Maxillomandibular osteotomy healing in a patient with hypophosphatemic rickets.

Hypophosphatemic rickets is a hereditary disease of childhood that affects bone metabolism. Patients with this disease can have poor bony healing at growth centers due to impaired mineralization of the cartilaginous bone plates. The orthopedic literature has shown appropriate long bone healing in patients with rickets who are undergoing concurrent medical management. However, there has never been a report of successful osteotomy or fracture of the maxillomandibular skeleton in a patient with rickets with documented radiographic and clinical resolution. This report describes a case of successful Le Fort I osteotomy with bilateral mandibular sagittal split osteotomies with concurrent medical management in an 18-year-old female with hypophosphatemic rickets. Before surgery the patient was consented and understood that because there has never been a documented case such as this, she might especially risk complications including non-union, malunion, or unfavorable osteotomy splits. The intraoperative quality of the patient's bone was of normal caliber and allowed routine osteotomy creation and internal fixation with no complications. She was followed for over 3 years and showed uneventful healing. While this disease is especially rare, practitioners should be aware that acceptable healing alongside appropriate medical management has been documented.

Post-traumatic stress disorder and incident fractures in the Danish population.

Psychological stress may be associated with increased risk of fractures. It is unknown whether post-traumatic stress disorder (PTSD), a marker of chronic severe psychological stress occurring in response to a traumatic event, influences fracture risk. In this nationwide cohort study, persons with PTSD had an increased risk of fractures compared to the general population. INTRODUCTION: We conducted a population-based national cohort study in Denmark to examine the association between PTSD and incident fractures. METHODS: We examined the incidence rate of overall and specific fractures among patients with clinician-diagnosed PTSD (n = 4114), compared with the incidence rate in the general population from 1995 to 2013, using Danish medical registry data. We further examined differences in associations by gender, age, psychiatric and somatic comorbidity, and follow-up time. We calculated absolute risks, standardized incidence ratios (SIRs), and 95% confidence intervals (95% CIs). RESULTS: Risk of any fracture among persons with PTSD was 24% (95% CI 20%, 28%) over the study period. The SIR for any fracture was 1.7 (95% CI 1.6, 1.9). We found little evidence of effect measure modification of the association between PTSD and fractures in our stratified analyses. CONCLUSIONS: Our findings suggest that PTSD is associated with increased fracture risk.

Magnetic Field Control of Cycloidal Domains and Electric Polarization in Multiferroic BiFeO_{3}.

The magnetic field induced rearrangement of the cycloidal spin structure in ferroelectric monodomain single crystals of the room-temperature multiferroic BiFeO_{3} is studied using small-angle neutron scattering. The cycloid propagation vectors are observed to rotate when magnetic fields applied perpendicular to the rhombohedral (polar) axis exceed a pinning threshold value of ∼5 T. In light of these experimental results, a phenomenological model is proposed that captures the rearrangement of the cycloidal domains, and we revisit the microscopic origin of the magnetoelectric effect. A new coupling between the magnetic anisotropy and the polarization is proposed that explains the recently discovered magnetoelectric polarization perpendicular to the rhombohedral axis.

Longitudinal enlargement of the lesion after spinal cord injury in the rat: a consequence of malignant edema?

STUDY DESIGN: Experimental animal study. OBJECTIVES: Quantitative analysis of secondary changes in lesion size after experimental spinal cord injury (SCI) in the rat, with special emphasis to the formation of dorsal column lesions. SETTING: Slovakia. METHODS: After SCI in the rat, animals survived for different periods ranging from 5 min to 7 days. Their whole spinal cords were cut transversally into 1 mm thick slabs. On each slab, the lesion profile was outlined. The overall shape of the lesion was reconstructed from a series of consecutive profiles and its length was measured. RESULTS: Immediately after injury, a spindle-shaped hemorrhagic contusive lesion was observed, with the length of ~15 mm. After a quiescent phase lasting for at least 1 h, there was a dramatic secondary enlargement of the lesion and its length increased up to 40 mm between 1 and 48 h. The fully developed lesion consisted of the spindle-shaped epicenter and long cranial and caudal protrusions located in the midline between dorsal columns. CONCLUSION: We propose that secondary enlargement of the lesion can be explained by posttraumatic swelling. The expanding tissues are pushed out in longitudinal axis along the mechanically weakest parts of the spinal cord. Additional data that support this hypothesis are presented. Our findings indicate that malignant posttraumatic edema might have an important role in pathomechanisms of secondary injury after SCI.

