Miracle-dz/UniFAR-FTUs huggingface dataset:
GERD: New Strategies and New Failures

Gastroesophageal reflux disease (GERD) is a common acid-related disorder presenting with a broad spectrum of symptoms with or without esophageal mucosal damage and/or complications. In general, the frequency and severity of symptoms and esophagitis correlate with the severity and duration of acid exposure, particularly during the nighttime. Acid suppression, with proton pump inhibitors (PPIs), is the mainstay of acute and maintenance treatment of GERD. Optimizing the choice of PPI and dose is essential for controlling GERD symptoms, accelerating healing of esophagitis, and preventing the long-term complications. Postprandial acid control is needed during the day particularly to control the symptoms. Additionally, nocturnal acid control especially in those with nighttime symptoms or severe mucosal injury is important for preventing complicated GERD. However, there is a substantial proportion of patients who do not respond to routine PPI therapy probably because of inadequate acid suppression or nonacid-related problems. Failure to respond to twice daily PPIs can be partly explained by the short half-lives of currently available PPIs that may fail to adequately control acid secretion after midnight, even if given before the evening meal. There has been considerable discussion in recent years over “nocturnal acid breakthrough,” which is really a misnomer, as this represents the pattern of nocturnal acid secretion when there is no drug available to inhibit secretion. Several approaches to properly controlling nocturnal acid secretion have included b.i. d. dosing of PPIs, adding an H2-receptor antagonist at night and the development of an instant release PPI. The former approaches have not been universally effective and clinical studies not yet performed with the latter. There are several new acid suppressing drugs in development and these include PPIs with longer half-lives, which give more prolonged nocturnal acid suppression. In addition, there are drugs which block the potassium channel (potassium competitive acid blockers) of the proton pump and which have a rapid onset of action. These drugs are under investigation and some may require more than 1 dose daily to adequately control acid secretion. In this review, we further explore different aspects of the need for new PPIs for the optimal management of GERD.
Spinal opioid receptor‐sensitive muscle afferents contribute to the fatigue‐induced increase in intracortical inhibition in healthy humans

We investigated the influence of spinal opioid receptor‐sensitive muscle afferents on cortical changes following fatiguing unilateral knee‐extensor exercise. On separate days, seven subjects performed an identical five sets of intermittent isometric right‐quadriceps contractions, each consisting of eight submaximal contractions [63 ± 7% maximal voluntary contraction (MVC)] and one MVC. The exercise was performed following either lumbar interspinous saline injection or lumbar intrathecal fentanyl injection blocking the central projection of spinal opioid receptor‐sensitive lower limb muscle afferents. To quantify exercise‐induced peripheral fatigue, quadriceps twitch force (Qtw,pot) was assessed via supramaximal magnetic femoral nerve stimulation before and after exercise. Motor evoked potentials and cortical silent periods (CSPs) were evaluated via transcranial magnetic stimulation of the motor cortex during a 3% MVC pre‐activation period immediately following exercise. End‐exercise quadriceps fatigue was significant and similar in both conditions (ΔQtw,pot−35 and −39% for placebo and fentanyl, respectively; P= 0.38). Immediately following exercise on both days, motor evoked potentials were similar to those obtained prior to exercise. Compared with pre‐exercise baseline, CSP in the placebo trial was 21 ± 5% longer postexercise (P < 0.01). In contrast, CSP following the fentanyl trial was not significantly prolonged compared with the pre‐exercise baseline (6 ± 4%). Our findings suggest that the central effects of spinal opioid receptor‐sensitive muscle afferents might facilitate the fatigue‐induced increase in CSP. Furthermore, since the CSP is thought to reflect inhibitory intracortical interneuron activity, which may contribute to central fatigue, our findings imply that spinal opioid receptor‐sensitive muscle afferents might influence central fatigue by facilitating intracortical inhibition.
Myocardial structural, contractile and electrophysiological changes in the guinea‐pig heart failure model induced by chronic sympathetic activation

