Miracle-dz/UniFAR-FTUs huggingface dataset:
Linking Biochemical Pathways and Networks to Adverse Drug Reactions

There is growing interest in investigating the biochemical pathways involved in cellular responses to drugs. Here we propose new methods to explore the relationships between drugs, biochemical pathways and adverse drug reactions (ADRs) at a large scale. Using sparse canonical correlation analysis of 832 drugs characterized by 173 pathways and 1385 ADRs profiles, we identified 30 highly correlated sets of drugs, pathways and ADRs. This included known and potentially novel associations. To evaluate the predictive performance of our method, the extracted correlated components were used to predict known ADR profiles from drug pathway profiles. A relatively high prediction performance (AUC: 0.894) was achieved. To further investigate their association, we developed a network-based approach to extracting potentially significant modules of pathway-ADR associations. Five statistically significant modules were extracted. We found that most of the nodes contained in the modules are either pathways linked to a very limited number of drugs or rare ADRs. The work provides a foundation for future investigations of ADRs in the context of biochemical pathways under different clinical conditions. Our method and resulting datasets will aid in: a) the systematic prediction of ADRs, and b) the characterization of novel mechanisms of action for existing drugs. This merits additional research to further assess its potential in improving personalized drug safety monitoring, as well as for the repositioning of drugs in the longer term.
Relation of Gallbladder Function and Helicobacter pylori Infection to Gastric Mucosa Inflammation in Patients with Symptomatic Cholecystolithiasis

Background: Inflammatory alterations of the gastric mucosa are commonly caused by Helicobacter pylori (Hp) infection in patients with symptomatic gallstone disease. However, the additional pathogenetic role of an impaired gallbladder function leading to an increased alkaline duodenogastric reflux is controversially discussed. Aim: To investigate the relation of gallbladder function and Hp infection to gastric mucosa inflammation in patients with symptomatic gallstones prior to cholecystectomy. Patients: Seventy-three patients with symptomatic gallstones were studied by endoscopy and Hp testing. Methods: Gastritis classification was performed according to the updated Sydney System and gallbladder function was determined by total lipid concentration of gallbladder bile collected during mainly laparoscopic cholecystectomy. Results: Fifteen patients revealed no, 39 patients mild, and 19 moderate to marked gastritis. No significant differences for bile salts, phospholipids, cholesterol, or total lipids in gallbladder bile were found between these three groups of patients. However, while only 1 out of 54 (<2%) patients with mild or no gastritis was found histologically positive for Hp, this infection could be detected in 14 (74%) out of 19 patients with moderate to marked gastritis. Conclusion: Moderate to marked gastric mucosa inflammation in gallstone patients is mainly caused by Hp infection, whereas gallbladder function is not related to the degree of gastritis. Thus, an increased alkaline duodenogastric reflux in gallstone patients seems to be of limited pathophysiological relevance.
The Energetics of Male Reproduction in an Aquatically Mating Pinniped, the Harbour Seal

The energy expenditure of breeding male harbour seals Phoca vitulina, on Sable Island, Nova Scotia, was investigated by measuring changes in body mass, body comosition, and water flux using isotope dilution. Seals lost 0.04% ± 0.04% (n = 34) of their initial mass per day during the breeding season (4 wk),and fat, water, and protein accounted for 64.3% ± 4.8%, 27.8% ± 3.3%, and 6.9 ± 1.4% of this was estimated as 33.3 ± 1.9 MJ d‐1, or 3.9 ± 0.2 W kg‐1 (n = 17), similar to rates measured in terrestrially mating pinniped species. However, unlike terrestrially mating pinni‐peds, male harbour seals did not fast during the breeding season, and energy intake from foraging accounted for 61.8% ± 4.0% of the total energy expended. Males derived most of their expended energy from food intake early in the breeding season. However, as oestrus females became increasingly available, reduced rates of food intake in males were coupled with increased rates of total energy expenditure. Larger males expended significantly more energy from body stores and more total energy than smaller males. Male harbour seals appeared to balance the energetic costs of reporduction against the constraints of small body size by foraging during deep‐diving trips before the appearance of oestrus females and by opportunistie feeding throughout the breeding season while at sea. We suggest that size dimorphism may be less pronounced in aquatically mating pinnipeds partly because the temporal and spatial separation of foraging and repro‐duction is less distinct than it is for terrestrially breedings pinnipeds.
Out-of-hospital births, U.S., 1978: birth weight and Apgar scores as measures of outcome.

