Miracle-dz/UniFAR-FTUs huggingface dataset:
Trisomic and Allelic Differences Influence Phenotypic Variability During Development of Down Syndrome Mice

Individuals with full or partial Trisomy 21 (Ts21) present with clinical features collectively referred to as Down syndrome (DS), although DS phenotypes vary in incidence and severity between individuals. Differing genetic and phenotypic content in individuals with DS as well as mouse models of DS facilitate the understanding of the correlation between specific genes and phenotypes associated with Ts21. The Ts1Rhr mouse model is trisomic for 33 genes (the “Down syndrome critical region” or DSCR) hypothesized to be responsible for many clinical DS features, including craniofacial dysmorphology with a small mandible. Experiments with Ts1Rhr mice showed that the DSCR was not sufficient to cause all DS phenotypes by identifying uncharacteristic craniofacial abnormalities not found in individuals with DS or other DS mouse models. We hypothesized that the origins of the larger, dysmorphic mandible observed in adult Ts1Rhr mice develop from larger embryonic craniofacial precursors. Because of phenotypic variability seen in subsequent studies with Ts1Rhr mice, we also hypothesized that genetic background differences would alter Ts1Rhr developmental phenotypes. Using Ts1Rhr offspring from two genetic backgrounds, we found differences in mandibular precursor volume as well as total embryonic volume and postnatal body size of Ts1Rhr and nontrisomic littermates. Additionally, we observed increased relative expression of Dyrk1a and differential expression of Ets2 on the basis of the genetic background in the Ts1Rhr mandibular precursor. Our results suggest that trisomic gene content and allelic differences in trisomic or nontrisomic genes influence variability in gene expression and developmental phenotypes associated with DS.
Nuclear phosphoinositide regulation of chromatin

Phospholipid signaling has clear connections to a wide array of cellular processes, particularly in gene expression and in controlling the chromatin biology of cells. However, most of the work elucidating how phospholipid signaling pathways contribute to cellular physiology have studied cytoplasmic membranes, while relatively little attention has been paid to the role of phospholipid signaling in the nucleus. Recent work from several labs has shown that nuclear phospholipid signaling can have important roles that are specific to this cellular compartment. This review focuses on the nuclear phospholipid functions and the activities of phospholipid signaling enzymes that regulate metazoan chromatin and gene expression. In particular, we highlight the roles that nuclear phosphoinositides play in several nuclear‐driven physiological processes, such as differentiation, proliferation, and gene expression. Taken together, the recent discovery of several specifically nuclear phospholipid functions could have dramatic impact on our understanding of the fundamental mechanisms that enable tight control of cellular physiology.
Metformin for primary colorectal cancer prevention in patients with diabetes: A case‐control study in a US population

Emerging evidence from observational studies has suggested that metformin may be beneficial in the primary prevention of colorectal cancer (CRC). However, to the authors' knowledge, none of these studies was conducted in a US population. Because environmental factors such as Western diet and obesity are implicated in the causation of CRC, a large case‐control study was performed to assess the effects of metformin on the incidence of CRC in a US population.
Prospective Comparison of Push Enteroscopy and Push-and-Pull Enteroscopy in Patients with Suspected Small-Bowel Bleeding

BACKGROUND AND AIMS:The management of patients with suspected mid-gastrointestinal bleeding has in the past been difficult, as push enteroscopy (PE) only allows limited endoscopic access for diagnosis and treatment. Recently published uncontrolled data on push-and-pull enteroscopy (PPE) using the double-balloon technique suggest that this new method has a high diagnostic yield and therapeutic efficacy. A prospective controlled study was therefore carried out to compare PPE with PE as the common nonsurgical gold standard method.METHODS:The diagnostic yield, complications, and various examination parameters were compared in 52 consecutive patients with suspected mid-gastrointestinal bleeding who were evaluated with both enteroscopy methods.RESULTS:No relevant complications were observed with either method. Sedoanalgesia, examination times, and X-ray exposure were lower with PE. The insertion depth was significantly greater with PPE than with PE (230 cm vs 80 cm, p < 0.0001). The overall diagnostic yield with PPE (38 of 52 patients, 73%) and the results of oral PPE only (33 of 52 patients, 63%) were superior to those with PE (23 of 52 patients, 44%; p < 0.0001). PPE identified additional lesions in deeper parts of the small bowel in PE-positive patients in 78% of cases (18 of 23 patients). CONCLUSIONS:For endoscopic examination of the small bowel in patients with suspected mid-gastrointestinal bleeding, PPE is superior to PE with regard to the length of small bowel visualized, as well as the diagnostic yield. As the method also allows endoscopic treatment to be carried out, PPE should always be considered before open surgery and intraoperative endoscopy in patients with mid-gastrointestinal bleeding.
A Tibial Shaft Fracture Sustained in Childhood or Adolescence Does Not Seem to Interfere with Attainment of Peak Bone Density