Widely used murine models of adrenergic‐induced cardiomyopathy offer little insight into electrical derangements seen in human heart failure owing to profound differences in the characteristics of ventricular repolarization in mice and rats compared with humans. We therefore sought to determine whether sustained adrenergic activation may produce a clinically relevant heart failure phenotype in the guinea‐pig, an animal species whose ventricular action potential shape and restitution properties resemble those determined in humans. Isoprenaline (ISO), a β‐adrenoceptor agonist, was infused at variable dosage and duration using either subcutaneously implanted osmotic minipumps or daily injections, in an attempt to establish the relevant treatment protocol. We found that 3 months of daily ISO injections (final dose of 1 mg kg−1, i.p.) promote heart failure evidenced by cardiac hypertrophy [increased cardiac weights, left ventricular (LV) posterior wall thickness, myocyte cross‐sectional area and LV protein content], cardiac dilatation (increased LV internal diameters), basal systolic dysfunction (reduced LV fractional shortening determined by echocardiography and flattened LV systolic pressure–volume and stress–strain relationships assessed in isolated, perfused heart preparations), reduced contractile reserve in the presence of acute β‐adrenoceptor stimulation, and pulmonary oedema (increased lung weights). These changes were associated with prolongation of LV epicardial action potential, effective refractory period and QT interval, an upward shift of the electrical restitution curve determined over a wide range of diastolic intervals, and reduced maximal restitution slope. The physiological right ventricular‐to‐LV difference in action potential duration was eliminated in ISO‐treated hearts, thereby contributing to impaired activation‐to‐repolarization coupling and reversed right ventricular‐to‐LV difference in repolarization time. In summary, we establish the guinea‐pig model of ISO‐induced cardiomyopathy, which enables the correlation of detrimental structural and contractile changes with repolarization abnormalities typically seen in human heart failure.
Ethnic differences in the burden of caregiving

Family caregivers of dementia patients experience varying levels of burden (or stress) associated with care giving tasks. Although this burden may lead to negative health effects for caregivers, very few studies have focused on ethnic differences in the correlates of perceived burden. In a pilot study, we examined correlates of perceived burden associated with providing care for a family member with dementia among African-American (n=20) and white (n=62) caregivers. In this limited sample, we found that mean burden scores were increased among whites if they were the spouse of the patient, and among African-Americans if annual family income was in excess of $20,000. We found no mean burden score differences for either group by past use of a variety of services. Although these results are preliminary, this ongoing study has the potential to provide needed information on sources and correlates of perceived burden among rural African-American and white caregivers.
The therapeutic potential of mesenchymal stem cell‐derived extracellular vesicles

Extracellular vesicles (EVs), membrane vesicles that are secreted by a variety of mammalian cell types, have been shown to play an important role in intercellular communication. The contents of EVs, including proteins, microRNAs, and mRNAs, vary according to the cell type that secreted them. Accordingly, researchers have demonstrated that EVs derived from various cell types play different roles in biological phenomena. Considering the ubiquitous presence of mesenchymal stem cells (MSCs) in the body, MSC‐derived EVs may take part in a wide range of events. In particular, MSCs have recently attracted much attention due to the therapeutic effects of their secretory factors. MSC‐derived EVs may therefore provide novel therapeutic approaches. In this review, we first summarize the wide range of functions of EVs released from different cell types, emphasizing that EVs echo the phenotype of their parent cell. Then, we describe the various therapeutic effects of MSCs and pay particular attention to the significance of their paracrine effect. We then survey recent reports on MSC‐derived EVs and consider the therapeutic potential of MSC‐derived EVs. Finally, we discuss remaining issues that must be addressed before realizing the practical application of MSC‐derived EVs, and we provide some suggestions for enhancing their therapeutic efficiency.
Breathing 40% O2 can attenuate postcontraction hyperaemia or muscle fatigue caused by static forearm contraction, depending on timing