An examination of 1978 natality data for the United States disclosed that low birth weight was less common among 30,819 infants born out of hospital than among 3,294,101 infants born in hospital in that year. When controls were applied for birth attendant, infants' race, and mothers' education, age, nativity, and parity, the data revealed that white, well-educated women between 25 and 39 years of age, who were having their second babies and were attended by midwives out of hospital, were at least risk of bearing low birth weight infants. The incidence rate of low birth weight babies was lower for midwife-attended births in every category examined. For college-educated white women, for example, the incidence rate was 2.0 percent among those attended by midwives, 4.6 percent among those giving birth in hospital, and 3.6 percent among those whose out-of-hospital deliveries were attended by physicians. Apgar scores for babies born both in and out of hospital were also studied but, because of inconsistent reporting, were given less attention. Excellent (9-10) Apgar scores were more common among babies born out of hospital than among those born in hospital (63 percent compared with 49 percent), particularly for out-of-hospital births attended by physicians. At least with respect to birth weight and Apgar scores, the claim that out-of-hospital births are inherently more dangerous than hospital births receives no support from these data. The findings also suggest the need for further refinement of vital statistics categories to permit the analysis of distinctions between births attended by certified nurse-midwives and those attended by lay midwives, as well as differences between births at home and those in alternative birth centers.
Inertia based microfluidic capture and characterisation of circulating tumour cells for the diagnosis of lung cancer.

BACKGROUND Routine clinical application of circulating tumour cells (CTCs) for blood based diagnostics is yet to be established. Despite growing evidence of their clinical utility for diagnosis, prognosis and treatment monitoring, the efficacy of a robust platform and universally accepted diagnostic criteria remain uncertain. We evaluate the diagnostic performance of a microfluidic CTC isolation platform using cytomorphologic criteria in patients undergoing lung cancer surgery. METHODS Blood was processed from 51 patients undergoing surgery for known or suspected lung cancer using the ClearBridge ClearCell FX systemTM (ClearBridge Biomedics, Singapore). Captured cells were stained on slides with haematoxylin and eosin (H&E) and independently assessed by two pathologist teams. Diagnostic performance was evaluated against the pathologists reported diagnosis of cancer from surgically obtained specimens. RESULTS Cancer was diagnosed in 43.1% and 54.9% of all cases. In early stage primary lung cancer, between the two reporting teams, a positive diagnosis of CTCs was made for 50% and 66.7% of patients. The agreement between the reporting teams was 80.4%, corresponding to a kappa-statistic of 0.61±0.11 (P<0.001), indicating substantial agreement. Sensitivity levels for the two teams were calculated as 59% (95% CI, 41-76%) and 41% (95% CI, 24-59%), with a specificity of 53% for both. CONCLUSIONS The performance of the tested microfluidic antibody independent device to capture CTCs using standard cytomorphological criteria provides the potential of a diagnostic blood test for lung cancer.
Providing Information to Help Medicare Beneficiaries Choose a Health Plan

Abstract Many Medicare beneficiaries have limited knowledge of the Medicare program and related health insurance options. This is due in part to the complexity of the Medicare program and supplemental health insurance market. A recent congressional mandate through the Balanced Budget Act of 1997 called for broad dissemination of information to educate beneficiaries about their health plan options and to encourage informed health plan decision-making. In response, the Health Care Financing Administration (HCFA) launched the National Medicare Education Program (NMEP) to support the educational objectives of the BBA. This paper provides an overview of the components of the NMEP information campaign. We also review lessons learned from our experience in designing and testing a prototype consumer handbook that explains the different health plan options to Medicare beneficiaries. Through our discussion of the handbook, we highlight several ways to communicate information effectively about a complex publicly funded program to an older adult population.
Dialysis modality choice in elderly patients with end-stage renal disease: a narrative review of the available evidence

