CRM1 inhibition induces tumor cell cytotoxicity and impairs osteoclastogenesis in multiple myeloma: molecular mechanisms and therapeutic implications.

The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.

Outcomes of bleb excision and conjunctival advancement for leaking or hypotonous eyes after glaucoma filtering surgery.

AIM: To determine outcomes of bleb excision and conjunctival advancement for leaking or hypotonous eyes after glaucoma filtering surgery. METHODS: In a retrospective case series the medical records of all patients who underwent bleb excision and conjunctival advancement surgery for bleb leaks or hypotony (defined as IOP less than 6 mm Hg, associated with reduced vision) at the Jules Stein Eye Institute and the Yale University Eye Center between January 1993 and June 2002 were reviewed. Only patients with more than 6 months of follow up were included. Complete success was defined as resolution of the pre-existing leak or hypotony, with maintenance of IOP > or =6 and < or =21 mm Hg, in the absence of further glaucoma surgery and without any glaucoma medication. Qualified success met the above criteria with or without the use of glaucoma medications. Success rates were analysed with Kaplan-Meier survival curves. RESULTS: 49 eyes were included in the study; 13 eyes had overt bleb leaks, 27 eyes had hypotony. Nineteen patients underwent resuturing of sclera and/or placement of a pericardial graft in addition to bleb excision and conjunctival advancement. Mean preoperative IOP increased from 3.2 (SD 2.4) mm Hg (range 0-10 mm Hg) to 13.8 (4.8) mm Hg (range 6-29 mm Hg) at last follow up (p<0.0001). Mean preoperative visual acuity improved from 0.6 (0.3) logMAR (range 0-2) to 0.3 (0.3) logMAR (range 0-2) at final follow up (p<0.0001). 16 eyes (40%) were classified as complete success and 17 additional eyes achieved qualified success, for a total of 33 eyes (83%) achieving at least qualified success. There was no significant difference in the rate of complete success (p = 0.95) or qualified success (p = 0.88) between the group of patients who underwent bleb excision and conjunctival advancement alone versus those who also had resuturing of sclera and/or placement of a pericardial graft. Failures included three eyes that had persistent hypotony without leak, requiring additional bleb revision, and four with uncontrolled IOP, two of whom underwent additional glaucoma surgery. CONCLUSION: Bleb excision with conjunctival advancement is a successful procedure for bleb repair. This technique provides successful resolution of leaks and hypotony, maintains glaucoma control with or without medication, and preserves vision with minimal postoperative complications in a majority of eyes.

Structured assessment of minor surgical skills (SAMSS) for family medicine residents.

PURPOSE: To develop a valid and reliable examination to assess the technical proficiency of family medicine residents' performance of minor surgical office procedures. METHOD: A multi-station OSCE-style examination using bench-model simulations of minor surgical procedures was developed. Participants were a randomly selected group of 33 family medicine residents (PGY-1 = 16, PGY-2 = 17) and 14 senior surgical residents who functioned as a validation group. Examiners were qualified surgeons and family physicians who used both checklists and global rating scales to score the participants' performances. RESULTS: When family medicine residents were evaluated by family physicians, interstation reliabilities were .29 for checklists and .42 for global ratings. When family medicine residents were evaluated by surgeons, the reliabilities were .53 for checklists and .75 for global ratings. Interrater reliability, measured as a correlation for total examination scores, was .97. Mean scores on the examination were 60%, 64%, and 87% for PGY-1 family medicine, PGY-2 family medicine, and surgery residents, respectively. The difference in scores between family medicine and surgery residents was significant (p < .001), providing evidence of construct validity. CONCLUSION: A new examination developed for assessing family medicine residents' skills with minor surgical office procedures is reliable and has evidence for construct validity. The examination has low reliability when family physicians serve as examiners, but moderate reliability when surgeons are the evaluators.

Relationship between visual field testing and scanning laser polarimetry in patients with a large cup-to-disk ratio.

