Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel and Evolving Therapies in the Treatment of Malignant Phaeochromocytoma: Experience with the mTOR Inhibitor Everolimus (RAD001)

Phaeochromocytoma and paraganglioma are rare neuroendocrine tumours (NETS). They may be benign or malignant but the pathological distinction is mainly made when metastases are present. Available treatments in the form of surgery, chemotherapy, and radionuclide therapy may improve symptoms and biochemical markers, but the results for the control of tumour bulk are less favourable. Furthermore, responses to treatment are frequently short-lived. This short review outlines the main molecular and histological features of malignant phaeochromocytoma and the difficulties in differentiating between benign and malignant disease. We list current therapies used for malignant pheochromocytoma; however, these generally achieve relatively low success rates. Hence, there is a need for new and more effective therapies. In vitro studies have implicated the PI3/Akt/mTOR pathway in the pathogenesis of malignant NETS, including phaeochromocytoma. Everolimus (RAD001, Novartis UK) is a compound that inhibits mTOR (mammalian Target Of Rapamycin) signalling. We have used RAD001 in four patients with progressive malignant paraganglioma/phaeochromocytoma in addition to other therapies (with institutional approval for compassionate use), and evaluated the effects of this treatment. We outline these four cases and review the theoretical background for this therapy, although the outcomes were relatively disappointing.
EFFECT OF SERUM ON HUMAN BONE MARROW STROMAL CELLS: EX VIVO EXPANSION AND IN VIVO BONE FORMATION

Background. Bone marrow stromal cell (BMSC) transplantation may offer an efficacious method for the repair of bone defects.This approach has been developed using BMSCs expanded ex vivo in medium with fetal bovine serum (FBS). For clinical applications, however, contact of BMSCs with FBS should be minimized. We studied the effect of FBS substitutes on both human BMSC proliferation in vitro and subsequent bone formation in vivo. Methods. BMSC proliferation was measured by colony forming efficiency (CFE) and by cell numbers at consecutive passages. Bone formation was studied in 6- to 8-week-old transplants of human BMSCs in immunocompromised mice. Results. Medium with FBS was more effective in stimulating BMSC proliferation than medium with either human serum (HS) or rabbit serum (RS). Compared to bone formed by BMSCs cultured continuously with FBS, bone formed by cells cultured with HS, or with FBS switched to HS, was considerably less extensive, while bone formed by cells cultured with FBS switched to serum-free medium (SFM) was considerably more extensive. The increase in bone formation was due to neither the SFM components nor to the proliferation status of BMSCs prior to transplantation. Conclusions. Our data demonstrate that for ex vivo expansion of human BMSCs, medium with FBS remains most effective. However, incubation of human BMSCs in SFM prior to in vivo transplantation significantly stimulates subsequent bone formation. This finding increases the practicality of using culture-expanded BMSCs for autologous human transplantation and suggests the presence of osteogenic inhibitors in serum.
Liver iron excess in patients with hepatocellular carcinoma developed on viral C cirrhosis

BACKGROUND Liver iron deposits are frequent in viral C cirrhotic patients but their role is not well defined. AIMS To investigate the effect of liver iron excess on the prevalence of hepatocellular carcinoma (HCC) in patients with viral C cirrhosis. METHODS Hepatic iron was evaluated retrospectively using a semiquantitative method in liver biopsies of 104 viral C cirrhotic patients, 48 with HCC and 56 controls (HCC free). Corrected total iron score (0–60) was defined by the sum of three scores: hepatocytic iron score (0–36), sinusoidal iron score (0–12), and portal iron score (0–12), multiplied by 3/3, 2/3, or 1/3 according to the heterogeneous iron localisation in the nodules. RESULTS After adjustment for known risk factors for HCC, regression analysis showed that iron deposits (corrected total iron score >0) were more frequent in HCC patients than in controls (odds ratio 4.94; 95% confidence interval 1.59–15.32; p=0.0056). The median of corrected total iron score was significantly higher in HCC patients than in controls (odds ratio 1.092; 95% confidence interval 1.01–1.13; p=0.021). This liver iron overload was sinusoidal (odds ratio 5.2; 95% confidence interval 1.82–15.11; p=0.0022). CONCLUSIONS Liver iron deposition was more frequent and more important in viral C cirrhotic patients with HCC than in HCC free controls. Liver iron overload seems to contribute to the development of HCC in patients with viral C cirrhosis.
External fixation of tibial pilon fractures and fracture healing

