Faculty Scholarship

Background—Fluoroquinolones target bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV (Topo IV). Fluoroquinolones trap a topoisomerase-DNA covalent complex as a topoisomerase-fluoroquinolone-DNA ternary complex and ternary complex formation is critical for their cytotoxicity. A divalent metal ion is required for type IIA topoisomerase-catalyzed strand breakage and religation reactions. Recent studies have suggested that type IIA topoisomerases use two metal ions, one structural and one catalytic, to carry out the strand breakage reaction. 

Methods—We conducted a series of DNA cleavage assays to examine the effects of fluoroquinolones and quinazolinediones on Mg2+-, Mn2+-, or Ca2+-supported DNA cleavage activity of Esherichia coli Topo IV. 

Results—In the absence of any drug, 20–30 mM Mg2+ was required for the maximum levels of the DNA cleavage activity of Topo IV, whereas approximately 1 mM of either Mn2+ or Ca2+ was sufficient to support the maximum levels of the DNA cleavage activity of Topo IV. Fluoroquinolones promoted the Topo IV-catalyzed strand breakage reaction at low Mg2+ concentrations where Topo IV alone could not efficiently cleave DNA.

Chiropractic was founded by D. D. Palmer, who performed his first spinal adjustments in 1895 and started the first chiropractic school, the Palmer School and Cure, in 1897, both in Iowa.1  Diplomas granted to early graduates proclaimed them competent to teach and practice chiropractic, and many of these newly minted chiropractors did just that, often tutoring individuals and small groups in offices and clinics rather than setting up school buildings.2  For many of these tutorial schools, whether they had any graduates or even any students is unknown, and some schools were known to have been diploma mills3 (teaching chiropractic by correspondence course seems like a questionable proposition).  However, many other schools operated by the standards for a quality course of study as defined at that time.4 The earliest school teaching chiropractic technique that is known to have been in operation in Minnesota was the National School of Neuropathy & Psycho-Magnetic Healing, located in Minneapolis in 1899.5  Including tutorial schools, approximately 30 schools operated in the state from 1899 to NWCC’s founding in 1941.6  The total number of schools operating is difficult to gauge with precision, as some underwent slight name changes and others adopted names nearly identical to those of other schools.  Many schools seem to have been in existence for no more than a year or two.7 Four early Minnesota chiropractic schools are known to have operated for at least a decade.

Background: Fluoroquinolones target bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV (Topo IV). Fluoroquinolones trap a topoisomerase-DNA covalent complex as a topoisomerase-fluoroquinolone-DNA ternary complex and ternary complex formation is critical for their cytotoxicity. A divalent metal ion is required for type IIA topoisomerase-catalyzed strand breakage and religation reactions. Recent studies have suggested that type IIA topoisomerases use two metal ions, one structural and one catalytic, to carry out the strand breakage reaction.

Methods: We conducted a series of DNA cleavage assays to examine the effects of fluoroquinolones and quinazolinediones on Mg(2+)-, Mn(2+)-, or Ca(2+)-supported DNA cleavage activity of Escherichia coli Topo IV.

Results: In the absence of any drug, 20-30 mM Mg(2+) was required for the maximum levels of the DNA cleavage activity of Topo IV, whereas approximately 1mM of either Mn(2+) or Ca(2+) was sufficient to support the maximum levels of the DNA cleavage activity of Topo IV. Fluoroquinolones promoted the Topo IV-catalyzed strand breakage reaction at low Mg(2+) concentrations where Topo IV alone could not efficiently cleave DNA.

Conclusions and general significance: At low Mg(2+) concentrations, fluoroquinolones may stimulate the Topo IV-catalyzed strand breakage reaction by promoting Mg(2+) binding to metal binding site B through the structural distortion in DNA. As Mg(2+) concentration increases, fluoroquinolones may inhibit the religation reaction by either stabilizing Mg(2+) at site B or inhibition the binding of Mg(2+) to site A. This study provides a molecular basis of how fluoroquinolones stimulate the Topo IV-catalyzed strand breakage reaction by modulating Mg(2+) binding.

Objective:  To assess the efficacy and comparative effectiveness of surgical and nonsurgical treatments for fecal incontinence (FI) in adults. 

Data sources: Ovid MEDLINE®, Embase®, PEDro®, CINAHL®, AMED, and the Cochrane Central Register of Controlled Trials (CENTRAL); hand searches of systematic reviews. 

 Methods: Two investigators screened abstracts of identified references for eligibility (examined treatments in adults with FI published from 1980 to the present that had a control/comparator group; case series were included for surgical interventions). Full-text articles were reviewed to identify patient-reported outcomes (FI episodes, FI severity, quality of life, urgency, pain, other). We extracted data, assessed risk of bias of individual studies, and evaluated strength of evidence for each comparison and outcome.