The number of elderly patients on maintenance dialysis has rapidly increased in the past few decades, particularly in developed countries, imposing a growing burden on dialysis centres. Hence, many nephrologists and healthcare authorities feel that greater emphasis should be placed on the promotion of home dialysis therapies such as peritoneal dialysis (PD) and home haemodialysis (HD). There is currently no general consensus as to the best dialysis modality for elderly patients with end-stage renal disease. In-centre HD is predominant in most countries, although it is widely recognized that PD has several advantages over HD, including the lack of need for vascular access, continuous slow ultrafiltration, less interference with patients' lifestyle and lower costs. Comparisons of outcomes between elderly patients on PD and HD rely on observational studies, as randomized controlled trials are lacking. The results of these studies are variable. However, most of them suggest that survival rates are largely similar between the two modalities, except for elderly patients with diabetes and/or beyond 1–3 years from dialysis initiation, in which cases HD appears to be superior. An equally important aspect to consider when choosing dialysis modality, particularly in this age group, is the quality of life, and in this regard most studies found no significant differences between PD and HD. In these circumstances, we believe that dialysis modality selection should be guided by patient's preference, based on comprehensive and unbiased information. A multidisciplinary team should review elderly patients starting on dialysis, aiming to identify possible barriers to PD and home HD, including physical, visual, cognitive, psychological and social problems, and to overcome such barriers by adequate care, education, psychological counselling and dialysis assistance.
Motor neuron disease with parkinsonism.

OBJECTIVE To report clinical characteristics of patients with combined features of parkinsonism and motor neuron disease (MND). DESIGN Medical chart review. SETTING University medical center. PATIENTS Thirteen patients, identified by computer-assisted search, who had diagnoses of both parkinsonism and MND. RESULTS Median age was 68 years. There were 7 men and 6 women. All had clinical and electrodiagnostic evidence of both upper and lower motor neuron degeneration. One or more clinical manifestations of parkinsonism were observed in all patients either before the diagnosis of MND (n = 2), at the time of initial evaluation (n = 10), or after the diagnosis of MND (n = 1). The median time from symptom onset to presentation was 18 months. Improvement was seen in 5 of the 11 patients treated with levodopa. Dementia and autonomic dysfunction were absent in all patients. Postmortem neuropathological evaluation, available in 1 patient, demonstrated degeneration of the substantia nigra with Lewy bodies, mild pallor of the medullary pyramids, and neurogenic atrophy of the skeletal muscle. CONCLUSION The onset of MND and parkinsonism within a relatively short period in most of our patients favors a common pathogenic mechanism over coincidental occurrence of 2 unrelated diseases. In patients with MND, it is important to recognize signs of parkinsonism that levodopa might alleviate.
Spectroscopic study of the chromophore–protein association and primary photoinduced events in the photoreceptor of Blepharisma japonicum