PURPOSE: To determine the relationship between quantitative nerve fiber layer measurements and visual field testing in patients with large cup-to-disk ratios. METHODS: Seventy-six patients with vertical cup-to-disk ratios by contour of at least 0.8 on stereoscopic photographs and 50 normal subjects were included. One eye was randomly selected for study. All patients underwent standard achromatic automated perimetry, short-wavelength automated perimetry, and retinal nerve fiber layer measurements with scanning laser polarimetry. Analysis of variance was used to evaluate differences between the subject groups. Significance of pairwise comparisons was determined using the Tukey-Kramer multiple comparison test. RESULTS: Statistically significant differences in nerve fiber layer measurements between patients with large cup-to-disk ratios and both abnormal standard achromatic automated perimetry and short-wavelength automated perimetry (n = 22) and patients with large cup-to-disk ratios and both normal standard achromatic automated perimetry and short-wavelength automated perimetry (n = 42) were found for superior nasal ratio, maximum modulation, ellipse modulation, and the linear discriminant function (Tukey-Kramer less than.05). There was no significant difference in patients with abnormal short-wavelength automated perimetry only (n = 9) as compared with patients with both normal standard achromatic automated perimetry and short-wavelength automated perimetry and patients with both abnormal standard achromatic automated perimetry and short-wavelength automated perimetry. Statistically significant differences between the normal subjects and patients with large cup-to-disk ratios and both abnormal standard achromatic automated perimetry and short-wavelength automated perimetry were found for all retinal nerve fiber layer parameters, with the exception of symmetry, superior ratio, and inferior ratio. CONCLUSION: Our results show considerable overlap in nerve fiber layer measurements in eyes with large cup-to-disk ratio and abnormal visual fields as compared with eyes with large cup-to-disk ratios and normal visual fields. This may limit the clinical usefulness of scanning laser polarimetry for detection of early glaucoma in patients with large cup-to-disk ratios. Longitudinal studies are needed to determine if patients with large cup-to-disk ratios with normal standard achromatic automated perimetry and abnormal short-wavelength automated perimetry subsequently develop standard achromatic automated perimetry defects and if scanning laser polarimetry can concurrently detect progression of nerve fiber layer damage.

New "horizontal" curriculum in family medicine residency.

PROBLEM ADDRESSED: Opportunities for residents in a family medicine program to experience continuity of care with a group of patients and to be immersed in the role of a family physician were thought by faculty to be insufficient. OBJECTIVES OF THE PROGRAM: To enhance residents' experience of continuity of care with a group of patients; to create a model for training that better simulates clinical practice; and to position core family medicine experiences as the central and continuing focus of the residency program. MAIN COMPONENTS OF THE PROGRAM: The new curriculum replaces block rotations in family medicine with "horizontal" experiences comprising 3 half-days of patient care and 1 half-day seminar each week for all residents through both years of the program. The remaining time in first year is spent on the major disciplines--medicine, pediatrics, emergency, and obstetrics--for which a horizontal family medicine-centred experience has also been introduced. The second-year curriculum is flexible and largely self-directed. Initial evaluations indicate improved continuity of care of family practice patients and broadened clinical exposure for residents. The program has been fully accredited by the College. CONCLUSIONS: A horizontal curriculum in family medicine, designed to address perceived deficiencies in the traditional block rotational model of training, can be developed and implemented in an urban teaching hospital.

A clinical score to reduce unnecessary antibiotic use in patients with sore throat.

OBJECTIVE: To validate a score based on clinical symptoms and signs for the identification of group A Streptococcus (GAS) infection in general practice patients with score throat. DESIGN: A single throat swab was used as the gold standard for diagnosing GAS infection. Clinical information was recorded by experienced family physicians on standardized encounter forms. Score criteria were identified by means of logistic regression modelling of data from patients enrolled in the first half of the study. The score was then validated among the remaining patients. SETTING: University-affiliated family medicine centre in Toronto. PATIENTS: A total of 521 patients aged 3 to 76 years presenting with a new upper respiratory tract infection from December 1995 to February 1997. OUTCOME MEASURES: Sensitivity, specificity and likelihood ratios for identification of GAS infection with the score approach compared with throat culture. Proportion of patients prescribed antibiotics, throat culture use, and sensitivity and specificity with usual physician care and with score-based recommendations were compared. RESULTS: A score was developed ranging in value from 0 to 4. The sensitivity of the score for identifying GAS infection was 83.1%, compared with 69.4% for usual physician care (p = 0.06); the specificity values of the 2 approaches were similar. Among patients aged 3 to 14 years, the sensitivity of the score approach was higher than that of usual physician care (96.9% v. 70.6%) (p < 0.05). The proportion of patients receiving initial antibiotic prescriptions would have been reduced 48% by following score-based recommendations compared with observed physician prescribing (p < 0.001), without any increase in throat culture use. CONCLUSIONS: An age-appropriate sore throat score identified GAS infection in children and adults with sore throat better than usual care by family physicians, with significant reductions in unnecessary prescribing of antibiotics. A randomized trial comparing the 2 approaches is recommended to determine the ability of the score approach to reduce unnecessary prescribing of antibiotics during routine clinical encounters.