 Results:  Sixty-three unique studies met inclusion criteria; an additional 53 surgical case series were examined for adverse effects. Enrolled adults were mostly female with mixed FI etiologies. Most randomized controlled trials (RCTs) were nonsurgical (n = 38); 13 examined pelvic floor muscle training (PFMT) and PFMT with biofeedback (PFMT-BF). Meta-analysis was not possible because numerous outcomes were used. Low-strength evidence suggests that dietary fiber (psyllium) decreases FI episodes (-2.5 per week) at 1 month; clonidine has no effect; and PFMT-BF with electrostimulation is no more effective than PFMT-BF for FI severity and the FI Quality of Life scale (FIQL) over 2 to 3 months. Low-strength evidence at 6 months suggests that dextranomer anal bulking injections are more effective than sham injections on the FIQL, the number of FI-free days, and the percent of adults with at least 50-percent reduction from baseline in FI episodes, but no more effective than PFMT-BF with or without electrostimulation on FI severity (PFMT-BF -5.4 vs. dextranomer -4.6 point Vaizey score improvements) and the FIQL, and no more effective than sham injection on FI severity (-2.5 vs. -1.7 point sham improvement in Cleveland Clinic FI score [CCFIS]) or FI episode frequency. Moderate-strength evidence suggests that Durasphere® (off label) bulking injections reduce FI severity up to 6 months (-4 to -5 points CCFIS), but gains diminish thereafter. Evidence was insufficient for all other surgical and nonsurgical comparisons. Surgical improvements varied. Noninvasive nonsurgical treatments had few minor adverse effects (AEs). Surgical treatments were associated with more frequent and more severe complications than nonsurgical interventions. AEs were most frequent for the artificial bowel sphincter (22–100% of adults). Surgical AEs ranged from minor to major (infection, bowel obstruction, perforation, fistula). Major surgical complications often required reoperation; fewer required permanent colostomy. Only 12 percent of RCTs were high quality.   

Conclusion: We found limited evidence to support any FI treatments beyond 3 to 6 months. Comparing the effectiveness of FI surgical and nonsurgical treatments is difficult because nonsurgical approaches generally precede surgery. Most current interventions show modest improvements in FI outcomes that meet minimal important differences (MIDs) in the short term, where MID is known. More invasive surgical procedures have substantial complications.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder occurring in 1:4000 worldwide.  Scoliosis is perhaps the most common skeletal problem in patients with NF1 with a prevalence of 1069%. There are two types: dystrophic and non dystrophic scoliosis.  Dystrophic scoliosis appears to have a poorer prognosis.  Dystrophic changes develop over time and may not necessarily appear at initial presentation.  Therefore the development and validation of a radiographic scheme to classify dystrophic scoliosis is needed to aide in distinguishing dystrophic from non dystrophic scoliosis and allow early detection and intervention and is our first objection. The second objective rests on the fact that NF1 has marked variability of clinical expression.  There is evidence that other genes may play a role in NF1 expression. Current research has identified candidate genetic SNP markers that can predict progressive and non-progressive curves in Adolescent Idiopathic Scoliosis (AIS) with a high degree of reliability.  If the same genetic markers are present in non-dystrophic scoliosis then this will allow earlier, more accurate prognostication, and perhaps improve treatment. Thus our hypothesis is that  NF1 patients with non-dystrophic or dystrophic scoliosis have the same genetic markers as patients with AIS. 

Background: No systematic review has examined the collective randomized and nonrandomized evidence for fecal incontinence treatment effectiveness across the range of surgical treatments.

Objective: The purpose of this study was to assess the efficacy, comparative effectiveness, and harms of surgical treatments for fecal incontinence in adults.

Data sources: Ovid MEDLINE, EMBASE, Physiotherapy Evidence Database, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine, and the Cochrane Central Register of Controlled Trials, as well as hand searches of systematic reviews, were used as data sources.

Study selection: Two investigators screened abstracts for eligibility (surgical treatment of fecal incontinence in adults, published 1980-2015, randomized controlled trial or observational study with comparator; case series were included for adverse effects). Full-text articles were reviewed for patient-reported outcomes. We extracted data, assessed study risk of bias, and evaluated strength of evidence for each treatment-outcome combination.

Interventions: Surgical treatments for fecal incontinence were included interventions.

Main outcome measures: Fecal incontinence episodes/severity, quality of life, urgency, and pain were measured.

Results: Twenty-two studies met inclusion criteria (13 randomized trials and 9 observational trials); 53 case series were included for harms. Most patients were middle-aged women with mixed FI etiologies. Intervention and outcome heterogeneity precluded meta-analysis. Evidence was insufficient for all of the surgical comparisons. Few studies examined the same comparisons; no studies were high quality. Functional improvements varied; some authors excluded those patients with complications or lost to follow-up from analyses. Complications ranged from minor to major (infection, bowel obstruction, perforation, and fistula) and were most frequent after the artificial bowel sphincter (22%-100%). Major surgical complications often required reoperation; few required permanent colostomy.

Limitations: Most evidence is intermediate term, with small patient samples and substantial methodologic limitations.

Conclusions: Evidence was insufficient to support clinical or policy decisions for any surgical treatments for fecal incontinence in adults. More invasive surgical procedures had substantial complications. The lack of compliance with study reporting standards is a modifiable impediment in the field. Future studies should focus on longer-term outcomes and attempt to identify subgroups of adults who might benefit from specific procedures.

There are substantial research knowledge gaps regarding orthopaedic outcomes after surgical procedures to treat hip fractures in vulnerable elderly patients. The article by Heng et al. serves to remind us that treating hip fractures must be done thoughtfully. Given the risks related to surgical hip fracture treatment, attention should be paid to treatment decisions for subgroups of high-risk patients. Not all older patients are equally likely to benefit from standard orthopaedic care. Some older adults are at high risk for inpatient hospital complications such as delirium, particularly those with prefracture cognitive impairment. Geriatric hip fractures are associated with high morbidity, mortality, and prolonged functional impairment. At least one-third of patients die within 1 year after a hip fracture and less than one-half ever regain their prefracture level of function. Given this trajectory, efforts such as cognitive screening and other measures of frailty can provide useful insights in planning treatment.