Postpartum osteoporosis associated with proximal tibial stress fracture

A 33-year-old woman presented with acute nonspecific knee pain, 6 months postpartum. MR imaging, computed tomography and radiography were performed and a proximal tibia plateau insufficiency fracture was detected. Bone densitometry demonstrated mild postpartum osteoporosis. To our knowledge these findings have not been described in this location and in this clinical setting. The etiology of the atraumatic fracture of the tibia is presumed to be due to a low bone mineral density. The bone loss was probably due to pregnancy, lactation and postpartum hormonal changes. There were no other inciting causes and the patient was normocalcemic. We discuss the presence of a postpartum stress fracture in a hitherto undescribed site in a patient who had lactated following an uncomplicated pregnancy and had no other identifiable cause for a stress fracture.

SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice

Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and chronic bronchitis and is a leading cause of morbidity and mortality worldwide. Tobacco smoke and deficiency in α1-antitrypsin (AAT) are the most prominent environmental and genetic risk factors, respectively. Yet the pathogenesis of COPD is not completely elucidated. Disease progression appears to include a vicious circle driven by self-perpetuating lung inflammation, endothelial and epithelial cell death, and proteolytic degradation of extracellular matrix proteins. Like AAT, serpinB1 is a potent inhibitor of serine proteases including neutrophil elastase and cathepsin G. Because serpinB1 is expressed in myeloid and lung epithelial cells and is protective during lung infections, we investigated the role of serpinB1 in preventing age-related and cigarette smoke-induced emphysema in mice. Fifteen-month-old mice showed increased lung volume and decreased pulmonary function compared with young adult mice (3 mo old), but no differences were observed between serpinB1-deficient (KO) and wild-type (WT) mice. Chronic exposure to secondhand cigarette smoke resulted in structural emphysematous changes compared with respective control mice, but no difference in lung morphometry was observed between genotypes. Of note, the different pattern of stereological changes induced by age and cigarette smoke suggest distinct mechanisms leading to increased airway volume. Finally, expression of intracellular and extracellular protease inhibitors were differently regulated in lungs of WT and KO mice following smoke exposure; however, activity of proteases was not significantly altered. In conclusion, we showed that, although AAT and serpinB1 are similarly potent inhibitors of neutrophil proteases, serpinB1 deficiency is not associated with more severe emphysema.

Illegitimate tasks associated with higher cortisol levels among male employees when subjective health is relatively low: an intra-individual analysis

Objectives Illegitimate tasks refer to tasks that do not conform to what can appropriately be expected from an employee. Violating role expectations, they constitute “identity-stressors”, as one’s professional role tends to become part of one’s identity. The current study investigated the impact of illegitimate tasks on salivary cortisol. We analyzed data on an intra-individual level, that is, by examining fluctuations in illegitimate tasks and cortisol within individuals. Furthermore, we investigated the moderating role of perceived health, expecting that illegitimate tasks evoke stronger reactions when perceived health is relatively poor. Methods Illegitimate tasks, salivary cortisol, and perceived health were assessed in each of three waves (time lag: 6 months) in a sample of 104 male employees. Data were analyzed by multilevel analysis using group mean centering. Results Controlling for social stressors, work interruptions, and emotional stability, the experience of more illegitimate tasks was associated with increased cortisol release if personal health resources were low compared to one’s mean value of perceived health. Results cannot be explained by inter-individual differences. Conclusions This is the first study showing that illegitimate tasks predict a biological indicator of stress, thus confirming and extending previous research on illegitimate tasks. The moderating role of perceived health confirms its importance as a personal resource, implying augmented vulnerability when perceived health is below its usual value. It is plausible to assume that increased stress reactions due to relatively poor health may further weaken available personal resources. Both avoiding illegitimate tasks and restoring personal health seem to be crucial.

Camel Streptococcus agalactiae populations are associated with specific disease complexes and acquired the tetracycline resistance gene tetM via a Tn916-like element

Camels are the most valuable livestock species in the Horn of Africa and play a pivotal role in the nutritional sustainability for millions of people. Their health status is therefore of utmost importance for the people living in this region. Streptococcus agalactiae, a Group B Streptococcus (GBS), is an important camel pathogen. Here we present the first epidemiological study based on genetic and phenotypic data from African camel derived GBS. Ninety-two GBS were characterized using multilocus sequence typing (MLST), capsular polysaccharide typing and in vitro antimicrobial susceptibility testing. We analysed the GBS using Bayesian linkage, phylogenetic and minimum spanning tree analyses and compared them with human GBS from East Africa in order to investigate the level of genetic exchange between GBS populations in the region. Camel GBS sequence types (STs) were distinct from other STs reported so far. We mapped specific STs and capsular types to major disease complexes caused by GBS. Widespread resistance (34%) to tetracycline was associated with acquisition of the tetM gene that is carried on a Tn916-like element, and observed primarily among GBS isolated from mastitis. The presence of tetM within different MLST clades suggests acquisition on multiple occasions. Wound infections and mastitis in camels associated with GBS are widespread and should ideally be treated with antimicrobials other than tetracycline in East Africa.