Blepharisma japonicum is a ciliated protozoan exhibiting a strong step-up photophobic response upon illumination. The photoreceptor chromophores responsible for this response have been identified to be hypericin-like chromophores (blepharismin and oxyblepharismin), complexed to a 200 kDa non-water-soluble protein. The present work opens up new perspectives on the primary phototransduction steps of B. japonicum ’s light perception through a joined approach by steady-state fluorescence spectroscopy, time-resolved fluorescence anisotropy and sub-picosecond transient absorption spectroscopy. The free chromophore of the light-adapted form of the cell (oxyblepharismin) was studied in various solvents and its spectroscopic properties, as well as its primary excited-state reactivity, compared with those of the corresponding pigment–protein complex, extracted by phosphate-concentration-step chromatography on a hydroxyapatite column. Fluorescence anisotropy together with SDS PAGE electrophoresis results confirm that oxyblepharismin is non-covalently bound to the apoprotein and show that, in the excited state, it is free to rotate in all directions within the binding site where it experiences a large local viscosity. Time-resolved anisotropy measurements on aromatic amino acids confirm that the molecular weight of the protein is of the order of 200 kDa. Although showing very similar steady-state spectra, free oxyblepharismin and its protein complex have noticeably different excited-state behaviours. In particular, the protein complex exhibits a pronounced short-lived absorption feature in the 640–750 nm range, decaying biexponentially in 4 ps and 56 ps. Those decays, also observed in other spectral regions, are not found in the corresponding kinetics of the isolated pigment in solution. This early behaviour of the protein complex might be the signature of the primary phototransduction process, possibly involving an electron transfer from the pigment to a neighbouring protein acceptor residue as it had been suggested in previous studies.
Novel Pharmacological Sensitivity of the Presynaptic Calcium Channels Controlling Acetylcholine Release in Skate Electric Organ

Abstract: The presynaptic terminals of skate (Raja montagui) electric organ were tested for their sensitivity to calcium channel antagonists. Acetylcholine (ACh) release and the elevation of intraterminal Ca2+ concentrations triggered by K+ depolarisation were studied. ACh release was measured as 3H efflux from slices of organ prelabelled with [3H]choline. Depolarisation caused a marked, Ca2+‐dependent increase in 3H efflux that was completely blocked by 100 µM Cd2+ and by 300 nMω‐conotoxin‐MVIIC (MVIIC). Inhibition by MVIIC was concentration dependent (IC50 of ∼20 nM) and reversible. No inhibition was seen with nifedipine (5 µM) or the two other peptide antagonists studied: ω‐conotoxin‐GVIA (GVIA) at 5 µM and ω‐agatoxin‐IVA (Aga‐IVA) at 1 µM. In a “nerve plate” preparation (a presynaptic plexus of nerve fibres, Schwann cells, and nerve terminals) changes in intraterminal Ca2+ concentrations were measured by microfluorimetry using fluo‐3. An increase in fluorescence, indicating a rise in the free [Ca2+], rapidly followed K+ depolarisation, and this change was restricted to the nerve terminals. This response was insensitive to nifedipine (5 µM), GVIA (5 µM), and Aga‐IVA (300 nM) but almost completely abolished by MVIIC (1 µM). MVIIC inhibition was concentration dependent and partially reversible. These results show that the nerve terminals in skate electric organ have calcium channels with a pharmacological sensitivity that is markedly different from the established L, N, and P types in other systems but shares some, but not all, of the features of the recently described Q type.
Differential Interaction of the E3 Ligase Parkin with the Proteasomal Subunit S5a and the Endocytic Protein Eps15*

Parkin is a multidomain E3 ligase associated with autosomal recessive Parkinson disease. The N-terminal ubiquitin-like domain (Ubld) of parkin functions with the S5a proteasomal subunit, positioning substrate proteins for degradation. In addition the parkin Ubld recruits the endocytotic protein Eps15, allowing the E3 ligase to ubiquinate Eps15 distal from its parkin-interacting site. The recognition sequences in the S5a subunit and Eps15 for the parkin Ubld are ubiquitin-interacting motifs (UIM). Each protein has two UIM sequences separated by a 50-residue spacer in S5a, but only ∼5 residues in Eps15. In this work we used NMR spectroscopy to determine how the parkin Ubld recognizes the proteasomal subunit S5a compared with Eps15, a substrate for ubiquitination. We show that Eps15 contains two flexible α-helices each encompassing a UIM sequence. The α-helix surrounding UIM II is longer than that for UIM I, a situation that is reversed from S5a. Furthermore, we show the parkin Ubld preferentially binds to UIM I in the S5a subunit. This interaction is strongly diminished in a K48A substitution, found near the center of the S5a interacting surface on the parkin Ubld. In contrast to S5a, parkin recruits Eps15 using both its UIM sequences resulting in a larger interaction surface that includes residues from β1 and β2, not typically known to interact with UIM sequences. These results show that the parkin Ubld uses differential surfaces to recruit UIM regions from the S5a proteasomal subunit compared with Eps15 involved in cell signaling.
Divergence of water balance mechanisms and acclimation potential in body color morphs of Drosophila ananassae.