Distal tibial fractures are rare and difficult to treat because the bones are subcutaneous. External fixation is commonly used, but the method often results in delayed union. The aim of the present study was to find out the factors that affect fracture union in tibial pilon fractures. For this purpose, prospective data collection of tibial pilon fractures was carried out in 1998-2004, resulting in 159 fractures, of which 83 were treated with external fixation. Additionally, 23 open tibial fractures with significant > 3 cm bone defect that were treated with a staged method in 2000-2004 were retrospectively evaluated. The specific questions to be answered were: What are the risk factors for delayed union associated with two-ring hybrid external fixation? Does human recombinant BMP-7 accelerate healing? What is the role of temporary ankle-spanning external fixation? What is the healing potential of distal tibial bone loss treated with a staged method using antibiotic beads and subsequent autogenous cancellous grafting compared to other locations of the tibia? The following risk factors for delayed healing after external fixation were identified: post-reduction fracture gap of >3 mm and fixation of the associated fibula fracture. Fracture displacement could be better controlled with initial temporary external fixation than with early definitive fixation, but it had no significant effect on healing time, functional outcome or complication rate. Osteoinduction with rhBMP-7 was found to accelerate fracture healing and to shorten the sick leave. A staged method using antibiotic beads and subsequent autogenous cancellous grafting proved to be effective in the treatment of tibial bone loss. Healing potential of the bone loss in distal tibia was at least equally good as in other locations of the tibia.
Caring for Underserved Patients Through Neighborhood Health Screening: Outcomes of a Longitudinal, Interprofessional, Student-Run Home Visit Program in Singapore

Purpose Service learning, an effective vehicle for teaching undergraduate public health while providing underserved communities with medical care, is not well established in Asia. The authors evaluated a service learning program, Neighborhood Health Screening (NHS), in Singapore. Method Medical and nursing undergraduate students provided in-home medical services to patients in a low-income neighborhood (January–June 2010). The authors assessed student-reported pedagogical effectiveness in nine domains, asked students for qualitative feedback on their experiences, assessed patients' satisfaction with NHS, and tracked clinical outcomes. Results Of the 240 medical and 34 nursing students who participated, 222 (93%) and 34 (100%), respectively, completed the questionnaire; 136 of the medical students (57%) also provided qualitative feedback. Most students felt NHS was beneficial across all domains. Male medical students were less likely to report increased understanding of deficiencies in the health care system and long-term management of chronic disease; preclinical students were more likely to report improvements in comprehending ethical issues, critical thinking and action skills, and gaining and applying knowledge. Qualitative feedback supported quantitative findings. Patients were satisfied with NHS: 266 (75%) agreed that NHS improved their health, and 301 (85%) felt NHS provided sufficient time to address their issues. After a single year, amongst patients with known hypertension, treatment increased from 63% to 93% (P < .001), and blood pressure control amongst those who were on treatment improved from 42% to 79% (P < .001). Conclusions Service learning can make an important contribution to medical teaching and patient care in Asia.
Increasing rates of prematurity and epidemiology of late preterm birth

Preterm birth rates in Australia have risen in the last two decades, mostly accounted for by the rise in late preterm births. Late preterm births (34–36 weeks) comprise 70% of all preterm births, which translates to approximately 16 000 births annually in Australia. The precise causes for this trend are unclear; however, possible aetiologies include increasing maternal age, increased use of artificial reproductive technologies and increased multiple births. Compared with term‐born children, late preterm children not only have increased mortality and in‐hospital morbidity including respiratory difficulties, but also long‐term cognitive, school performance, behaviour and psychiatric problems. The potential public health and educational burden of late preterm birth is considerable. More research is required in this area to understand the risk factors for late preterm birth and to help identify those children at highest risk of developmental deficits.
Different pattern of aquaporin‐4 expression in extensor digitorum longus and soleus during early development

