Direct interaction of Smn with dp103, a putative RNA helicase: a role for Smn in transcription regulation?

Spinal muscular atrophy is an autosomal recessive neurodegenerative disease of childhood, resulting from deletion or mutation of the survival motor neuron ( SMN ) gene on chromosome 5q13. SMN exists as part of a 300 kDa multi-protein complex, incorporating several proteins critically required in pre-mRNA splicing. Although SMN mutations render SMN defective in this role, the specific alpha-motor neuron degenerative phenotype seen in the disease remains unexplained. Here we demonstrate the isolation from mouse brain of the murine homologue of a recently identified novel RNA helicase of the DEAD box family, DP103, and its direct and specific binding of SMN. Previous work has shown that DP103 binds viral proteins known to interact with a cellular transcription factor to modulate gene expression. We suggest that the interaction between SMN and DP103 is further evidence for a role for SMN in transcriptional regulation and that SMN may be involved in the regulation of neuron-specific genes essential in neuronal development.

HLA class II typing of whole genome amplified mouth swab DNA.

Postal collection of mouth swabs provides a cheap and convenient means of DNA sampling but hitherto has not provided sufficient genetic material for HLA typing by polymerase chain reaction using sequence-specific primers (PCR-SSP). This study examined the feasibility of collecting mouth swabs from a test population by post, amplifying the DNA by whole genome amplification and genotyping for selected HLA class II alleles. We optimised a strategy for whole genome amplification or primer extension preamplification using a random 15 base pair primer which resulted in a 1,000-fold increase in DNA template. The amplified DNA was of sufficient quality for analysis of selected HLA Class II alleles by PCR-SSP and PCR using sequence-specific oligonucleotide probes. To test the reliability of our data, blood DNA from 30 individuals in 10 families, previously tested for all DRB1 alleles in a routine diagnostic laboratory, was then tested in our laboratory for DRB1 *03 and *04 following whole genome amplification. Further whole genome amplified product from another 10 families was tested for DRB1 *03, *04 in our laboratory and then tested for all DRB1 alleles in a routine diagnostic laboratory. One repeat typing was required to achieve 100% concordance between laboratories. Amplification of whole genome amplified DNA by PCR-SSP was then extended successfully to low-resolution HLA DRB1, DQA1, DQB1 and DPB1 typing. Mouth swab collection by post, followed by whole genome amplification of DNA provides an effective strategy for genetic analysis of large cohorts. We have optimised conditions for HLA class II typing on whole genome amplified DNA collected by mouth swab, but this method could potentially be applied to low concentrations of DNA from other sources.

MR imaging of a hemorrhagic and granulomatous cyst of the ligamentum flavum with pathologic correlation.

Cysts of the ligamentum flavum are uncommon causes of neurologic signs and symptoms and usually are seen in persons over 50 years of age. We report a case of an epidural cyst located in the ligamentum flavum, which contributed to spinal stenosis in a 30-year-old man. Radiologic features were similar to those of a synovial cyst, but synovium was not identified histologically. The imaging and pathologic features were unusual, including hemorrhage and a fibrohistiocytic reaction with giant cells.

Fine mapping of the diabetes-susceptibility locus, IDDM4, on chromosome 11q13.

Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 (IDDM4). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (lambda(s)=1.09) with linkage (MLS>=0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [P=.02, corrected P=.72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P=3x10-4, corrected P=. 01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917*03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P=1.5x10-6, corrected P=4.3x10-4). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated.

Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6).

Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease susceptibility genes. However, because the extent of association of single marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-predisposing chromosomes, the most associated marker allele in a region will not necessarily be closest to the disease locus. To overcome this problem we describe a haplotype-based approach developed for mapping of the putative type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region were genotyped in 1708 type 1 diabetic Caucasian families from seven countries. The most likely ancestral diabetogenic chromosome was reconstructed in a stepwise fashion by analysing linkage disequilibrium between a previously defined haplotype of three adjacent markers and the next marker along the chromosome. A plot of transmission from heterozygous parents to affected offspring of single marker alleles present on the ancestral chromosome versus the physical distance between them, was compared with a plot of transmission of haplotypes of groups of three adjacent markers. Analysing transmission of haplotypes largely negated apparent decreases in transmission of single marker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrate the utility of polymorphic microsatellite markers to trace and delineate extended and presumably ancient haplotypes in the analysis of common disease and in the search for identical-by-descent chromosome regions that carry an aetiological variant.

Factors influencing the retention of cemented implant-supported crowns.