A non-coding genomic duplication at the HMX1 locus is associated with crop ears in highland cattle.

Highland cattle with congenital crop ears have notches of variable size on the tips of both ears. In some cases, cartilage deformation can be seen and occasionally the external ears are shortened. We collected 40 cases and 80 controls across Switzerland. Pedigree data analysis confirmed a monogenic autosomal dominant mode of inheritance with variable expressivity. All affected animals could be traced back to a single common ancestor. A genome-wide association study was performed and the causative mutation was mapped to a 4 Mb interval on bovine chromosome 6. The H6 family homeobox 1 (HMX1) gene was selected as a positional and functional candidate gene. By whole genome re-sequencing of an affected Highland cattle, we detected 6 non-synonymous coding sequence variants and two variants in an ultra-conserved element at the HMX1 locus with respect to the reference genome. Of these 8 variants, only a non-coding 76 bp genomic duplication (g.106720058_106720133dup) located in the conserved region was perfectly associated with crop ears. The identified copy number variation probably results in HMX1 misregulation and possible gain-of-function. Our findings confirm the role of HMX1 during the development of the external ear. As it is sometimes difficult to phenotypically diagnose Highland cattle with slight ear notches, genetic testing can now be used to improve selection against this undesired trait.

Major histocompatibility complex and other allergy-related candidate genes associated with insect bite hypersensitivity in Icelandic horses

Insect bite hypersensitivity (IBH) is an allergic dermatitis of horses caused by bites of insects. IBH is a multifactorial disease with contribution of genetic and environmental factors. Candidate gene association analysis of IBH was performed in a group of 89 Icelandic horses all born in Iceland and imported to Europe. Horses were classified in IBH-affected and non-affected based on clinical signs and history of recurrent dermatitis, and on the results of an in vitro sulfidoleukotriene (sLT)-release assay with Culicoides nubeculosus and Simulium vittatum extract. Different genetic markers were tested for association with IBH by the Fisher's exact test. The effect of the major histocompatibility complex (MHC) gene region was studied by genotyping five microsatellites spanning the MHC region (COR112, COR113, COR114, UM011 and UMN-JH34-2), and exon 2 polymorphisms of the class II Eqca-DRA gene. Associations with Eqca-DRA and COR113 were identified (p < 0.05). In addition, a panel of 20 single nucleotide polymorphisms (SNPs) in 17 candidate allergy-related genes was tested. During the initial screen, no marker from the panel was significantly (p < 0.05) associated with IBH. Five SNPs associated with IBH at p < 0.10 were therefore used for analysis of combined genotypes. Out of them, SNPs located in the genes coding for the CD14 receptor (CD14), interleukin 23 receptor (IL23R), thymic stromal lymphopoietin (TSLP) and transforming growth factor beta 3 (TGFB3) molecules were associated with IBH as parts of complex genotypes. These results are supported by similar associations and by expression data from different horse populations and from human studies.

Genomic signatures of relaxed disruptive selection associated with speciation reversal in whitefish