Aquaporin‐4 (AQP4) is the neuromuscular water channel expressed at the sarcolemma of mammalian fast‐twitch fibers that mediates a high water transport rate, which is important during muscle activity. Clinical interest in the neuromuscular expression of AQP4 has increased as it is associated with the protein complex formed by dystrophin, the product of the gene affected in Duchenne muscular dystrophy. The expression of AQP4 during development has not been characterized. In this study, we analyzed the expression of AQP4 in extensor digitorum longus (EDL) and soleus, a fast‐ and slow‐twitch muscle, respectively, during the first weeks after birth. The results show that AQP4 expression in both types of skeletal muscle occurs postnatally. The time course of expression of AQP4 in the two types of muscles was also different. Whereas the expression of AQP4 protein levels in the EDL showed a progressive increase during the first month after birth, reaching levels found in adults by day 24, the levels of the protein in the soleus showed a transient peak between day 12 and day 24 and declined thereafter, an effect that may be related to the transient high number of fast motor units innervating the soleus muscle during this time. The results suggest that AQP4 expression in skeletal muscle is under neuronal influence and contribute to the understanding of the molecular events of fiber differentiation during development. Muscle Nerve, 2007
Troponin C–Mediated Calcium Sensitization Induced by Levosimendan Does Not Impair Relaxation

Levosimendan is a novel positive inotropic drug targeted to increase contraction force of the heart through its calcium-dependent binding to troponin C (cTnC). We investigated the calcium-sensitizing effect of levosimendan on contractile proteins as well as its positive inotropic and lusitropic effects in paced guinea pig papillary muscle. We also studied the effect on energy consumption of myosin–actin crossbridges in a myosin ATPase assay. The calcium sensitization induced by levosimendan in fibers skinned with saponin was dependent on the perforation velocity of cell membranes. Levosimendan was almost ineffective in slowly perforated fibers, but was the most potent calcium sensitizer in fibers with rapidly perforated cells. The perforation-dependent calcium sensitization was probably due to changes in phosphorylation state of contractile proteins during the slow dissection of fibers. It is noteworthy that the calcium-sensitizing effect of levosimendan was not affected by acidic pH. Levosimendan at therapeutically relevant (0.3–10 μM) concentrations markedly increased calcium sensitivity both at pH 6.7 and 7.0, being more potent than EMD 53998, pimobendan, and MCI-154. The lack of effect of levosimendan on maximum tension supports the hypothesis that levosimendan increases calcium sensitivity through its action on cTnC. Unlike EMD 53998, levosimendan did not increase myosin ATPase activity, indicating that it did not increase the cycling rate of myosin–actin crossbridges. In paced papillary muscles, levosimendan induced positive inotropic effect without changing relaxation time. Thus, levosimendan was devoid of the main negative factors described for calcium sensitizers.
Characterization of Acinetobacter calcoaceticus catM, a repressor gene homologous in sequence to transcriptional activator genes

