4 +/- 5.8 in the cesarean delivery group (P <.02). Notwithstanding this difference, the fetal-pelvic index had a low overall ability to predict fetal-pelvic disproportion (0.65) and had associated sensitivity and specificity of 0.27 and 0.84, respectively. Predictive thresholds other than zero were tested, but optimal predictive ability, at a fetal-pelvic index cutoff of 2, was only 70% (sensitivity 0.20, specificity 0.95). CONCLUSION: In our patient population the fetal-pelvic index was only moderately predictive of fetal-pelvic disproportion. Factors other than those assessed by the fetal-pelvic index are probably important in determining the route of delivery. Further studies are indicated.

Ethical issues in managed care for the obstetrician and gynecologist.

The practice of medicine is now managed. Of this there is no doubt. The individual physician is placed in an ever-increasingly vulnerable position. He or she must cope with a myriad of contractual arrangements with strange concepts such as "withholds," "capitation," "covered lives," "limited liability on the part of the managed care organization;" "outcomes analysis," "practice guidelines," and, last but not least, "gag rules." Patients are being denied care that the physician may consider, if not essential, at least most desirable. On the one hand, the physician must serve a fiduciary obligation to the patient and act as the patient's advocate; on the other hand, the physician's income may be proportionally dependent on limiting the extent of the patient's access to unlimited care. The physician may be limited by restrictions imposed by the managed care organization as to what disclosures he or she may make to the patient regarding limitations of care. We will explore these issues from an ethical perspective and attempt to offer some insights on the basis of a review of the comments of many knowledgeable commentators on this topic, and we will explore the virtues that physicians will need to rely on to come to grips with the dilemmas they will face in the future with managed care.

Case-control study of salmeterol and near-fatal attacks of asthma.

BACKGROUND: A case-control study was undertaken to investigate the hypothesis that the use of the long acting beta agonist salmeterol increases the risk of a near-fatal attack of asthma. METHODS: The cases comprised admissions to the intensive care unit (ICU) for asthma in 14 major hospitals within the Wessex region in 1992. For each of the cases four age-matched controls were selected from asthma admissions to the same hospital during the same period. Information on prescribed drug therapy for the 48 cases and 185 controls was collected from the hospital admission records. RESULTS: The patients admitted to the ICU had greater chronic asthma severity and had generally been prescribed more asthma drugs than the control admissions to hospital. The relative risk of a near-fatal attack of asthma in patients prescribed inhaled salmeterol was 2.32 (95% CI 1.05 to 5.16), p = 0.04. However, the salmeterol relative risk decreased to 1.42 (95% CI 0.49 to 4.10), p = 0.52 when the analysis was restricted to the more chronically severe patients (those in the subgroup of patients with a hospital admission for asthma in the previous 12 months). These findings suggest that the increased unadjusted relative risk with salmeterol is predominantly due to confounding by severity--that is, the increased relative risk is due to patients with more severe asthma (at greatest risk of a near-fatal asthma attack) being preferentially prescribed salmeterol. This interpretation is supported by the finding in this study that, within the control group (selected from the population of asthmatics requiring hospital admission), salmeterol was preferentially prescribed to the most severe patients (a threefold greater prescription of salmeterol to control patients if they had been admitted to hospital in the 12 months prior to the index admission). There was no increased risk of a near-fatal attack of asthma in patients prescribed a beta agonist by metered dose inhaler (OR 0.75 (95% CI 0.31 to 1.78), p = 0.51). In contrast, the relative risks for beta agonists delivered by nebulisation (OR 3.86 (95% CI 1.99 to 7.50), p < 0.001) and oral theophylline (OR 2.45 (95% CI 1.26 to 4.78), p < 0.01) were increased and did not markedly decrease when the analysis was restricted to the more severe asthmatic subjects. CONCLUSIONS: Although these findings are not conclusive, particularly because of the small numbers involved in some subgroup analyses, they suggest that the use of salmeterol by patients with chronic severe asthma is not associated with a significantly increased risk of a near-fatal attack of asthma. If a near-fatal asthma attack is considered to be an intermediate step in a process by which a severe attack of asthma may become fatal, these results would suggest that salmeterol is unlikely to be associated with an increased risk of death, at least by this mechanism.

The evolution of the Hox cluster: insights from outgroups.

Two burgeoning research trends are helping to reconstruct the evolution of the Hox cluster with greater detail and clarity. First, Hox genes are being studied in a broader phylogenetic sampling of taxa: the past year has witnessed important new data from teleost fishes, onychophorans, myriapods, polychaetes, glossiphoniid leeches, ribbon worms, and sea anemones. Second, commonly accepted notions of animal relationships are being challenged by alternative phylogenetic hypotheses that are causing us to rethink the evolutionary relationships of important metazoan lineages, especially arthropods, annelids, nematodes, and platyhelminthes.

Homeoboxes in sea anemones (Cnidaria:Anthozoa): a PCR-based survey of Nematostella vectensis and Metridium senile.

Homeobox genes belong to a phylogenetically widespread family of regulatory genes that play important roles in pattern formation and cell-fate specification in several model systems (e.g., Drosophila, mouse, and C. elegans). Although the evolution of many classes of homeobox genes predates the diversification of the Bilateria, comparatively little is known about homeobox genes in outgroups to the Bilateria, such as the Cnidaria. We used the polymerase chain reaction to recover 12 partial homeoboxes from 2 species of sea anemones, Metridium senile and Nematostella vectensis (phylum Cnidaria; class Anthozoa). These homeoboxes appear to represent 9 distinct, mutually paralogous homeobox genes, 5 of which belong to previously identified cnidarian homeobox classes, and 4 of which appear to represent previously unidentified classes. The evolutionary relationships between the homeodomains of sea anemones and of bilaterian animals were assessed through database searches and phylogenetic analyses. As many as 5 of the anemone homeoboxes may belong to the Hox class, which suggests that the Hox gene complement of cnidarians is larger than previously expected. Homologs of the even-skipped gene of Drosophila were also identified in both Metridium and Nematostella.