Little is known of the role of O2‐dependent mechanisms in the hyperaemia associated with static muscle contraction or recovery from fatigue. Thus, in recreationally active, young, male subjects, forearm contraction was performed twice at 100% maximal voluntary effort until exhaustion, with a 7 min recovery period, whilst 40% O2 (hyperoxia) was breathed during the contractions only, or during recovery only, or room air (normoxia) was breathed throughout. When hyperoxia was limited to the contractions, postcontraction increases in forearm blood flow, measured by venous occlusion plethysmography, were ∼25% lower (P < 0.05, n= 10) than during normoxia throughout. Furthermore, the postcontraction increase in venous lactate and fall in pH were attenuated (P < 0.05, n= 8). However, there was no effect on fatigue; time to voluntary exhaustion of contraction 2 was ∼25% less than for contraction 1 in both conditions. By contrast, when hyperoxia was limited to recovery (n= 10), there was no effect on postcontraction increases in forearm blood flow, but fatigue was ameliorated; time to voluntary exhaustion of contraction 2 was comparable to that of contraction 1. These results allow the novel conclusions that, even during static forearm contraction at 100% maximal voluntary effort, additional O2 dissolved in plasma can attenuate the contribution made by O2‐dependent dilator substances to postcontraction hyperaemia and that these substances may be released from the muscle fibres or blood vessel wall. Furthermore, they indicate that even in recreationally active individuals, recovery from fatigue can be improved by additional O2 made available during recovery, and the O2‐dependent mechanisms that contribute to fatigue are different from those that induce postcontraction hyperaemia.
The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer.

UNLABELLED Neurotrophic factors possess an emerging role in the pathophysiology of several gastrointestinal disorders, regulating innervation, pain sensation and disease-associated neuroplasticity. Here, we aimed at characterizing the role of the neurotrophic factor neurturin (NRTN) and its receptor glial-cell-line-derived neurotrophic factor receptor alpha-2 (GFRα-2) in pancreatic cancer (PCa) and pancreatic neuropathy. For this purpose, NRTN and GFRα-2 were studied in normal human pancreas and PCa tissues via immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, immunoblotting and correlated to abdominal pain. The impact of NRTN/GFRα-2 on PCa cell (PCC) biology was investigated via exposure to hypoxia, 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide viability and matrigel invasion assays in native and specific small interfering RNA-silenced PCCs. To assess the influence of NRTN on pancreatic neuroplasticity and neural invasion (NI), its impact was explored via an in vitro 'neuroplasticity assay' and a 3D neural migration assay. NRTN and GFRα-2 demonstrated a site-specific upregulation in PCa, predominantly in nerves, PCCs and extracellular matrix. Patients with severe pain demonstrated higher intraneural GFRα-2 immunoreactivity than patients with no pain. PCa tissue and PCCs contained increased amounts of NRTN, which was suppressed under hypoxia. NRTN promoted PCC invasiveness, and silencing of NRTN limited both PCC proliferation and invasion. Depletion of NRTN from PCa tissue extracts and PCC supernatants decreased axonal sprouting in neuronal cultures but did not influence glial density. Silencing of NRTN in PCCs boosted NI. We conclude that increased NRTN/GFRα-2 in PCa seems to promote an aggressive PCC phenotype and neuroplasticity in PCa. Accelerated NI following NRTN suppression constitutes a novel explanation for the attraction of PCC to nerves in the hypoxic PCa tumor microenvironment. SUMMARY PCa is characterized by intrapancreatic neuroplasticity and NI. Here, we show that PCC produce the neurotrophic factor NRTN, which reinforces their biological properties, triggers neuroplastic alterations, NI and influences pain sensation via the GFRα-2 receptor.
Original Articles: Bladder Cancer

ABSTRACTThe efficacy of immunotherapy with keyhole-limpet hemocyanin or bacillus Calmette-Guerin for superficial bladder cancer is well known. A strong similarity has been noted between keyhole-limpet hemocyanin antigen and schistosomal antigen. In regard to this finding, we investigated the mechanisms of specific immunotherapy with keyhole-limpet hemocyanin in schistosomal associated transitional cell carcinoma. Keyhole-limpet hemocyanin was used for its ability to prevent tumor recurrence and because of its similarity to schistosomal antigen for intravesical specific immunotherapy in 13 patients with superficial transitional cell bladder tumors (Ta, Tis, T1) associated with urinary schistosomiasis. Keyhole-limpet hemocyanin immunotherapy reduced the recurrence rate of superficial bladder tumors to 15.4% compared to 76.9% before therapy.
Telomere length and regulatory proteins in human skeletal muscle with and without ongoing regenerative cycles