Two structural genes needed for catechol degradation, catA and catB, encode the respective enzymes catechol 1,2-dioxygenase (EC 1.13.11.1) and muconate cycloisomerase (EC 5.5.1.1). Catechol is an intermediate in benzoate degradation, and the catA and catB genes are clustered within a 17-kilobase-pair (kbp) region of Acinetobacter calcoaceticus chromosomal DNA containing all of the structural genes required for the conversion of benzoate to tricarboxylic acid cycle intermediates. catA and catB were transcribed in the same direction and were separated by 3.8 kbp of DNA. The 3.8-kbp sequence revealed that directly downstream from catA and potentially transcribed in the same direction were two open reading frames encoding polypeptides of 48 and 36 kilodaltons (kDa). Genetic disruption of these open reading frames did not discernably alter either catechol metabolism or its regulation. A third open reading frame, beginning 123 bp upstream from catB and transcribed divergently from this gene, was designated catM. This gene was found to encode a 28-kDa trans-acting repressor protein that, in the absence of cis,cis-muconate, prevented expression of the cat structural genes. Constitutive expression of the genes was caused by a mutation substituting Arg-156 with His-156 in the catM-encoded repressor. The repressor protein proved to be a member of a diverse family of procaryotic regulatory proteins which, with rare exception, are transcriptional activators. Repression mediated by catM was not the sole transcriptional control exercised over catA in A. calcoaceticus. Expression of catA was elicited by either benzoate or cis,cis-muconate in a genetic background from which catM had been deleted. This induction required DNA in a segment lying 1 kbp upstream from the catA gene. It is likely that an additional gene, lying outside the region containing the structural genes necessary for benzoate metabolism, contributes to this control.
Under continuous dizocilpine infusion an N-methyl-D-aspartate receptor independent form of cocaine sensitization develops in rats

N-methyl-D-aspartate (NMDA) receptor blockade is thought to prevent the development of cocaine-induced sensitization. Moreover, when cocaine is administered daily along with dizocilpine infusion to previously sensitized rats, the extinction of sensitization occurs. We report here two sets of experiments: (1) Rats were infused with dizocilpine through a subcutaneous mini-pump (0.1 mg/kg/day) during the induction of cocaine sensitization and, after 2 or 7 days of wash-out, were challenged with: cocaine, dizocilpine plus cocaine or 3-((±)2-carboxypiperazin-4-yl)-propyl-L-phosphonic acid (CPP) plus cocaine. Cocaine induced stereotypy scores significantly lower than that produced by the two drug combinations. Animals infused with dizocilpine alone did not present stereotypies when challenged either with dizocilpine or with dizocilpine plus cocaine. (2) Rats previously sensitized to cocaine received dizocilpine by infusion and daily cocaine treatments for a week. During the first days of infusion, sensitization appeared to be significantly decreased, but it resumed the initial intensity on days 6–7. After 2 and 9 days of wash-out, the expression of sensitization could be retrieved only by dizocilpine plus cocaine. Two distinct forms of sensitization to cocaine thus seem to exist: one dependent on and the second independent of NMDA receptor activity.
The Antinociceptive Effects of Intravenous Dexmedetomidine in Colorectal Distension-Induced Visceral Pain in Rats: The Role of Opioid Receptors

BACKGROUND: In comparison with cutaneous pain, the role of &agr;2-adrenoceptor (&agr;2-AR) agonists in visceral pain has not been extensively examined. We aimed to characterize the antinociceptive effect of IV dexmedetomidine on visceral pain in rats and to determine whether antinociception thus produced is mediated by opioid receptors. METHODS: Male Sprague Dawley rats (250–300 g) were instrumented with a venous catheter for drug administration and with enameled nichrome electrodes for electromyography of the external oblique muscles. Colorectal distension (CRD) was used as the noxious visceral stimulus, and the visceromotor response to CRD was quantified electromyographically before and 5, 15, 30, 60, 90, and 120 min after dexmedetomidine or clonidine administration. Antagonists were administered 10 min before dexmedetomidine. After confirmation of normal distribution of data, one-way analysis of variance with the Tukey-Kramer post hoc test was used for multiple comparison. RESULTS: IV administration of dexmedetomidine (2.5–20 &mgr;g/kg) and clonidine (10–80 &mgr;g/kg) produced a dose-dependent reduction in visceromotor response with 50% effective dose values of 10.5 and 37.6 &mgr;g/kg, respectively. Administration of the nonspecific &agr;2-AR antagonist yohimbine (1 mg/kg), but not the peripherally restricted &agr;2-AR antagonist MK-467 (1 mg/kg), abolished the antinociceptive effect of dexmedetomidine (10 &mgr;g/kg). In addition, inhibition of opioid receptors by naloxone (1 mg/kg) attenuated the antinociceptive effect of dexmedetomidine. CONCLUSION: Our data indicate that IV dexmedetomidine exerts pronounced antinociception against CRD-induced visceral pain and suggest that the antinociceptive effect of dexmedotimidine is mediated in part by opioid receptors, but peripheral &agr;2-ARs are not involved.
Impact of WHO recommendations to eliminate industrial trans-fatty acids from the food supply in Latin America and the Caribbean.