Adjustment disorder and risk of Parkinson's disease.

BACKGROUND AND PURPOSE: It has been postulated that stress is part of the etiological process of Parkinson's disease (PD). The risk of PD was examined in a cohort of patients with adjustment disorders, a diagnosis made in the presence of a severe response to a stressful life event. METHODS: Using Danish medical registries, PD occurrence was examined in a nationwide population-based cohort of patients with adjustment disorder diagnosed between 1995 and 2011. The standardized incidence ratio of PD was calculated as the ratio of observed to expected cases, stratified by time and potential risk factors, including depression and anxiety. RESULTS: Our adjustment disorder cohort (67 786 patients) was followed for a median of 8 years (interquartile range 4, 12.6 years). During follow-up, 119 patients developed PD, versus 64 expected, corresponding to a standardized incidence ratio of 1.84 (95% confidence interval 1.53, 2.20). Consistent results were observed after stratification on potential risk factors, including depression and anxiety. CONCLUSION: Adjustment disorder, a diagnosis made in the presence of severe response to stressful life events, was associated with an increased risk of PD.

Clinical outcome of subchromosomal events detected by whole-genome noninvasive prenatal testing.

OBJECTIVE: A novel algorithm to identify fetal microdeletion events in maternal plasma has been developed and used in clinical laboratory-based noninvasive prenatal testing. We used this approach to identify the subchromosomal events 5pdel, 22q11del, 15qdel, 1p36del, 4pdel, 11qdel, and 8qdel in routine testing. We describe the clinical outcomes of those samples identified with these subchromosomal events. METHODS: Blood samples from high-risk pregnant women submitted for noninvasive prenatal testing were analyzed using low coverage whole genome massively parallel sequencing. Sequencing data were analyzed using a novel algorithm to detect trisomies and microdeletions. RESULTS: In testing 175,393 samples, 55 subchromosomal deletions were reported. The overall positive predictive value for each subchromosomal aberration ranged from 60% to 100% for cases with diagnostic and clinical follow-up information. The total false positive rate was 0.0017% for confirmed false positives results; false negative rate and sensitivity were not conclusively determined. CONCLUSION: Noninvasive testing can be expanded into the detection of subchromosomal copy number variations, while maintaining overall high test specificity. In the current setting, our results demonstrate high positive predictive values for testing of rare subchromosomal deletions.

Breast cancer risk in hyperprolactinemia: a population-based cohort study and meta-analysis of the literature.

OBJECTIVE: To enhance the precision of the risk estimate for breast cancer in hyperprolactinemia patients by collecting more data and pooling our results with available data from former studies in a meta-analysis. DESIGN: Population-based cohort study and meta-analysis of the literature. METHODS: Using nationwide registries, we identified all patients with a first-time diagnosis of hyperprolactinemia during 1994-2012 including those with a new breast cancer diagnoses after the start of follow-up. We calculated standardised incidence ratios (SIRs) as a measure of relative risk (RR) using national cancer incidence rates. We performed a meta-analysis, combining data from our study with data in the existing literature. RESULTS: We identified 2457 patients with hyperprolactinemia and 20 breast cancer cases during 19,411 person-years of follow-up, yielding a SIR of 0.99 (95% CI 0.60-1.52). Data from two additional cohort studies were retrieved and analyzed. When the three risk estimates were pooled, the combined RR was 1.04 (95% CI 0.75-1.43). CONCLUSIONS: We found no increased risk of breast cancer among patients with hyperprolactinemia.

Pneumonia and the incidence of cancer: a Danish nationwide cohort study.