Drosophila ananassae is a desiccation sensitive species, but the physiological basis of its abundance in the drier subtropical areas is largely unknown. We tested the hypothesis whether body color morphs of D. ananassae differ in the mechanistic basis of water conservation as well as desiccation acclimation potential, consistent with their distribution under dry or wet habitats. We observed reduced rate of water loss consistent with the greater desiccation potential of dark morph as compared with light morph, despite lack of quantitative differences in cuticular lipid mass between them. Dark morph evidenced greater wet and dry mass (∼1.17-fold) as well as higher hemolymph content (∼1.70-fold) and (∼17%) dehydration tolerance to sustain longer survival under desiccation stress (LT50 17.5 hr) as compared with light morph (LT50 4.3 hr). We found significant differences in the storage of energy metabolites in the body color morphs of D. ananassae, that is, carbohydrate content was significantly higher (∼0.18 mg/mg dry mass) in the dark morph as compared to light morph, but greater (∼0.05 mg/mg dry mass) body lipid content was evident in the light morph. Under desiccation stress, dark and light morphs utilized mainly carbohydrates but also lipids to a lesser extent. However, the rate of utilization of energy metabolites did not vary between dark and light morphs. Further, the dark morph consumed higher energy content derived from carbohydrates under desiccation stress as compared with the light morph. Finally, we found contrasting patterns of acclimation to desiccation stress in the two body color morphs, that is, increase in desiccation survival (4.7 hr), as well as in dehydration tolerance (∼6%) due to acclimation of the dark morph but no such effects were observed in the light morph. Thus, divergence in water balance mechanisms as well as acclimation potential reflects evolved physiological adaptations of the dark morph under drier but of the light morph to wet climatic conditions.
Physical, psychosocial and economic impact of rheumatoid arthritis: a pilot study of patients seen at a tertiary care referral centre.

BACKGROUND Rheumatoid arthritis is associated with marked physical disability. In addition, it has an impact on patients' psyche and social well-being, and entails a major financial burden. The impact of the disease in different cultural and social backgrounds is varied. Limited data are available from India on this aspect. METHODS Patients with rheumatoid arthritis satisfying the 1987 modified American College of Rheumatology criteria were included. Besides demographic data, functional impact was assessed using the Health Assessment Questionnaire (HAQ). The psychosocial impact was measured using the medical outcomes study short form 36 (SF-36) with minor modifications. Data on direct and indirect health costs were collected by direct interview. RESULTS The mean age of 101 patients (90 women) was 43.2 years and mean duration of disease was 8 years. Their mean (SD) HAQ score was 0.97 (0.69) with 8 patients having scores > 2. On the SF-36 scale (0-100) the mean (SD) score for various domains were: physical functioning 49.90 (28.55), social functioning 55.51 (20.59), role limitation due to physical problems 32.67 (41.34), role limitation due to emotional problems 47.54 (40.08), mental health 47.36 (7.99), general health perception 52.38 (8.30), energy and vitality 58.56 (6.09), and bodily pain 49.26 (18.87). The summary score for the physical component was 37.95 (9.03) and for the mental component it was 47.71 (4.81). While the physical component summary score had excellent negative correlation with the HAQ score (r = -0.84), correlation with the mental component summary score was poor (r = 0.32). The annual average total cost burden per patient was Rs 16 758, of which Rs 11 617 (67%) was spent on health services and the rest on non-health services (travel, home help and loss of wages). CONCLUSION Rheumatoid arthritis causes significant physical and social disability besides being an economic burden. Indian patients had good scores for mental and social health suggesting good family support systems or reluctance to express their feelings despite physical disability.