New insights suggest the existence of telomere regulatory mechanisms in several adult tissues. In this study, we aimed to assess in vivo telomere length and the presence of specific proteins involved in telomere regulation in a model of human skeletal muscle with (patients with dermatomyosis or polymyositis) and without ongoing regenerative events (healthy subjects). Mean (meanTRF) and minimal telomere (miniTRF) lengths and the expression of telomerase, tankyrase 1, TRF2 (telomeric repeat binding factor 2) and POT1 (protection of telomeres 1) were investigated in skeletal muscle samples from 12 patients (MYO) and 13 healthy subjects (CON). There was no significant shortening of telomeres in skeletal muscle from patients compared with control subjects (MYO, meanTRF length 11.0 ± 1.8 kbp and miniTRF length 4.7 ± 0.8 kbp; CON, meanTRF length 10.4 ± 1.1 kbp and miniTRF length 4.6 ± 0.5 kbp). Theoretically, telomere length can be controlled by endogenous mechanisms. Here, we show for the first time that expression levels of telomerase, tankyrase 1, TRF2 and POT1 were, respectively, six‐, seven‐, three‐ and fivefold higher in the nuclear fraction of skeletal muscle of MYO compared with CON (P < 0.05). This suggests the existence of endogenous mechanisms allowing for telomere regulation in skeletal muscle with ongoing cycles of degeneration and regeneration and a model where regulatory factors are possibly involved in the protection of skeletal muscle telomeres.
Third degree obstetric tears; outcome after primary repair

BACKGROUND: Disruption of the anal sphincter occurs in 0.5 to 2.5% of women during delivery. Defects of the sphincter are major causes of fecal incontinence. More than 30% of women who suffer from third degree perineal tears develop incontinence. We sought to determine the incidence of symptoms and injury to the anal sphincter among women who gave birth during a 5 year period. We also investigated the sensitivity of manometry and endosonography as well as the correlation of these two diagnostic modalities. METHODS: Thirty-eight women were examined one to five years after delivery. We used a questionnaire to assess symptoms of anal incontinence. Anal manometry and endosonography were performed. RESULTS: Twenty (57%) women had symptoms; most of them (34%) in the form of flatulence incontinence. The rest were incontinent of either liquid or solid stools. Four of these women were re-operated. Seventeen percent of the women suffered from anal incontinence during sexual intercourse. Only seven women had been in contact with a doctor regarding these problems. CONCLUSION: The fact that 57% of the women that took part in this study reported complications, leads us to the conclusion that the primary repair of third degree anal sphincter tears is unsatisfactory. It is important to decide whether any changes in primary repair may improve results in the future. Sexual dysfunction is also a complication of third degree obstetric tear with primary repair. It is important that the women who suffer from anal sphincter tear, as well as doctors, are given information about possible symptoms and the treatment available.
Knowledge sharing: a game people play

Examines the dynamics of knowledge sharing using the multi‐person game‐theoretic framework. Proposes that an individual’s knowledge sharing tendency is driven by a set of contextualised concerns and interests not unlike the notion of payoff in game theory. Furthermore, the decision to share or withhold knowledge depends on that which yields a higher payoff. With this premise, submits two objectives. One is to investigate if an individual’s perceived payoff of sharing knowledge is contingent on the knowledge sharing behaviour of others. The other is to analyse the perceived payoff of knowledge sharing and determine if it can be characterised by an archetypical game in the game‐theoretic model. An empirical study was conducted among nearly 100 students in a local institute of higher education. The scope was confined to the students’ willingness to post asynchronous entries to an electronic discussion forum. Finds that the individual student’s perceived payoff of sharing knowledge was contingent on the knowledge sharing behaviour of others. Furthermore, the perceived payoff of knowledge sharing among them could be characterised by a multi‐person assurance game. In conclusion, discusses three implications for managers who aim to sustain asynchronous knowledge sharing in their organisations.
Characterising and profiling health Web user and site types: going beyond "hits"