Background: Speciation reversal: the erosion of species differentiation via an increase in introgressive hybridization due to the weakening of previously divergent selection regimes, is thought to be an important, yet poorly understood, driver of biodiversity loss. Our study system, the Alpine whitefish (Coregonus spp.) species complex is a classic example of a recent postglacial adaptive radiation: forming an array of endemic lake flocks, with the independent origination of similar ecotypes among flocks. However, many of the lakes of the Alpine radiation have been seriously impacted by anthropogenic nutrient enrichment, resulting in a collapse in neutral genetic and phenotypic differentiation within the most polluted lakes. Here we investigate the effects of eutrophication on the selective forces that have shaped this radiation, using population genomics. We studied eight sympatric species assemblages belonging to five independent parallel adaptive radiations, and one species pair in secondary contact. We used AFLP markers, and applied FST outlier (BAYESCAN, DFDIST) and logistic regression analyses (MATSAM), to identify candidate regions for disruptive selection in the genome and their associations with adaptive traits within each lake flock. The number of outlier and adaptive trait associated loci identified per lake were then regressed against two variables (historical phosphorus concentration and contemporary oxygen concentration) representing the strength of eutrophication. Results: Whilst we identify disruptive selection candidate regions in all lake flocks, we find similar trends, across analysis methods, towards fewer disruptive selection candidate regions and fewer adaptive trait/candidate loci associations in the more polluted lakes. Conclusions: Weakened disruptive selection and a concomitant breakdown in reproductive isolating mechanisms in more polluted lakes has lead to increased gene flow between coexisting Alpine whitefish species. We hypothesize that the resulting higher rates of interspecific recombination reduce either the number or extent of genomic islands of divergence surrounding loci evolving under disruptive natural selection. This produces the negative trend seen in the number of selection candidate loci recovered during genome scans of whitefish species flocks, with increasing levels of anthropogenic eutrophication: as the likelihood decreases that AFLP restriction sites will fall within regions of heightened genomic divergence and therefore be classified as FST outlier loci. This study explores for the first time the potential effects of human-mediated relaxation of disruptive selection on heterogeneous genomic divergence between coexisting species.

Divergent evolutionary processes associated with colonization of offshore islands

Oceanic islands have been a test ground for evolutionary theory, but here, we focus on the possibilities for evolutionary study created by offshore islands. These can be colonized through various means and by a wide range of species, including those with low dispersal capabilities. We use morphology, modern and ancient sequences of cytochrome b (cytb) and microsatellite genotypes to examine colonization history and evolutionary change associated with occupation of the Orkney archipelago by the common vole (Microtus arvalis), a species found in continental Europe but not in Britain. Among possible colonization scenarios, our results are most consistent with human introduction at least 5100 bp (confirmed by radiocarbon dating). We used approximate Bayesian computation of population history to infer the coast of Belgium as the possible source and estimated the evolutionary timescale using a Bayesian coalescent approach. We showed substantial morphological divergence of the island populations, including a size increase presumably driven by selection and reduced microsatellite variation likely reflecting founder events and genetic drift. More surprisingly, our results suggest that a recent and widespread cytb replacement event in the continental source area purged cytb variation there, whereas the ancestral diversity is largely retained in the colonized islands as a genetic ‘ark’. The replacement event in the continental M. arvalis was probably triggered by anthropogenic causes (land-use change). Our studies illustrate that small offshore islands can act as field laboratories for studying various evolutionary processes over relatively short timescales, informing about the mainland source area as well as the island.

Risk factors associated with cast complications in horses: 398 cases (1997-2006)

OBJECTIVE To determine the frequency of and risk factors for complications associated with casts in horses. DESIGN Multicenter retrospective case series. ANIMALS 398 horses with a half-limb or full-limb cast treated at 1 of 4 hospitals. PROCEDURES Data collected from medical records included age, breed, sex, injury, limb affected, time from injury to hospital admission, surgical procedure performed, type of cast (bandage cast [BC; fiberglass tape applied over a bandage] or traditional cast [TC; fiberglass tape applied over polyurethane resin-impregnated foam]), limb position in cast (flexed, neutral, or extended), and complications. Risk factors for cast complications were identified via multiple logistic regression. RESULTS Cast complications were detected in 197 of 398 (49%) horses (18/53 [34%] horses with a BC and 179/345 [52%] horses with a TC). Of the 197 horses with complications, 152 (77%) had clinical signs of complications prior to cast removal; the most common clinical signs were increased lameness severity and visibly detectable soft tissue damage Cast sores were the most common complication (179/398 [45%] horses). Casts broke for 20 (5%) horses. Three (0.8%) horses developed a bone fracture attributable to casting Median time to detection of complications was 12 days and 8 days for horses with TCs and BCs, respectively. Complications developed in 71%, 48%, and 47% of horses with the casted limb in a flexed, neutral, and extended position, respectively. For horses with TCs, hospital, limb position in the cast, and sex were significant risk factors for development of cast complications. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that 49% of horses with a cast developed cast complications.

Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors

BACKGROUND & AIMS Sporadic pancreatic neuroendocrine tumors (pNETs) are rare and genetically heterogeneous. Chromosome instability (CIN) has been detected in pNETs from patients with poor outcomes, but no specific genetic factors have been associated with CIN. Mutations in death domain-associated protein gene (DAXX) or ATR-X gene (ATRX) (which both encode proteins involved in chromatin remodeling) have been detected in 40% of pNETs, in association with activation of alternative lengthening of telomeres. We investigated whether loss of DAXX or ATRX, and consequent alternative lengthening of telomeres, are related to CIN in pNETs. We also assessed whether loss of DAXX or ATRX is associated with specific phenotypes of pNETs. METHODS We collected well-differentiated primary pNET samples from 142 patients at the University Hospital Zurich and from 101 patients at the University Hospital Bern (both located in Switzerland). Clinical follow-up data were obtained for 149 patients from general practitioners and tumor registries. The tumors were reclassified into 3 groups according to the 2010 World Health Organization classification. Samples were analyzed by immunohistochemistry and telomeric fluorescence in situ hybridization. We correlated loss of DAXX, or ATRX, expression, and activation of alternative lengthening of telomeres with data from comparative genomic hybridization array studies, as well as with clinical and pathological features of the tumors and relapse and survival data. RESULTS Loss of DAXX or ATRX protein and alternative lengthening of telomeres were associated with CIN in pNETs. Furthermore, loss of DAXX or ATRX correlated with tumor stage and metastasis, reduced time of relapse-free survival, and decreased time of tumor-associated survival. CONCLUSIONS Loss of DAXX or ATRX is associated with CIN in pNETs and shorter survival times of patients. These results support the hypothesis that DAXX- and ATRX-negative tumors are a more aggressive subtype of pNET, and could lead to identification of strategies to target CIN in pancreatic tumors.

Influence of Anchoring on Miscarriage Risk Perception Associated with Amniocentesis

INFLUENCE OF ANCHORING ON MISCARRIAGE RISK PERCEPTION ASSOCIATED WITH AMNIOCENTESIS Publication No. ___________ Regina Nuccio, BS Supervisory Professor: Claire N. Singletary, MS, CGC Amniocentesis is the most common invasive procedure performed during pregnancy (Eddleman, et al., 2006). One important factor that women consider when making a decision about amniocentesis is the risk of miscarriage associated with the procedure. People use heuristics such as anchoring, the action of using a prior belief regarding the magnitude of risk as a frame of reference for new information to be synthesized, to better understand risks that they encounter in their lives. This study aimed to determine a woman’s perception of miscarriage risk associated with amniocentesis before and after a genetic counseling session and to determine what factors are most likely to anchor a woman’s perception of miscarriage risk associated with amniocentesis. Most women perceived the risk as low or average pre-counseling and were likely to indicate the numeric risk of amniocentesis as <1% risk. A higher percentage of patients correctly identified the numeric risk as <1% post-counseling when compared to pre-counseling. However, the majority of patients’ feeling about the risk perception did not change after the genetic counseling session (60%), regardless of how they perceived the risk before discussing amniocentesis with a genetic counselor. Those whose risk perception did change after discussing amniocentesis with a genetic counselor showed a decreased risk perception (p<0.0001). Of the multitude of factors studied, only two showed significance: having a friend or relative with a personal or family history of a genetic disorder was associated with a lower risk perception (p=0.001) and having a child already was associated with a lower risk perception (p=0.038). The lack of significant factors may reflect the uniqueness of each patient’s heuristic framework and reinforces the importance of genetic counseling to elucidate individual concerns.

A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosus.

A gain-of-function R620W polymorphism in the PTPN22 gene, encoding the lymphoid tyrosine phosphatase LYP, has recently emerged as an important risk factor for human autoimmunity. Here we report that another missense substitution (R263Q) within the catalytic domain of LYP leads to reduced phosphatase activity. High-resolution structural analysis revealed the molecular basis for this loss of function. Furthermore, the Q263 variant conferred protection against human systemic lupus erythematosus, reinforcing the proposal that inhibition of LYP activity could be beneficial in human autoimmunity.

Severe aortic and arterial aneurysms associated with a TGFBR2 mutation.

BACKGROUND: A 24-year-old man presented with previously diagnosed Marfan's syndrome. Since the age of 9 years, he had undergone eight cardiovascular procedures to treat rapidly progressive aneurysms, dissection and tortuous vascular disease involving the aortic root and arch, the thoracoabdominal aorta, and brachiocephalic, vertebral, internal thoracic and superior mesenteric arteries. Throughout this extensive series of cardiovascular surgical repairs, he recovered without stroke, paraplegia or renal impairment. INVESTIGATIONS: CT scans, arteriogram, genetic mutation screening of transforming growth factor beta receptors 1 and 2. DIAGNOSIS: Diffuse and rapidly progressing vascular disease in a patient who met the diagnostic criteria for Marfan's syndrome, but was later rediagnosed with Loeys-Dietz syndrome. Genetic testing also revealed a de novo mutation in transforming growth factor beta receptor 2. MANAGEMENT: Regular cardiovascular surveillance for aneurysms and dissections, and aggressive surgical treatment of vascular disease.