This study is a retrospective analysis of the influence of cement, coping type, and fixture site on the cementation failure of 36 selected implant-supported single crowns placed between 1991 and 1995. Fisher's exact test and a log linear analysis were performed on the data. Crowns constructed with a milled-metal coping, cemented with a temporary cement, or placed in the maxillary premolar site were more likely to be associated with cement failure than those cemented with zinc phosphate, constructed with cast metal or ceramic copings, or placed in the anterior maxilla. We were unable to account for some variables-for example, bite force or oral habits. For this reason we consider that we would overstate the strength of this case analysis if we drew general conclusions from our results. However, we have altered our treatment protocol to reduce the initial cost and the maintenance associated with recementing implant-supported crowns, discontinuing the use of the milled-gold cylinder in view of the lack of any clear clinical advantage and the results of this study. In addition, and because only one internal gold screw in our series of patients has loosened, we now use a permanent cement.

Eating the curriculum.

The alimentary metaphor--learning as ingestion--is well established in medical education: students are spoonfed, forcefed; they cram, digest, and metabolize information; and they regurgitate it on tests. In the author's experience, these metaphors are inextricably bound with the attitudes and information they describe, organize, and sometimes generate in medical education. Alimentary imagery shapes discussions of the curriculum, and its perversities characterize and help perpetuate much that needs changing in North American medical education. Medical school teachers speak of their life's work as feeding students, not as chiefs but as the anxious caretakers of problem eaters, and the images used most often to describe the teacher-learner relationship suggest an underlying infantilization of medical students. Alimentary metaphors are not in themselves evil. A closer look at medicine's uses of the metaphor of learning as eating suggests a healthier educational philosophy. Despite the "full plate" that students are served, they are metaphorically starving. Fundamental curriculum reform should help them learn to be healthy eaters-using lessons from parents, pediatricians, and child psychologists about how to do this, which are discussed in detail. The difficult-to-achieve but imperative goal of medical education should be to put students in charge of their own "eating" and thereby produce intellectually curious, self-motivated, active, and "well-nourished" physicians who know how to feed themselves in the right amounts and at reasonable levels, maintain a healthy skepticism about the information they consume, and periodically check that information for freshness.

Respiratory effects of intravenous midazolam.

Thirty-four healthy, young-adult patients receiving intravenous midazolam for third-molar surgery had their respiratory parameters measured by respiratory inductive plethysmography. Tidal volume and minute volume showed significant changes during the initial 5-10 minutes of sedation, the changes being maximal during the first 5 minutes from the completion of injection of midazolam. The measurement of phase angle, an indicator of respiratory asynchrony, showed no significant change from normal, although a few patients showed some asynchrony of breathing, suggesting some amount of respiratory obstruction. A few patients showed a short period of apnoea and a small fall in the oxygen saturation. None of these changes caused any clinical concerns. It is suggested that the absence of stimulation after injection of midazolam, particularly in the initial few minutes, may contribute to the potential onset of respiratory problems.

Effectiveness of preoperative analgesics on postoperative dental pain: a study.

Patients undergoing extractions of third molar teeth under general anesthesia were given a placebo, diclofenac (a nonsteroidal anti-inflammatory drug) 100 mg, or methadone (an opiate) 10 mg 60 to 90 min prior to surgery, and their pain scores and postoperative medication requirements were measured for 3 days. All patients received local anesthetic blocks and analgesic drugs during the perioperative period. There were no significant differences between the three groups in the pain scores and medication requirements during the period of study. It was concluded that preoperative use of nonsteroidal anti-inflammatory drugs and opiates may not offer a preemptive analgesic effect in patients who have had adequate analgesia during the surgery. Continued use of analgesic drugs during the postoperative period is perhaps more useful for this purpose. There appears to be a higher incidence of vomiting following opiates (methadone), precluding its clinical use in day-care patients.

Narrative, literature, and the clinical exercise of practical reason.

Although science supplies medicine's "gold standard," knowledge exercised in the care of patients is, like moral knowing, a matter of narrative, practical reason. Physicians draw on case narrative to store experience and to apply and qualify the general rules of medical science. Literature aids in this activity by stimulating moral imagination and by requiring its readers to engage in the retrospective construction of a situated, subjective account of events. Narrative truths are provisional, uncertain, derived from narrators whose standpoints are always situated, particular, and uncertain, but open to comparison and reinterpretation. Reading is thus a model for knowing in both morality and clinical medicine. While principles remain essential to bioethics and science must always inform good clinical practice, the tendency to collapse morality into principles and medicine into science impoverishes both practices. Moral knowing is not separable from clinical judgment. While ethics must be open to discussion and interpretation by patients, families, and society, it is nevertheless substantively and epistemologically an inextricable part of a physician's clinical practice.

The study of literature in medical education.

