Miracle-dz/UniFAR-FTUs huggingface dataset:
Inputs from low threshold muscle and cutaneous afferents of hand and forearm to areas 3a and 3b of baboon's cerebral cortex.

The posterior wall of the central sulcus in forelimb area of SI has been expolred with extracellular micro‐electrodes in baboons lightyl anaesthetized with nitrous oxide and sodium thiopentone. 2. The excitatory responses of 130 single units to low intensity electrical stimulation of the deep radial (muscle) and the superficial radial (cutaneous) nerves have been investigated. 3. Units that responded only to muscle nerve stimulation were located in area 3a but overlapped into area 3b. Units that responded only to cutaneous nerve stimulation were found mainly in area 3b but a number occurred in area 3a. Units that responded to both muscle and nerve stimuli (convergent units) were found throughout area 3a and the rostral part of area 3b. 4. Latency analyses of all three response groups revealed a single population of units responding to low threshold muscle nerve stimulation (mean latency 8.5 msec), and both early and late populations responding to low threshold cutaneous nerve stimulation (mean latencies 9.5 and 13.6 msec respectively). A number of the convergent units had very similar latencies for both inputs. 5. Electrical stimulation within area 3a deminstrated a projection from areas 1 and 3b to area 3a; such a pathway may provide a route for excitation of the late skin population which was found mainly in area 3a. 6. In area 3a units commonly responded to light touch, local pressure or deep pressure but only rarely to movement of hairs. A number of the convergent units responded to natural stimulation of cutaneous receptors.
A conceptual model: Redesigning how we provide palliative care for patients with chronic obstructive pulmonary disease

ABSTRACT Background: Despite significant needs, patients with chronic obstructive pulmonary disease (COPD) make limited use of palliative care, in part because the current models of palliative care do not address their key concerns. Objective: Our aim was to develop a tailored model of palliative care for patients with COPD and their family caregivers. Method: Based on information gathered within a program of studies (qualitative research exploring experiences, a cohort study examining service use), an expert advisory committee evaluated and integrated data, developed responses, formulated principles to inform care, and made recommendations for practice. The informing studies were conducted in two Australian states: Victoria and South Australia. Results: A series of principles underpinning the model were developed, including that it must be: (1) focused on patient and caregiver; (2) equitable, enabling access to components of palliative care for a group with significant needs; (3) accessible; and (4) less resource-intensive than expansion of usual palliative care service delivery. The recommended conceptual model was to have the following features: (a) entry to palliative care occurs routinely triggered by clinical transitions in care; (b) care is embedded in routine ambulatory respiratory care, ensuring that it is regarded as “usual” care by patients and clinicians alike; (c) the tasks include screening for physical and psychological symptoms, social and community support, provision of information, and discussions around goals and preferences for care; and (d) transition to usual palliative care services is facilitated as the patient nears death. Significance of results: Our proposed innovative and conceptual model for provision of palliative care requires future formal testing using rigorous mixed-methods approaches to determine if theoretical propositions translate into effectiveness, feasibility, and benefits (including economic benefits). There is reason to consider adaptation of the model for the palliative care of patients with other nonmalignant conditions.
Viral infection in bone marrow transplants: Is JC virus involved?

Hemorrhagic cystitis is characterized by hematuria due to inflammation of the bladder. In bone marrow transplants, this disease is linked to the infection by human polyomavirus BK, whereas the role of the human polyomavirus JC is unclear. The transcriptional control regions of both viruses contain important cellular transcription factor binding sites that undergo rearrangement process generating suitable variants that could be more active for viral replication and for the onset of hemorrhagic cystitis. In this study urine obtained from seven patients with bone marrow transplant were examined. Polyomavirus genomes were quantified by PCR and viral loads were compared. The transcriptional regions of both viruses were amplified and sequenced to determine the presence of variants. Subtypes of polyomaviruses were determined by amplification and sequencing of the viral protein 1 region. The results showed that four of seven patients were positive for BK DNA, two of seven patients had BK and JC DNA and one of seven had JC DNA. Positive samples were amplified and sequenced successively for transcriptional regions. The viral archetype was always found in both viruses. Finally, typing showed that BK virus subtype I infected patients with BK, whereas JC virus genotype IA and genotype 1B were found in patients infected with JC. The data suggest that new and different approaches are required to improve the morbidity and mortality caused by polyoma‐associated hemorrhagic cystitis, since it known that BK virus is involved in the onset of hemorrhagic cystitis, whereas the role of JC virus should be investigated further. J. Med. Virol. 82:138–145, 2010. © 2009 Wiley‐Liss, Inc.
Metabotropic glutamate receptor subtype 4 selectively modulates both glutamate and GABA transmission in the striatum: implications for Parkinson’s disease treatment