Infection around joint replacements in patients who have a renal or liver transplantation.

The results of thirty-five joint (hip or knee) replacements in nineteen patients who had an organ transplantation were retrospectively reviewed. The patients received a standard immunosuppressive induction regimen at the time of the transplantation and were maintained on a combination of prednisone, azathioprine, and cyclosporine A. All patients received antibiotics perioperatively, but antibiotic-impregnated bone cement was not used for any procedure. Six joint replacements, in three patients who were an average of 48.2 years old at the time of the arthroplasty, were performed before a renal transplantation. Twenty-four joint replacements, in fourteen patients who were an average of 40.9 years old at the time of the arthroplasty, were performed after an organ transplantation. Two patients, who were an average of 53.8 years old at the time of the arthroplasty, each had a joint replacement both before and after a liver transplantation (a total of five joint replacements). The average duration of follow-up from the first joint replacement was 8.8 years (range, one to twenty-three years). The Harris hip score or The Hospital for Special Surgery knee score was determined at the time of the latest follow-up examination. An infection developed around the implant in five patients who had had the joint replacement after a transplantation. The average interval from implantation of the prosthesis until detection of the infection was 3.4 years (range, one to six years). One patient who had a liver transplant was infected with Pseudomonas aeruginosa and another one was infected with Escherichia coli. One patient who had a renal transplant was infected with Staphylococcus epidermidis; one, with Enterococcus; and one, with Serratia marcescens. We found that patients who had a joint replacement after an organ transplantation had a very high risk of devastating infection. The rate of such infection was 19 per cent (five of twenty-seven joint replacements in sixteen patients).

Model for assessing psychosocial problems.

The Model for the Assessment of Psychosocial Problems (MAPP) can help family medicine residents effectively assess patients with psychosocial problems. Following a patient-centred clinical method, MAPP provides a guide to exploring problems and an approach that allows residents and patients jointly to define problems and decide upon management. Emphasis is placed on clarifying patients' expectations of physicians.

The sagittal alignment of the cervical spine in adolescent idiopathic scoliosis.

To assess the sagittal orientation of the cervical and thoracolumbar spine, 38 adolescents with idiopathic scoliosis were studied. The C7 plumb line and Cobb angles from C2-6, T1-12, and L1-S1 were measured on preoperative films. Lateral radiographs with > 1-year follow-up after surgical correction were available for the same measurements in 28 patients. The preoperative curve from C2-6 was 6 +/- 11 degrees of kyphosis. There was a significant correlation between the loss of thoracic kyphosis and the development of cervical kyphosis for the entire group preoperatively (p = 0.009). Postoperatively, cervical kyphosis increased to 11 +/- 9 degrees at 1-year follow-up (p = 0.05). There was no progression of cervical kyphosis in patients with "thoracic hypokyphosis" (kyphosis < 20 degrees). Cervical kyphosis increased in patients with "normal" thoracic kyphosis (20-40 degrees) and in patients with hyperkyphosis (kyphosis > 40 degrees) after surgery, despite preservation of thoracolumbar sagittal contour. There were no significant differences between the sagittal contour of patients treated with Cotrel-Dubousset or Harrington instrumentation.

Intraoperative hand retractor.

A technique is described that greatly reduces the problems inherent in obtaining clear radiographs of the fingers. The method is simple, inexpensive, and readily available for use in the operating room. Additionally, it allows the surgeon to leave the operative field and stand behind a lead shield while radiographs are taken.

Intensive cognitive-behaviour group therapy for diagnostically heterogeneous groups of patients with psychiatric disorder.

This uncontrolled study evaluates the efficacy of a combined treatment of medications (for the majority of patients) and a closed group, intensive (two-week) cognitive-behaviour therapy programme for heterogeneous groups of psychiatric patients. Five hundred and thirty-one patients at a private psychiatric clinic were included in the study. Self-report measures of depression, anxiety, self-esteem and "locus of control" were administered before and after treatment and at intervals up to one year later. Statistically and clinically significant improvements were found in all measures and these improvements were maintained up to one year. The results provide support for the efficacy of the treatment.

Plasma concentrations of dothiepin and its metabolites are not correlated with clinical efficacy in major depressive illness.