The study of literature encourages the development of otherwise hard-to-teach clinical competencies. It provides access to the values and experiences of physicians, patients, and families; it calls for the exercise of skill in observation and interpretation, develops clinical imagination, and, especially through writing, preserves fluency in ordinary language and promotes clarity of observation, expression, and self-knowledge. Faculty in one-third of U.S. medical schools teach literature in courses that, although concentrated in the preclinical years, range from the first day of school, through residency programs. Once focused on the work of physician-authors and realist fiction about illness that encouraged moral reflection about the practice of medicine, literary study in medicine now encompasses a wide range of literature and narrative types, including the patient history and the clinical case. Literary study is intended not only to enrich students' moral education but also to increase their narrative competence, to foster a tolerance for the uncertainties of clinical practice, and to provide a grounding for empathic attention to patients. Literature may be included in medical humanities courses, and it may provide rich cases for ethics courses or introductions to the patient-physician relationship; it also may be the focus of small, elective, or selective courses, frequently on particular social issues or on the experience of illness. Reading, discussion, writing, and role-play rather than lectures are the methods employed; faculty include those with PhDs in literature and MDs who have strong interests in the contributions of literature to practice.(ABSTRACT TRUNCATED AT 250 WORDS)

Six years' experience with Brånemark osseointegrated implants.

Over 6 years of the implant programme in the University of Otago School of Dentistry, the rate of use of osseointegrated implants to support or retain a dental prosthesis has increased. This increased use has been most marked in young adults who have required the restoration of a single space in the anterior maxillae. The treatment outcome is unequivocally positive, with an overall fixture retention rate of over 99 percent.

Literature and medicine: contributions to clinical practice.

Introduced to U.S. medical schools in 1972, the field of literature and medicine contributes methods and texts that help physicians develop skills in the human dimensions of medical practice. Five broad goals are met by including the study of literature in medical education: 1) Literary accounts of illness can teach physicians concrete and powerful lessons about the lives of sick people; 2) great works of fiction about medicine enable physicians to recognize the power and implications of what they do; 3) through the study of narrative, the physician can better understand patients' stories of sickness and his or her own personal stake in medical practice; 4) literary study contributes to physicians' expertise in narrative ethics; and 5) literary theory offers new perspectives on the work and the genres of medicine. Particular texts and methods have been found to be well suited to the fulfillment of each of these goals. Chosen from the traditional literary canon and from among the works of contemporary and culturally diverse writers, novels, short stories, poetry, and drama can convey both the concrete particularity and the metaphorical richness of the predicaments of sick people and the challenges and rewards offered to their physicians. In more than 20 years of teaching literature to medical students and physicians, practitioners of literature and medicine have clarified its conceptual frameworks and have identified the means by which its studies strengthen the human competencies of doctoring, which are a central feature of the art of medicine.

Implant-based treatment for the loss of a single tooth.

This article describes the authors' experience in the provision of single-tooth replacement by means of Brånemark implant treatments. Over a 5-year period, 45 treatments have been undertaken with a current fixture retention rate of 100 percent. Careful planning and attention to detail in surgical, prosthodontic, and technical aspects have resulted in an excellent functional and aesthetic treatment with high acceptance by patients.

Success and failure in partial edentulism treated with implant-supported bridges.

This report describes success and failure in the use of fixed bridges supported by Brånemark implants, placed in the mandible bilaterally in one patient and unilaterally in the other. The non-intrusive nature and excellent functional characteristics of such bridges make them an attractive alternative to a removable partial denture in making good the loss of posterior mandibular teeth. However, there are biomechanical principles which must be considered in the design of such appliances. In particular, designs which minimise bending moments should be chosen to avoid the type of failure described in one of our patients. Repeated loosening of screw components should be considered as a possible indicator of bending overload. Where space permits, this problem is most easily overcome by placing three implants in staggered formation.

Primary reconstruction of the mandible with iliac bone and titanium implants following resection of a recurrent odontogenic keratocyst.

An aggressive surgical management of a mandibular odontogenic keratocyst in a young female patient is described. This management stratagem was followed in view of a histological finding of epithelial dysplasia and the possible, although unlikely, chance of squamous cell carcinoma developing in the cyst lining. Primary bone grafting and immediate fixture placement of implants were used to make good the mandibular resection site. This was thought to be the best option for management, minimising the number of surgical interventions and providing a framework for fixed bridgework in an area of the mouth that is difficult to reconstruct adequately. A successful outcome to the treatment has been observed, with graft survival, osseointegration of fixtures, the provision of functional and aesthetically pleasing implant-borne bridgework and, to date, the absence of clinical or radiographic evidence of recurrence of the cyst.

Patient-controlled sedation using midazolam.

Midazolam was given for sedation as an initial bolus, followed by either a continuous infusion or a patient controlled infusion during third molar extractions. The results showed that there were no significant changes in blood pressure, pulse rate or oxygen saturation during the procedure. Both methods gave good amnesia to events at the start, (100%), as well as to events during, (70% and 75%), and at the end, (61% and 70%), of surgery. There was high acceptance of both methods of sedation (93% and 98% respectively). There was no patient preference for either method of sedation, nor was the operator able to distinguish between the two methods. Hence it is concluded that patient controlled infusion and continuous infusion of midazolam are both satisfactory methods of sedation for patients undergoing surgery under local anaesthesia.