BACKGROUND The World Health Organization (WHO) has deemed that there is enough evidence to recommend the elimination of industrially produced trans-fatty acids (TFA) from the food supply. This article evaluates government-led public health strategies in countries in Latin America and the Caribbean (LAC), and factors perceived to affect following WHO's recommendation to eliminate industrially produced TFA. METHODS Descriptive, prospective multiple case studies integrated data from open-ended questionnaires to representatives of ministries of health, and systematic review of internal and publicly available documents in 13 LAC countries. FINDINGS Overall, government efforts to follow WHO recommendations have not been well co-ordinated throughout the region. Evidence for this includes the lack of standardization of TFA definitions. For example, some countries exclude naturally occurring TFA from the definitions, whereas others leave the option open to their inclusion. As a consequence, the criteria for trans-free nutrient claims and labelling requirements are inconsistent across the region. Government-led strategies varied from banning or limiting TFA content in the food supply to voluntary labelling of TFA. The identified challenges to the implementation of policies to reduce TFA include the shortage of information on TFA content of diets and foods, consumer unawareness of TFA and lack of monitoring and surveillance. The identified enabling factors were intersectoral collaboration with industry, mandatory labelling regulation and international and national visibility of the topic, which facilitated reduction of TFA content. INTERPRETATION A co-ordinated effort is required to achieve virtual elimination of all TFA in the region, as recommended by WHO. Standardization of the definition of TFA across the region would facilitate regulation, consumer education efforts and monitoring and surveillance efforts. Simultaneously, countries need to determine their level of exposure to TFA through the implementation of small surveys to assess blood TFA levels using blood spots, and the evaluation of TFA in fat sources that are commonly used.
The secretory leukocyte protease inhibitor (SLPI) suppresses cancer cell invasion but promotes blood‐borne metastasis via an invasion‐independent pathway

An invasion‐independent pathway has been proposed as a novel mechanism in blood‐borne metastasis, where tumour cells enveloped by sinusoidal tumour vessels enter the circulation without vascular invasion. We previously identified the secretory leukocyte protease inhibitor (SLPI) as a candidate gene responsible for this pathway. In this study, the functional role of SLPI in metastatic dissemination was investigated. We transfected the SLPI gene into a poorly metastatic clone of the MCH66 mouse mammary tumour cell line. Over‐expression of SLPI promoted in vivo growth and spontaneous metastasis to the lung, whereas it suppressed invasive activity in vitro. The inoculated tumours of SLPI‐transfectants exclusively induced a sinusoidal vasculature and subsequently produced endothelial‐coated tumour emboli, which are morphological indices of the invasion‐independent pathway. In addition, exogenous SLPI inhibited the migration activity through Matrigel of both tumour cells and human umbilical vein endothelial cells (HUVECs). In vivo angiogenesis assays also demonstrated that SLPI suppressed the migration of newly formed blood vessels. These results suggest that an anti‐migratory effect of SLPI on tumour‐associated endothelial cells may induce vascular remodelling to form a sinusoidal architecture, and consequently promote invasion‐independent metastasis. This study provides a new model for metastasis, based on the mechanism regulated by anti‐invasive factors, such as SLPI. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Structure and function of apolipoprotein A-I and high-density lipoprotein

Structural biology and molecular modeling have provided intriguing insights into the atomic details of the lipid-associated structure of the major protein component of HDL, apo A-I. For the first time, an atomic resolution map is available for future studies of the molecular interactions of HDL in such biological processes as ABC1-regulated HDL assembly, LCAT activation, receptor binding, reverse lipid transport and HDL heterogeneity. Within the context of this paradigm, the current review summarizes the state of HDL research.