High peak bone mass or density in early adulthood is an important protective factor against osteoporotic fractures in later life, but it is not known whether injuries on growing bones affect the attainment of peak bone mass and density. The purpose of this study was therefore to examine with dual‐energy X‐ray absorptiometry the areal bone mineral density (BMD) of the injured and uninjured extremity (the femoral neck, trochanter area of the femur, distal femur, patella, proximal tibia, and distal tibia), lumbar spine, and distal radius of young adults with a history of early life tibial shaft fracture and to find out whether the fracture had affected the attainment of peak bone density of these patients. The second objective was to clarify whether any background or clinical follow‐up variable would predict the BMD difference between the affected and unaffected extremity. Thus, the BMD and clinical status of 45 patients (34 men and 11 women), who had sustained a tibial shaft fracture in childhood or in adolescence (between 7 and 15 years of age) an average 11 years before the study, were examined. The results showed that the fracture had created a small but statistically significant injured‐to‐uninjured side BMD difference (proximal tibia −1.7%; p = 0.011, and distal tibia 2.6%; p = 0.014), while the other sites showed no significant side‐to‐side differences. There were neither significant differences in the spinal or radial BMDs between the patients and their age‐, height‐, and weight‐matched healthy controls. A further analysis of the data showed that the better the muscle strength in the injured lower limb, the lower the side‐to‐side BMD deficit in the proximal tibia of the same limb (r = 0.51; p < 0.001). Smoking had a significant association with the relative BMD in the injured distal tibia (mean injured‐to‐uninjured side BMD difference: smokers 6.1% vs. nonsmokers −0.6%, p = 0.016). Also patient's age at the time of the injury showed an association: the younger the patient at the time of the injury, the lower the side‐to‐side BMD deficit in the injured distal tibia (r = −0.35; p = 0.048). In conclusion, this study indicates that early life tibial fracture leads to a small long‐term BMD deficit in the fractured bone while the other sites of the skeleton seem not to be affected. Thus, a tibial shaft fracture sustained in childhood or adolescence seems to only marginally interfere the attainment of peak bone density, the important predictor of the osteoporotic fractures in later life.
Gray platelet syndrome.

Gray platelet syndrome is a bleeding disorder associated with abnormal platelets, which are small blood cells involved in blood clotting. People with this condition tend to bruise easily and have an increased risk of nosebleeds (epistaxis). They may also experience abnormally heavy or extended bleeding following surgery, dental work, or minor trauma. Women with gray platelet syndrome often have irregular, heavy periods ( menometrorrhagia). These bleeding problems are usually mild to moderate, but they have been life-threatening in a few affected individuals.
Comparison of the cardioprotective effects of dexmedetomidineand remifentanil in cardiac surgery