ROLE OF PROSTAGLANDIN E2 IN THE REGULATION OF PANCREATIC STELLATE CELLS HYPER ACTIVITY ASSOCIATED WITH PANCREATIC CANCER

Pancreatic cancer is one of the most lethal type of cancer due to its high metastasis rate and resistance to chemotherapy. Pancreatic fibrosis is a constant pathological feature of chronic pancreatitis and the hyperactive stroma associated with pancreatic cancer. Strong evidence supports an important role of cyclooxygenase-2 (COX-2) and COX-2 generated prostaglandin E2 (PGE2) during pancreatic fibrosis. Pancreatic stellate cells (PSC) are the predominant source of extracellular matrix production (ECM), thus being the key players in both diseases. Given this background, the primary objective is to delineate the role of PGE2 on human pancreatic stellate cells (PSC) hyper activation associated with pancreatic cancer. This study showed that human PSC cells express COX-2 and synthesize high levels of PGE2. PGE2 stimulated PSC migration and invasion; expression of extra cellular matrix (ECM) genes and tissue degrading matrix metallo proteinases (MMP) genes. I further identified the PGE2 EP receptor responsible for mediating these effects on PSC. Using genetic and pharmacological approaches I identified the receptor required for PGE2 mediates PSC hyper activation. Treating PSC with Specific antagonists against EP1, EP2 and EP4, demonstrated that blocking EP4 receptor only, resulted in a complete reduction of PGE2 mediated PSC activation. Furthermore, siRNA mediated silencing of EP4, but not other EP receptors, blocked the effects of PGE2 on PSC fibrogenic activity. Further examination of the downstream pathway modulators revealed that PGE2 stimulation of PSC involved CREB and not AKT pathway. The regulation of PSC by PGE2 was further investigated at the molecular level, with a focus on COL1A1. Collagen I deposition by PSC is one of the most important events in pancreatic cancer. I found that PGE2 regulates PSC through activation of COL1A1 expression and transcriptional activity. Downstream of PGE2, silencing of EP4 receptor caused a complete reduction of COL1A1 expression and activity supporting the role of EP4 mediated stimulation of PSC. Taken together, this data indicate that PGE2 regulates PSC via EP4 and suggest that EP4 can be a better therapeutic target for pancreatic cancer to reduce the extensive stromal reaction, possibly in combination with chemotherapeutic drugs can further kill pancreatic cancer cells.

Risk factors associated with first symptomatic infection of {\it Cryptosporidium parvum\/} in an infant population in Bilbeis, Egypt

Diarrhea disease is a leading cause of morbidity and mortality, especially in children in developing countries. An estimate of the global mortality caused by diarrhea among children under five years of age was 3.3 million deaths per year. Cryptosporidium parvum was first identified in 1907, but it was not until 1970 that this organism was recognized as a cause of diarrhea in calves. Then it was as late as 1976 that the first reported case of human Cryptosporidiosis occurred. This study was conducted to ascertain the risk factors of first symptomatic infection with Cryptosporidium parvum in a cohort of infants in a rural area of Egypt. The cohort was followed from birth through the first year of life. Univariate and multivariate analyses of data demonstrated that infants greater than six months of age had a two-fold risk of infection compared with infants less than six months of age (RR = 2.17; 95% C.I. = 1.01-4.82). When stratified, male infants greater than six months of age were four times more likely to become infected than male infants less than six months of age. Among female infants, there was no difference in risk between infants greater than six months of age and infants less than six months of age. Female infants less than six months of age were twice more likely to become infected than male infants less than six months of age. The reverse occurred for infants greater than six months of age, i.e., male infants greater than six months of age had twice the risk of infection compared to females of the same age group. Further analysis of the data revealed an increased risk of Cryptosporidiosis infection in infants who were attended in childbirth by traditional childbirth attendants compared to infants who were attended by modern childbirth attendants (nurses, trained midwives, physicians) (RR = 4. 18; 95% C.I. = 1.05-36.06). The final risk factor of significance was the number of people residing in the household. Infants in households which housed more than seven persons had an almost two-fold risk of infection compared with infants in homes with fewer than seven persons. Other risk factors which suggested increased risk were lack of education among the mothers, absence of latrines and faucets in the homes, and mud used as building material for walls and floors in the homes. ^