OBJECTIVES: To examine the risk of a subsequent pulmonary or extra-pulmonary cancer diagnosis following a first-time hospital-based diagnosis of pneumonia. DESIGN: Population-based cohort study using Danish medical registries. SETTING: All hospitals in Denmark. SUBJECTS: A total of 342,609 patients with a first-time hospital-based (inpatient, emergency room or outpatient clinic) diagnosis of pneumonia between 1995 and 2011. MAIN OUTCOME MEASURES: We quantified the excess risk of various cancers amongst pneumonia patients compared to the expected risk in the general population, using relative [standardised incidence ratios (SIRs)] and absolute risk calculations. Follow-up started 1 month after a hospital-based diagnosis of pneumonia and ended on 31 December 2011. RESULTS: A total of 28,496 cancers were observed, compared with 21,625 expected, amongst 342,609 pneumonia patients followed for a median of 4.2 years. The absolute risk of a cancer diagnosis 1 to <6 months following a pneumonia diagnosis was 1.4%, with a corresponding SIR of 2.48 [95% confidence interval (CI) 2.41-2.55]. This was mainly due to an increased risk of lung cancer (eightfold) and haematological cancers (fourfold). The SIR for any cancer remained increased at 1.35 (95% CI 1.30-1.40) during 6-12 months of follow-up, and 1.20 (95% CI 1.18-1.22) during 1-5 years of follow-up. Beyond 5 years, an increased risk was maintained for lung, oesophageal, liver and bladder cancers, squamous cell carcinoma of the skin, lymphoma and multiple myeloma. CONCLUSIONS: A hospital-based pneumonia diagnosis was associated with an increased risk of a cancer diagnosis, especially in the ensuing months, but the absolute risk was small.

Tuberculosis and risk of cancer: a Danish nationwide cohort study.

OBJECTIVES: To investigate the short- and long-term risk of cancer in patients with active tuberculosis (TB). DESIGN: Using Danish nationwide databases, we quantified cancer risk in TB patients during 1978-2011 compared with the general population. RESULTS: We observed 1747 cancers in 15 024 TB patients (median follow-up 8.5 years), reflecting a standardised incidence ratio (SIR) of 1.52 (95%CI 1.45-1.59). All-time SIR for extra-pulmonary cancer was 1.29 (95%CI 1.22-1.36) and for lung cancer it was 3.40 (95%CI 3.09-3.74). Absolute cancer risk 3 months after TB was 1.83% (SIR 11.09, 95%CI 9.82-12.48), with highly increased SIRs for malignant pleural mesothelioma (368.4), lung cancer (40.9), Hodgkin's lymphoma (30.6), ovarian cancer (26.4) and non-Hodgkin's malignant lymphoma (23.8). Between the 3-month and 5-year follow-up, the SIR for any cancer was 1.59 (95%CI 1.46-1.72), including 19- and 3-fold increases for malignant pleural mesothelioma and lung cancer. Beyond 5 years, the SIR of cancer was 1.17 (95%CI 1.10-1.25). Elevated long-term risks persisted for haematological (SIR 1.34, 95%CI 1.01-1.74) and tobacco-related cancers (SIR 1.78, 95%CI 1.60-1.97). CONCLUSION: TB is a marker of occult lung cancer and several extra-pulmonary cancers. TB also predicts increased long-term risk of cancer, possibly related to chronic inflammation and shared risk factors, including immunosuppression and smoking.

Cancer incidence among patients with a hospital diagnosis of pruritus: a nationwide Danish cohort study.