Background/aim: Myocardial protection is an important factor of open heart surgery and biological biomarkers (lactate, CKMB, cardiac troponin I, and pyruvate) are used to assess myocardial damage. This study compares the effects of dexmedetomidine and remifentanil on myocardial protection during coronary artery bypass grafting (CABG) surgery. Materials and methods: Patients scheduled for elective CABG surgery (n = 60) were included in this study. Anesthesia induction was introduced with propofol, fentanyl, and vecuronium bromide. Anesthesia was maintained with remifentanil infusion and sevoflurane in the remifentanil group (Group R) and with dexmedetomidine infusion and sevoflurane in the dexmedetomidine group (Group D). Blood samples for biochemical markers were taken from the coronary sinus catheter before cardiopulmonary bypass (T1), 20 min after aortic cross-clamping (T2), 20 min after removal of the aortic cross-clamping (T3), and 10 min after separation from cardiopulmonary bypass (T4). Results: Demographic data were similar between the groups. Lactate level at the T2 period and CKMB levels during the study period were lower in Group D than in Group R. In both groups, all values except pyruvate significantly increased over time. Conclusion: The dexmedetomidine-sevoflurane combination may improve the cardioprotective effect in comparison with remifentanil-sevoflurane in CABG surgery.
Pegylated-liposomal doxorubicin versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposi's sarcoma: results of a randomized phase III clinical trial.

PURPOSE Kaposi's sarcoma (KS), the most common neoplasm in patients with AIDS, is a significant clinical problem for which current therapies are frequently unsatisfactory. We conducted a randomized phase III clinical trial to compare the efficacy and toxicities of a new form of therapy, pegylated-liposomal doxorubicin, with standard combination chemotherapy in patients with advanced AIDS-related KS (AIDS-KS). PATIENTS AND METHODS Two hundred fifty-eight patients with advanced AIDS-KS were randomly assigned to receive either pegylated-liposomal doxorubicin (20 mg/m2) or the combination of doxorubicin (20 mg/m2), bleomycin (10 mg/m2) and vincristine (1 mg) (ABV) every 14 days for six cycles. Standard response criteria, toxicity criteria, and predefined indicators of clinical benefit were examined to evaluate outcomes. RESULTS Among 133 patients randomized to receive pegylated-liposomal doxorubicin, one achieved a complete clinical response and 60 achieved a partial response for an overall response rate of 45.9% (95% confidence interval [CI], 37% to 54%). Among 125 patients randomized to receive ABV, 31 achieved a partial response (24.8%; 95% confidence interval [CI], 17% to 32%). This difference was statistically significant (P < .001). In addition to objective responses, prospectively defined clinical benefits and toxicity outcomes also favored pegylated-liposomal doxorubicin. CONCLUSION Pegylated-liposomal doxorubicin is more effective and less toxic than the standard combination chemotherapy regimen ABV for treatment of AIDS-KS.
Nucleotide-Binding Oligomerization Domain 2 Signaling Promotes Hyperresponsive Macrophages and Colitis in IL-10–Deficient Mice

IL-10 contributes to the maintenance of intestinal homeostasis via the regulation of inflammatory responses to enteric bacteria. Loss of IL-10 signaling results in spontaneous colitis in mice and early onset enterocolitis in humans. Nucleotide-binding oligomerization domain (NOD) 2 is an intracellular receptor of bacterial peptidoglycan products, and, although NOD2 mutations are associated with Crohn’s disease, the precise role of NOD2 in the development of intestinal inflammation remains undefined. To determine the role of NOD2 in the development of colitis on the clinically relevant genetic background of IL-10–deficient signaling, we generated mice lacking IL-10 and NOD2 (IL-10−/−NOD2−/−). Loss of NOD2 in IL-10−/− mice resulted in significant amelioration of chronic colitis, indicating that NOD2 signaling promotes the development of intestinal inflammation in IL-10−/− mice. Contrary to previous reports investigating immune function in NOD2−/− mice, T cell proliferative capacity and IL-2 production were not impaired, and immune polarization toward type 1 immunity was not affected. However, loss of NOD2 in IL-10–deficient macrophages reduced IL-6, TNF-α, and IL-12p40 production in response to bacterial stimulation. Further analysis of the intrinsic macrophage response before the onset of inflammation revealed that, in the absence of IL-10, synergistic signaling between various TLRs and NOD2 resulted in hyperresponsive, proinflammatory macrophages, thus providing the appropriate immune environment for the development of colitis. Data presented in this study demonstrate that NOD2 signaling contributes to intestinal inflammation that arises through loss of IL-10 and provides mechanistic insight into the development of colitis in inflammatory bowel disease patients with impaired IL-10 signaling.
Binaural Interaction in Auditory Brain Stem Responses: Parametric Studies

The effects of click stimulus presentation rate, spectrum, and polarity on binaural interaction in auditory brain stem responses (BI/ABR) were observed in guinea pigs and in normal-hearing human adults. The effects of repetition rate on the BI/ABR in both species were similar to those seen in ABRs. Six of 16 human subjects showed an unusual “early BI” only at high click intensity and high repetition rates; this is probably due to acoustic reflex effects. Animal data from stimulus spectrum experiments suggest a mid-to-high frequency dependence of the BI/ABR, while human data are less clear. Results are discussed relative to suggested recording strategies for the BI/ABR.
Diagnosis and treatment of pediatric flatfoot.