Alterations of striatal synaptic transmission have been associated with several motor disorders involving the basal ganglia, such as Parkinson’s disease. For this reason, we investigated the role of group‐III metabotropic glutamate (mGlu) receptors in regulating synaptic transmission in the striatum by electrophysiological recordings and by using our novel orthosteric agonist (3S)‐3‐[(3‐amino‐3‐carboxypropyl(hydroxy)phosphinyl)‐hydroxymethyl]‐5‐nitrothiophene (LSP1‐3081) and l‐2‐amino‐4‐phosphonobutanoate (L‐AP4). Here, we show that both drugs dose‐dependently reduced glutamate‐ and GABA‐mediated post‐synaptic potentials, and increased the paired‐pulse ratio. Moreover, they decreased the frequency, but not the amplitude, of glutamate and GABA spontaneous and miniature post‐synaptic currents. Their inhibitory effect was abolished by (RS)‐α‐cyclopropyl‐4‐phosphonophenylglycine and was lost in slices from mGlu4 knock‐out mice. Furthermore, (S)‐3,4‐dicarboxyphenylglycine did not affect glutamate and GABA transmission. Finally, intrastriatal LSP1‐3081 or L‐AP4 injection improved akinesia measured by the cylinder test. These results demonstrate that mGlu4 receptor selectively modulates striatal glutamate and GABA synaptic transmission, suggesting that it could represent an interesting target for selective pharmacological intervention in movement disorders involving basal ganglia circuitry.
An efficient therapeutic approach to patients with acute promyelocytic leukemia using a combination of arsenic trioxide with low‐dose all‐trans retinoic acid

The use of arsenic trioxide (As2O3, ATO) combined with all‐trans retinoic acid (ATRA) has recently been reported to induce remission in patients with acute promyelocytic leukemia (APL). However, its efficiency remains inconclusive mainly due to the small number of the available cases. In this study, therefore, we present a clinical study using a combination of ATO with low‐dose ATRA (LD‐ATRA) to treat 108 APL patients (80 newly diagnosed patients, 28 relapsed patients). Therapeutic outcomes using the ATO/LD‐ATRA approach were compared with those of APL patients treated either with ATO alone (65 patients) or ATRA alone (51 patients). The results showed that the ATO/LD‐ATRA approach provided significantly better therapeutic outcomes as compared to either ATO or ATRA alone, as evidenced by lower mortality, a higher CR rate and a reduced period to CR. In addition, the toxic side‐effects have been no worse with the combined ATO/LD‐ATRA treatment than with either ATO or ATRO alone and in some cases have been reduced. These data suggest that the ATO/LD‐ATRA regimen is superior to either regimen given alone to patients with APL. Copyright © 2004 John Wiley & Sons, Ltd.
Kinetic mechanism of the single-stranded DNA recognition by Escherichia coli replicative helicase DnaB protein. Application of the matrix projection operator technique to analyze stopped-flow kinetics.