BACKGROUND: Pruritus is a frequent complaint in patients with cancer. However, no large study has examined pruritus as a marker of undiagnosed cancer. OBJECTIVES: To examine the association between inpatient, outpatient and emergency hospital diagnoses of pruritus and subsequent cancer diagnoses. METHODS: In this nationwide Danish cohort study, we used medical databases to identify all patients (n = 12,813) with a diagnosis of pruritus during the period 1978-2011 and followed them until a first-time cancer diagnosis, emigration, death or 31 December 2011. We computed standardized incidence ratios (SIRs) for cancer as the observed to expected number of cancers based on national cancer incidence rates. We calculated the 1-year absolute risk of cancer, treating death as a competing risk. RESULTS: The overall SIR of cancer was 1.13 [95% confidence interval (CI) 1.07-1.20]: 1.22 (95% CI 1.13-1.33) among men and 1.05 (95% CI 0.97-1.14) among women. The SIR was 1.20 (95% CI 1.08-1.33) among patients with a previous diagnosis of dermatological disease and 1.10 (95% CI 1.02-1.18) among patients without such a diagnosis. Both haematological and various solid cancers were observed at increased rates. Overall, the highest SIRs were observed during the first 3 months of follow-up, declining rapidly thereafter. The 1-year absolute risk of a cancer diagnosis was 1.63% and 155 patients with pruritus would have needed to be examined to detect one excess cancer. CONCLUSIONS: Pruritus may be a marker of occult cancer. Further studies are needed to assess the prognostic benefit of screening for cancer in patients with pruritus.

Prenatal exposure to acid-suppressive drugs and the risk of childhood asthma: a population-based Danish cohort study.

BACKGROUND: Proton pump inhibitors (PPIs) may activate the immune system and cause asthma. AIM: To investigate the association of prenatal exposure to PPIs and histamine 2-receptor antagonists (H2RAs) with risk of asthma. METHODS: In this cohort study, 197,060 singletons born between 1996 and 2008 in northern Denmark were followed until the end of 2009. Data were obtained through Danish medical registries. Asthma in offspring was defined as at least two prescriptions of both a ß-agonist and an inhaled glucocorticoid and/or a hospital diagnosis of asthma during the follow-up. Cox proportional-hazard regression was used to compute incidence rate ratios, adjusting for covariates. RESULTS: A total of 2238 (1.1%) children were prenatally exposed to PPIs and 24,506 (12.4%) children developed asthma during follow-up (median follow-up = 6.8 years). The adjusted IRR (aIRR) of asthma associated with prenatal exposure to PPIs was 1.41 (95% confidence interval (CI): 1.27-1.56), compared with those unexposed. The association did not vary by trimester of exposure, and prenatal exposure to H2RAs was associated with similar increase in risk. The aIRR for maternal PPI and H2RA use in the year after, but not during pregnancy was 1.32 (95% CI: 1.20-1.46) and 1.13 (0.93-1.36), respectively, compared with non-use during and in the year after pregnancy. CONCLUSIONS: Prenatal exposure to both PPIs and H2RAs was associated with an increased risk of asthma in our study. Because the observed association is not drug specific and also observed for maternal postnatal use it may be explained by a 'class effect' or maternal underlying condition.

Are nanoporous materials radiation resistant?

The key to perfect radiation endurance is perfect recovery. Since surfaces are perfect sinks for defects, a porous material with a high surface to volume ratio has the potential to be extremely radiation tolerant, provided it is morphologically stable in a radiation environment. Experiments and computer simulations on nanoscale gold foams reported here show the existence of a window in the parameter space where foams are radiation tolerant. We analyze these results in terms of a model for the irradiation response that quantitatively locates such window that appears to be the consequence of the combined effect of two length scales dependent on the irradiation conditions: (i) foams with ligament diameters below a minimum value display ligament melting and breaking, together with compaction increasing with dose (this value is typically ∼5 nm for primary knock on atoms (PKA) of ∼15 keV in Au), while (ii) foams with ligament diameters above a maximum value show bulk behavior, that is, damage accumulation (few hundred nanometers for the PKA's energy and dose rate used in this study). In between these dimensions, (i.e., ∼100 nm in Au), defect migration to the ligament surface happens faster than the time between cascades, ensuring radiation resistance for a given dose-rate. We conclude that foams can be tailored to become radiation tolerant.

Towards expansion of human hair follicle stem cells in vitro.