Foot and ankle specialists acknowledge that flatfoot deformity is a frequently encountered pathology in the pediatric population. Flattening of the medial arch is a universal finding in flatfoot and it is common in both pediatric and adult populations. Pediatric flatfoot comprises a group of conditions occurring in infants, children, and adolescents (1) that are distinguished by anatomy and etiologic factors (2, 3–8). Flatfoot may exist as an isolated pathology or as part of a larger clinical entity (4). These entities include generalized ligamentous laxity, neurologic and muscular abnormalities, genetic conditions and syndromes, and collagen disorders. Pediatric flatfoot can be divided into flexible and rigid categories. Flexible flatfoot is characterized by a normal arch during nonweightbearing and a flattening of the arch on stance (Fig 1). Flexible flatfoot may be asymptomatic or
Organizational Aspects of System Failure: A Case Study at the Los Angeles Police Department

The Pattern Recognition and Information Correlation System ( PA T R I C ) w a s an on li ne s uppo r t sys t e m u s i ng a c r i m i na l da t aba s e which promised to fulfill an urgent function for the community of Southern California. Yet PATRIC was phased out at the Los Angeles Police Department without ever having become fully operative. The experience raises questions about the ability of bureau-cratic service organizations to implement and manage unconventional technology and large scale projects. The evidence suggests that human and organizational factors, on which a support system's s
Recent therapeutic approaches in control of parasitic diseases with special reference to schistosomiasis

Control of schistosomiasis relies on a single drug, praziquantel (PZQ). Given the rising concerns about the potential emergence of PZQ-resistant strains, it has now become necessary to search for novel therapeutics. Efforts have been made for developing new schistosomicidal drugs, or testing existing drugs originally used for non-related diseases. However, the current pace for antischistosomal drug discovery is slow; hence, repositioning of existing approved drugs can offer a safe, rapid and cost effective solution. The literature regarding antischistosomal compounds contains a large number of natural products screened for their schistosomicidal properties. However, only a few of these may be promising drug leads in the development of a therapeutic reserve for schistosomiasis. Therefore, it is important to continue to identify new drugs and to explore alternative strategies to improve screening efficacy. Most of the extracts or natural compounds were only evaluated with In vitro studies; it is expected that they will be evaluated using in vivo experimental models. Further, it must be mentioned that the results of In vitro assays with many drugs do not correspond to what is observed in vivo; however, In vitro screening could identify novel anthelmintics that could eventually translate into practical applications. Thus, while In vitro tests are recommended initially, the assessment of therapeutic activity using in vivo models should be performed. The analysis of the S. mansoni genome and transcriptome offers great possibilities for identifying possible new drug targets and will facilitate further exploration of differences between host and parasite metabolic pathways. In addition to the isolation and structural determination of new drugs from natural products and information from the originating plant, the integration of the pharmacological properties of natural products with the functional genomics and proteomic studies in schistosome and In vitro screening methods with improved automatic high-content screening will be important tools to identify possible new drugs in the future and shed light on the approaches of helminth chemotherapy.
Family firm and analyst forecasts in an emerging economy