Plasma concentration-antidepressant response relationships for dothiepin, nordothiepin, dothiepin-S-oxide, and nordothiepin-S-oxide were investigated in 50 patients (33 women and 17 men), who had had a major depressive episode. Depression and anxiety were assessed at the start of therapy and after 2 and 4 weeks by measurement of a Hamilton rating score for depression (HRSD), a Beck depression inventory (BECK), visual analog scores for depression (VASDEP) and anxiety (VASANX), and a physician's global (GLOBAL) score. There were significant (p < 0.001) decreases in both mean depression (32-69%) and mean anxiety (30-44%) scores at weeks 2 and 4, but there were no robust linear or polynomial correlations between percent decrease in depression or anxiety scores and plasma concentrations of dothiepin or its metabolites at week 4. It is suggested that measurement of the nordothiepin/dothiepin ratio may assist in the assessment of compliance.

Family Orientation in Family Medicine Training: A survey of Canadian programs.

Teaching about the family has become an important part of the family medicine curriculum. The family orientation index, a 39-item questionnaire, was designed to evaluate the family orientation of services and care provided as well as the teaching and research. The questionnaire was distributed to 55 program directors at 16 Canadian universities. The response rate was 84%. The results indicate that the family orientation of services is less than optimal.

Abnormalities of the optic fundus.

Common abnormalities of the optic fundus are illustrated in this article. The authors provide brief clinical descriptions and discuss a test used to screen for a shallow anterior chamber of the eye before dilating the pupil.

Structural relationships of the major glycoproteins from human alveolar proteinosis surfactant.

Alveolar proteinosis is a disease characterized by accumulation of proteinaceous material in the alveolar space of the lung. Two major collagenase-sensitive polypeptides, alveolar proteinosis peptides of 34 kDa kilodaltons (APP-34) and of 62 kDa (APP-62), were isolated from bronchioalveolar lavage of patients with alveolar proteinosis. These proteins co-purified during fast-performance liquid chromatography (FPLC) chromatofocusing and were separated from each other by electroelution following SDS-polyacrylamide gel electrophoresis. Immunoblot analysis of these proteins demonstrated that both shared antigenic sites with the normal human surfactant-associated protein of Mr 34,000 (SAP-34) using both polyclonal and monoclonal antibodies generated against SAP-34. Removal of asparagine-linked oligosaccharides from the 34 kDa and 62 kDa alveolar proteinosis proteins with endoglycosidase F resulted in polypeptides of 28 kDa from APP-34 and 56 kDa from APP-62. Amino acid analysis and tryptic peptide maps of the electroeluted APP-34 and APP-62 proteins were essentially identical and similar to that previously reported for human SAP-34, supporting the likely relationship of APP-34 and APP-62 as monomer and dimer of the normal SAP-34. APP-34 and APP-62 were both sensitive to bacterial collagenase, yielding collagenase-resistant fragments of 21 kDa, similar in migration and amino acid composition to the fragment generated by collagenase digestion of normal human SAP-34. High molecular weight aggregates of APP-34 and APP-62 were the result of sulfhydryl-dependent and non-sulfhydryl-dependent cross-linking. A domain in the C-terminal non-collagenous portion of the molecules which forms sulfhydryl-dependent oligomers was identified. The two major polypeptides accumulating in the airway of patients with alveolar proteinosis are monomeric (34 kDa) and dimeric (62 kDa) forms of the major surfactant-associated glycoprotein, SAP-34.

What do family practice residents do in prevention and counselling?

A study was undertaken to measure what family practice residents do in prevention and counselling during routine check-ups on adults. A series of Health Monitoring and Promotion (HMP) measures were used to assess the content of the check-up. The residents were given a sheet of guidelines in an attempt to augment performance of the HMP measures. Using one-way glass, 353 patient encounters were observed. Analysis of 171 encounters before and 182 encounters after the introduction of the guidelines showed that the guidelines positively influenced the residents' behavior by increasing the number of HMP measures performed. Preventive items of a physical nature were carried out 61.2% of the time before the introduction of the guidelines and 69.7% after, with more pronounced improvement when dealing with the 18-39 age group and among men. Similar changes occurred on historical items of a preventive type, but history-taking from women was more positively influenced. Preventive counselling was carried out 20% of the time and was uninfluenced by the guidelines. There was a high level of breast and testicle examination, but a low level of teaching self-examination. Counselling on retirement, lifestyle, 'passages' and similar issues was uninfluenced by the instrument.