Identifies Internet health user types according to three factors: site attributes most favoured, health topics most sought, and the health sites they visited. Knowing what type of consumer uses a site is important, as this should inform menu structure and provide an understanding of why certain kinds of people visit certain sites. Web sites even in the same field will not appeal to all users. Much of this differentiation will come down to design and feel of the site, although site attributes and information needs also impact here. Data were obtained from an online questionnaire placed on the SurgeryDoor Web site, a site which provides consumer health information. In all a total of 1,068 responses were received. Shows that useful groupings can indeed be constructed. Users were also classified according to additional health sites visited, also a preference metric, and this additionally is related to site attribute preferences, information needs and user characteristics.
Time course of hepatic gluconeogenesis during hindlimb suspension unloading

• What is the central question of this study? The rate of liver gluconeogenesis during hindlimb suspension unloading has not been determined. • What is the main finding and its importance? Hepatic gluconeogenesis is significantly increased under conditions of hindlimb suspension unloading, which simulates the muscular atrophy occurring during spaceflight. This finding supports earlier hypothesis. This metabolic shift in the living animal warrants further study.
Drug reaction with eosinophilia and systemic syndrome: Systemic drug reaction

Drug reaction with eosinophilia and systemic (DRESS) syndrome is a severe systemic drug reaction with a reported mortality of 10% 5 . The estimated incidence of this syndrome ranges from 1 in 1000 to 1 in 10,000 drug exposures. The syndrome consists of a severe skin eruption, fever, hematologic abnormalities (eosinophilia or atypical lymphocytes), and internal organ involvement. Here, we report a case of DRESS syndrome in a young male who presented with acute hepatitis.
Non-Glutamatergic Clozapine Augmentation Strategies: A Review and Meta-Analysis

Abstract Persistent negative symptoms and cognitive impairment are major clinical problems in the treatment of schizophrenia. There is no convincing evidence regarding the efficacy of augmentation of clozapine with a second antipsychotic, ethyl eicosapentaenoic acid (E-EPA), an antidepressant, a mood stabilizer or extract of Ginkgo biloba in clozapine-resistant schizophrenia. We present an overview of studies in which the potential clinical utility of the addition of non-glutamatergic agents to clozapine is assessed. We performed a meta-analysis on the efficacy of both risperidone and aripiprazole compared to placebo. We compared the effects of the addition of a second antipsychotic or an antidepressant to clozapine on positive, negative, overall and affective symptoms of schizophrenia in double-blind placebo-controlled trials.
Cerebral Creatine Deficiencies: A Group of Treatable Intellectual Developmental Disorders

Abstract Currently there are 91 treatable inborn errors of metabolism that cause intellectual developmental disorders. Cerebral creatine deficiencies (CDD) comprise three of these: arginine: glycine amidinotransferase [AGAT], guanidinoacetate methyltransferase [GAMT], and X-linked creatine transporter deficiency [SLC6A8]. Intellectual developmental disorder and cerebral creatine deficiency are the hallmarks of CDD. Additional clinical features include prominent speech delay, autism, epilepsy, extrapyramidal movement disorders, and signal changes in the globus pallidus. Patients with GAMT deficiency exhibit the most severe clinical spectrum. Myopathy is a distinct feature in AGAT deficiency. Guanidinoacetate (GAA) is the immediate product in the creatine biosynthetic pathway. Low GAA concentrations in urine, plasma, and cerebrospinal fluid are characteristic diagnostic markers for AGAT deficiency, while high GAA concentrations are characteristic markers for GAMT deficiency. An elevated ratio of urinary creatine /creatinine excretion serves as a diagnostic marker in males with SLC6A8 deficiency. Treatment strategies include oral supplementation of high-dose creatine-monohydrate for all three CDD. Guanidinoacetate-reducing strategies (high-dose ornithine, arginine-restricted diet) are additionally employed in GAMT deficiency. Supplementation of substrates for intracerebral creatine synthesis (arginine, glycine) has been used additionally to treat SLC6A8 deficiency. Early recognition and treatment improves outcomes. Normal outcomes in neonatally ascertained siblings from index families with AGAT and GAMT deficiency suggest a potential benefit of newborn screening for these disorders.