Purpose The purpose of this paper is to examine how family firms affect analyst forecast dispersion, accuracy and optimism and how earnings smoothness as the moderating factor, affects these relationships in an emerging market context. Design/methodology/approach This paper uses the population sample of firms listed on the Taiwan Stock Exchange from 2009 to 2010 as the research sample, which includes 963 firm-year observations. Findings The findings show that analysts following family firms are more likely to have more dispersed, less accurate and more optimism biased forecasts than those following nonfamily firms. Earning smoothness is mainly used by nonfamily firms as a signaling strategy to improve analyst forecast quality. In contrast, earnings smoothness is mainly used by families as a garbling strategy, stimulating forecast optimism. Only earnings smoothness in family firms with a high level of family ownership concentration is likely to be signaling-oriented to improve analyst forecast accuracy and mitigate analyst optimism biases. Originality/value Emerging markets are not only featured by prevailing principal-principal conflicts but also have multiple levels of agency conflicts among large shareholders, minority shareholders and professionally hired managers. This research reveals the multiple governance roles of family owners in affecting analyst forecast quality, including their entrenchment role in extracting private benefits of control through opaque environments and market discipline distortion role in aligning interests between managers and families without prioritizing meeting or beating analyst forecasts, both at the cost of minority shareholders. This research further disentangles the intertwined signaling oriented and garbiling oriented incentives associated with earnings smoothness under family governance.
Phosphorylation of p16 INK4A Correlates with Cdk4 Association* 210

Progression through the eukaryotic cell cycle is driven by the activity of cyclin-dependent kinases. The cyclin D-dependent kinase Cdk4 promotes progression through the G1 phase of the cell cycle and is deregulated in many human tumors. The tumor suppressor protein p16 INK4A (p16) forms a complex with Cdk4 and inhibits kinase activity. Here we report that p16 is phosphorylated, and the phosphorylated form of p16 is preferentially associated with Cdk4 in normal human fibroblasts. We mapped phosphorylation sites on exogenously overexpressed p16 to serines 7, 8, 140, and 152 and found that endogenous p16 associated with Cdk4 is phosphorylated at serine 152. All mapped phosphorylation sites lie outside of the conserved kinase-binding domain of p16 but in regions of the protein affected by mutations in familial and sporadic cancer. Our results suggest a novel regulation of p16 activity.
ENDORPHINS: PHYSIOLOGY AND CLINICAL IMPLICATIONS *

Most drugs are mimics of endogenous substances. They interact with specific receptors to bring about a biochemical alteration of cell function, ultimately producing a pharmacologic action. But since drugs are plant products or made chemically, evolution could not have developed specific receptors for them. Receptors with which many drugs interacr are actually receptors for endogenous compounds which play a normal role in organism physiology. An accident of molecular shape permits certain foreign compounds to act as drugs by fitting into these receptors, either activating or blocking them. The discovery of endogenous opioids (endorphins) followed an established tradition in pharmacology, exemplified by the discovery of acetylcholine. Claude Bernard had observed, in the mid-nineteenth century, that the arrow poison curare paralyzed skeletal muscle, and he localized its site of action to the region between nerve terminals and the muscle itself, now known as the neuromuscular junction. For many years in the early part of the current century Langley studied the “receptive substance” in muscle and also in ganglia. He found that nicotine behaved as an agonist at the neuromuscular junction, where curare blocked its action, and he also identified nicotine receptors in the sympathetic ganglia. The work of Dale established the main principles of receptor pharmacology, especially the existence of agonists and antagonists, and specificity of receptors as evidenced in structure-activity relationships among similar drugs. Finally, Loewi’s demonstration of chemical transmission led to the proof that acetylcholine was the endogenous ligand of Bernard’s “curare receptor” and Langley’s “nicotine receptor”. There were two prerequisites for discovery of endorphins. Firstly, it was necessary to believe they existed to be motivated to make the search. Secondly, it was necessary to have a suitable assay system for detecting and measuring them so that they could be purified and characterized. As to the first prerequisite, four independent groups had been engaged in the search since 1972. Knowledge of the existence of stereospecific opiate receptors, first demonstrated by the author in 1971, helped indicate the likelihood of an endogenous ligand. Of great importance, too, were the extensive studies of Kosterlitz with the guinea pig ileum preparationstudies that defined the properties of opiate receptors there by the pharmacologic method of structure-activity relationships. Finally, Akil, Mayer, and Liebeskind showed analgesia produced by electrical stimulation of the periaqueductal gray could be blocked in part by naloxone, a specific “pure” antagonist of the opiates, suggesting this analgesia was mediated by an endogenous opiate-like compound.