OBJECTIVES: Multipotential human hair follicle stem cells can differentiate into various cell lineages and thus are investigated here as potential autologous sources for regenerative medicine. Towards this end, we have attempted to expand these cells, directly isolated from minimal amounts of hair follicle explants, to numbers more suitable for stem-cell therapy. MATERIALS AND METHODS: Two types of human follicle stem cells, commercially available and directly isolated, were cultured using an in-house developed medium. The latter was obtained from bulge areas of hair follicles by mechanical and enzymatic dissociation, and was magnetically enriched for its CD200(+) fraction. Isolated cells were cultured for up to 4 weeks, on different supports: blank polystyrene, laminin- and Matrigel(TM) -coated surfaces. RESULTS: Two-fold expansion was found, highlighting the slow-cycling nature of these cells. Flow cytometry characterization revealed: magnetic enrichment increased the proportion of CD200(+) cells from initially 43.3% (CD200+, CD34: 25.8%; CD200+, CD34+: 17.5%) to 78.2% (CD200+, CD34: 41.5%; CD200+, CD34+: 36.7%). Enriched cells seemed to have retained and passed on their morphological and molecular phenotypes to their progeny, as isolated CD200(+) presenting cells expanded in our medium to a population with 80% of cells being CD200(+): 51.5% (CD200(+), CD34(-)) and 29.6% (CD200(+), CD34(+)). CONCLUSIONS: This study demonstrates the possibility of culturing human hair follicle stem cells without causing any significant changes to phenotypes of the cells.

Irritable bowel syndrome and risk of colorectal cancer: a Danish nationwide cohort study.

BACKGROUND: Little is known about the risk of colorectal cancer among patients with irritable bowel syndrome (IBS). METHODS: We conducted a nationwide cohort study using data from the Danish National Registry of Patients and the Danish Cancer Registry from 1977 to 2008. We included patients with a first-time hospital contact for IBS and followed them for colorectal cancer. We estimated the expected number of cancers by applying national rates and we computed standardised incidence ratios (SIRs) by comparing the observed number of colorectal cancers with the expected number. We stratified the SIRs according to age, gender, and time of follow-up. RESULTS: Among 57,851 IBS patients, we identified 407 cases of colon cancer during a combined follow-up of 506,930 years (SIR, 1.14 (95% confidence interval (CI): 1.03-1.25) and 115 cases of rectal cancer, corresponding to a SIR of 0.67 (95% CI: 0.52-0.85). In the first 3 months after an IBS diagnosis, the SIR was 8.42 (95% CI: 6.48-10.75) for colon cancer and 4.81 (95% CI: 2.85-7.60) for rectal cancer. Thereafter, the SIRs declined and 4-10 years after an IBS diagnosis, the SIRs for both colon and rectal cancer remained below 0.95. CONCLUSION: We found a decreased risk of colorectal cancer in the period 1-10 years after an IBS diagnosis. However, in the first 3 months after an IBS diagnosis, the risk of colon cancer was more than eight-fold increased and the risk of rectal cancer was five-fold increased. These increased risks are likely to be explained by diagnostic confusion because of overlapping symptomatology.

Systemic sclerosis and the risk of cancer: a nationwide population-based cohort study.

BACKGROUND: Earlier studies reported an increased cancer risk among patients with systemic sclerosis. Study size limitations and paucity of population-based study designs may have resulted in imprecise risk estimates. OBJECTIVES: To assess cancer risk among patients with systemic sclerosis in a nationwide follow-up study. METHODS: Patients with a first diagnosis of systemic sclerosis from 1977 to 2006 were identified from the nationwide Danish National Registry of Patients (DNRP), whose records encompass all hospitalizations and outpatient visits. Patients' DNRP records were linked to the Danish Cancer Registry. We compared their cancer incidence with that expected from cancer incidence in the general population, calculating standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: Two thousand and forty patients with systemic sclerosis were identified and followed for 16,003 person-years, with a median follow-up time of 6·4 years (interquartile range 2·2-11·5). Among these patients, 222 cases of cancer were identified. The overall SIR for cancer was 1·5 (95% CI 1·3-1·7), with a gender-specific SIR of 2·2 (95% CI 1·7-2·8) for men and 1·3 (95% CI 1·1-1·6) for women. The most frequent cancers were smoking- and alcohol-related cancers including lung cancer (SIR = 1·6, 95% CI 1·2-2·0), haematological cancers (SIR = 2·5, 95% CI 1·5-4·0) and immune-related cancers (SIR = 1·4, 95% CI 1·0-1·9). CONCLUSIONS: Systemic sclerosis is a risk factor for cancer, particularly smoking- and alcohol-related cancers. Men with systemic sclerosis generally are at higher cancer risk than women. Both primary and secondary cancer preventive measures are needed in the care of patients with systemic sclerosis.

Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study.

OBJECTIVE: The aim of the study was to examine whether exposure to abacavir increases the risk for myocardial infarction (MI). DESIGN, SETTING AND SUBJECTS: This was a prospective nationwide cohort study which included all Danish HIV-infected patients on highly active antiretroviral therapy (HAART) from 1995 to 2005 (N = 2952). Data on hospitalization for MI and comorbidity were obtained from Danish medical databases. Hospitalization rates for MI after HAART initiation were calculated for patients who used abacavir and those who did not. We used Cox's regression to compute incidence rate ratios (IRR) as a measure of relative risk for MI, while controlling for potential confounders (as separate variables and via propensity score) including comorbidity. MAIN OUTCOME: Relative risk of hospitalization with MI in abacavir users compared with abacavir nonusers. RESULTS: Hospitalization rates for MI were 2.4/1000 person-years (PYR) [95% confidence interval (CI) 1.7-3.4] for abacavir nonusers and 5.7/1000 PYR (95% CI 4.1-7.9) for abacavir users. The risk of MI increased after initiation of abacavir [unadjusted IRR = 2.22 (95% CI 1.31-3.76); IRR adjusted for confounders = 2.00 (95% CI 1.10-3.64); IRR adjusted for propensity score = 2.00 (95% CI 1.07-3.76)]. This effect was also observed among patients initiating abacavir within 2 years after the start of HAART and among patients who started abacavir as part of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen. CONCLUSIONS: We confirmed the association between abacavir use and increased risk of MI. Further studies are needed to control for potential confounding not measured in research to date.

Isolation of tumour stem-like cells from benign tumours.

BACKGROUND: Cancerous stem-like cells (CSCs) have been implicated as cancer-initiating cells in a range of malignant tumours. Diverse genetic programs regulate CSC behaviours, and CSCs from glioblastoma patients are qualitatively distinct from each other. The intrinsic connection between the presence of CSCs and malignancy is unclear. We set out to test whether tumour stem-like cells can be identified from benign tumours. METHODS: Tumour sphere cultures were derived from hormone-positive and -negative pituitary adenomas. Characterisation of tumour stem-like cells in vitro was performed using self-renewal assays, stem cell-associated marker expression analysis, differentiation, and stimulated hormone production assays. The tumour-initiating capability of these tumour stem-like cells was tested in serial brain tumour transplantation experiments using SCID mice. RESULTS: In this study, we isolated sphere-forming, self-renewable, and multipotent stem-like cells from pituitary adenomas, which are benign tumours. We found that pituitary adenoma stem-like cells (PASCs), compared with their differentiated daughter cells, expressed increased levels of stem cell-associated gene products, antiapoptotic proteins, and pituitary progenitor cell markers. Similar to CSCs isolated from glioblastomas, PASCs are more resistant to chemotherapeutics than their differentiated daughter cells. Furthermore, differentiated PASCs responded to stimulation with hypothalamic hormones and produced corresponding pituitary hormones that are reflective of the phenotypes of the primary pituitary tumours. Finally, we demonstrated that PASCs are pituitary tumour-initiating cells in serial transplantation animal experiments. CONCLUSION: This study for the first time indicates that stem-like cells are present in benign tumours. The conclusions from this study may have applications to understanding pituitary tumour biology and therapies, as well as implications for the notion of tumour-initiating cells in general.