Kinetics of the Escherichia coli primary replicative helicase DnaB protein binding to a single-stranded DNA, in the presence of the ATP non-hydrolyzable analog AMP-PNP, have been performed, using the fluorescence stopped-flow technique. This is the first direct determination of the mechanism of the ssDNA recognition by a hexameric helicase. Binding of the fluorescent etheno-derivative of a ssDNA to the enzyme is characterized by a strong increase of the nucleic acid fluorescence, which provides an excellent signal to quantitatively study the mechanism of ssDNA recognition by the helicase. The kinetic experiments have been performed with a ssDNA 20-mer, depsilonA(pepsilonA)(19), that encompasses the entire, total ssDNA-binding site of the helicase and with the 10-mer depsilonA(pepsilonA)(9), which binds exclusively to the ssDNA strong subsite within the total ssDNA-binding site. Association of the DnaB helicase with the 20-mer is characterized by three relaxation times, which indicates that the binding occurs by the minimum three-step mechanism where the bimolecular binding step is followed by two isomerization steps. This mechanism is described by the equation: Helicase+ssDNAk1/(k1)<-->(k-1)(H-ssDNA)1(k2)<-->(k-2)(H-ssDNA)2 (k3)<-->(k-3)(H-ssDNA)3. The value of the bimolecular rate constant, k(1), is four to six orders of magnitude lower than the value expected for the diffusion-controlled reaction. Moreover, quantitative amplitude analysis suggests that the major conformational change of the ssDNA takes place in the formation of the (H-ssDNA)(1). These results indicate that the determined first step includes formation of the collision and an additional transition of the protein-ssDNA complex, most probably the local opening of the protein hexamer. The data indicate that the binding mechanism reflects the interactions of the ssDNA predominantly through the strong ssDNA-binding subsite. The analysis of the stopped-flow kinetics has been performed using the matrix-projection operator technique, which provides a powerful method to address stopped-flow kinetics, particularly, the amplitudes. The method allowed us to determine the specific fluorescence changes accompanying the formation of all the intermediates. The sequential nature of the determined mechanism indicates the lack of the kinetically significant conformational equilibrium of the DnaB hexamer as well as a transient dissociation of the hexamer prior to the ssDNA binding. The significance of these results for the functioning of the DnaB helicase is discussed.
Detection of bone metastases in breast cancer by 18FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions.

PURPOSE 99mTechnetium methylene diphosphonate (99mTc MDP) bone scintigraphy is currently the method of choice for the detection of bone metastases, but 18F-fluoro-deoxy-D-glucose positron emission tomography (18FDG PET) offers superior spatial resolution and improved sensitivity. We have compared 18FDG PET with 99mTc MDP bone scintigraphy in patients with skeletal metastases from breast cancer and have analyzed the data in subgroups based on radiographic characteristics of lesions. PATIENTS AND METHODS Twenty-three women with breast cancer and confirmed bone metastases were studied with both 99mTC MDP bone scintigraphy and 18FDG PET, and the number of lesions detected and the quantitation of uptake (standardized uptake values [SUVs]) of 18FDG in osteolytic and osteoblastic metastases were compared. Survival was compared for both lytic and blastic bone metastases and for patients with high and low accumulation of 18FDG. RESULTS 18FDG PET detected more lesions than 99mTc MDP scintigraphy (mean, 14.1 and 7.8 lesions, respectively; P < .01). However, 18FDG detected fewer bone metastases compared with 99mTc MDP scintigraphy in a subgroup of patients with osteoblastic disease (P < .05). Higher SUVs were observed for osteolytic than osteoblastic disease (mean, 6.77 and 0.95, respectively; P < .01). Survival was lower in patients with osteolytic disease compared with the remainder (P=.01). A difference in survival was not found for those patients with high SUVs (> 3.6; P=.4). CONCLUSION 18FDG PET is superior to bone scintigraphy in the detection of osteolytic breast cancer metastases, which led to a poorer prognosis. In contrast, osteoblastic metastases show lower metabolic activity and are frequently undetectable by PET. The biologic explanation for this observation remains to be elucidated.
Alternative medicine use by rheumatology patients in a universal health care setting.

OBJECTIVE To assess the prevalence, extent of use, and cost of alternative medicine by patients attending a rheumatology clinic. METHODS Two hundred and thirty-five unselected consecutive patients attending a rheumatology clinic were evaluated by questionnaire to record their current use of alternative medicine practices. RESULTS Sixty-six percent of patients had used alternative medicine interventions in the preceding 12 months; 54% used over the counter products, 39% spiritual aids (including prayer, relaxation, meditation), and 13% each had visited alternative practitioners or used dietary interventions. Patients in the upper middle income group and French speaking patients used more bought products, but no other differences were observed when the groups were analyzed according to level of education, income or cultural background. The current annual cost for the patients of alternative medical therapies was $100. CONCLUSION Our results demonstrate a moderate use of alternative medicine by rheumatology patients, mostly inexpensive products and no cost spiritual aids. Universal health care may have a negative impact on the extent of use of more costly practices.
Mining mammalian genomes for folding competent proteins using Tat‐dependent genetic selection in Escherichia coli

Recombinant expression of eukaryotic proteins in Escherichia coli is often limited by poor folding and solubility. To address this problem, we employed a recently developed genetic selection for protein folding and solubility based on the bacterial twin‐arginine translocation (Tat) pathway to rapidly identify properly folded recombinant proteins or soluble protein domains of mammalian origin. The coding sequences for 29 different mammalian polypeptides were cloned as sandwich fusions between an N‐terminal Tat export signal and a C‐terminal selectable marker, namely β‐lactamase. Hence, expression of the selectable marker and survival on selective media was linked to Tat export of the target mammalian protein. Since the folding quality control feature of the Tat pathway prevents export of misfolded proteins, only correctly folded fusion proteins reached the periplasm and conferred cell survival. In general, the ability to confer growth was found to relate closely to the solubility profile and molecular weight of the protein, although other features such as number of contiguous hydrophobic amino acids and cysteine content may also be important. These results highlight the capacity of Tat selection to reveal the folding potential of mammalian proteins and protein domains without the need for structural or functional information about the target protein.
Picking Cherries or Lemons: A Unified Theory of Cross‐Border Mergers and Acquisitions

This article provides a theoretical framework that enhances understanding of empirical evidence suggesting that international mergers and acquisitions, a key source of foreign direct investment, seemingly target inâ€ country firms that are at the extremes of the productivity spectrumâ€”either highâ€ productivity firms, soâ€ called cherries, or lowâ€ productivity firms, the â€œlemons. â€ The framework demonstrates that foreign firms with intermediate inputs seek highâ€ productivity domestic firms, while foreign firms with managerial expertise seek lowâ€ productivity domestic firms. We also show that because of the difference in available outside options, highâ€ productivity domestic firms can demand a significantly higher portion of profits in the partnership than lowâ€ productivity domestic firms.
The evolving role of response-adapted PET imaging in Hodgkin lymphoma

18F-fluorodeoxyglucose positron emission tomography with (FDG-PET) has a well-established role in the pre- and post-treatment staging of Hodgkin lymphoma (HL), however its use as a predictive therapeutic tool via responded-adapted therapy continues to evolve. There have been a multitude of retrospective and noncontrolled clinical studies showing that early (or interim) FDG-PET is highly prognostic in HL, particularly in the advanced-stage setting. Response-adapted treatment approaches in HL are attempting to diminish toxicity for low-risk patients by minimizing therapy, and conversely, intensify treatment for high-risk patients. Results from phase III noninferiority studies in early-stage HL with negative interim FDG-PET that randomized patients to chemotherapy alone versus combined modality therapy showed a continued small improvement in progression-free survival for patients who did not receive radiation. Preliminary reports of data escalating therapy for positive interim FDG-PET in early-stage HL and for de-escalation of therapy [i.e. bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (BEACOPP)] for negative interim FDG-PET in advanced stage HL (i.e. deletion of bleomycin) have demonstrated improved outcomes. Maturation of these studies and continued follow up of all response-adapted studies are needed. Altogether, the treatment of HL remains an individualized clinical management choice for physicians and patients. Continued refinement and optimization of FDG-PET is needed, including within the context of targeted therapeutic agents. In addition, a number of new and novel techniques of functional imaging, including metabolic tumor volume and tumor proliferation, are being explored in order to enhance staging, characterization, prognostication and ultimately patient outcome.
Diversity of β-Lactamases Produced by Ceftazidime-Resistant Pseudomonas aeruginosa Isolates Causing Bloodstream Infections in Brazil

ABSTRACT A retrospective survey was conducted to characterize β-lactamases in a collection of 43 ceftazidime-resistant Pseudomonas aeruginosa isolates recovered from patients with bloodstream infections hospitalized at a Brazilian teaching hospital between January and December 2005. Resistance rates for carbapenems, aminoglycosides, and quinolones were over 80%, with only colistin remaining active against all isolates. Pulsed-field gel electrophoresis analysis identified seven different genotypes. AmpC overproduction was found to be the sole β-lactamase-mediated mechanism responsible for ceftazidime resistance in four isolates (9.3%). Nine isolates (20.9%) produced an extended-spectrum β-lactamase (ESBL), either GES-1 (n = 7, 16.3%) or CTX-M-2 (n = 2, 4.6%). Carbapenemase activity was detected in 30 (70%) additional isolates. Among those isolates, two isolates (4.6%) produced the ESBL GES-5, possessing the ability to hydrolyze imipenem; a single isolate (2.3%) produced the metallo-β-lactamase (MBL) IMP-1; and 27 isolates produced the MBL SPM-1 (62.8%). None of the isolates coproduced both ESBL and MBL. Insertion sequence elements ISCR4 and ISCR1 were associated with blaSPM-1 and blaCTX-M-2 genes, respectively, whereas the blaGES-1 and blaGES-5 genes were part of class 1 integron structures. This study underlines the spread of MBL- and ESBL-producing P. aeruginosa isolates as an important source of ceftazidime resistance in Brazil.
The legacy of public subsidies for innovation: input, output and behavioural additionality effects

In many countries significant amounts of public funding are devoted to supporting firms’ R&D and innovation projects. Here, using panel data on the innovation activities of Irish manufacturing firms we examine the legacy effects of public subsidies for new product development and R&D. We examine five alternative mechanisms through which such effects may occur: input additionality, output additionality, and congenital, inter-organisational and experiential behavioural additionality. Tests suggest contrasting legacy effects with R&D subsidies generating legacy output additionality effects while new product development subsidies have legacy congenital and inter-organisational behavioural additionality effects. Our results have implications for innovation policy design and evaluation.
Motoneurons dorsolateral to the central canal innervate perineal muscles in the mongolian gerbil

The Mongolian gerbil provides a model in which sexually dimorphic areas in the hypothalamus are correlated with sociosexual behaviors such as scent marking and male copulatory behavior. To extend this model, investigations were conducted to determine whether sexually dimorphic areas existed in the spinal cord that could be relevant to male sexual behavior. The focus of these investigations was the perineal muscles associated with the penis. Therefore, this research identified the spinal motoneurons that innervate the bulbocavernosus, levator ani, anal sphincter, and ischiocavernosus muscles of Mongolian gerbils. The motoneuron pool that innervates the bulbocavernosus, levator ani, and anal sphincter was designated the spinal nucleus of the bulbocavernosus (SNB), as for other species of rodents. The motoneuron pool innervating the ischiocavernosus was identified as the dorsolateral nucleus, again, to be consistent with the designation for other rodents. The motoneurons of the gerbil SNB were distributed dorsolateral to the central canal in the lumbosacral transition zone of the spinal column. These motoneurons are located in the region classically defined as area X of the spinal cord. The number of SNB motoneurons was sexually dimorphic, with male gerbils having about five times as many SNB motoneurons as do female gerbils. The size of SNB motoneurons was also sexually dimorphic. The SNB motoneurons of males were 1. 5 times larger than the SNB motoneurons of females. The effects of adult castration on the male SNB were also studied. After castration, the size, but not the number, of SNB motoneurons in males was significantly decreased. This decrease was prevented by testosterone treatment. The percentage of calcitonin gene‐related peptide (CGRP)‐immunoreactive SNB motoneurons was also affected by adult castration. The percentage of CGRP‐immunoreactive motoneurons was significantly decreased after adult castration. Again, this decrease was reversed by testosterone treatment. These findings suggest that the SNB of gerbils is sexually dimorphic and is sensitive to circulating levels of gonadal steroids. The unique placement of the SNB motoneurons suggests that an alternative laminar organizational scheme may be necessary for Mongolian gerbil. © 1995 Wiley‐Liss, Inc.