Quality of Life in the Management of Home Parenteral Nutrition.

INTRODUCTION: Home parenteral nutrition (HPN) is a rare but challenging therapy for patients with mostly severe underlying diseases. We aimed to investigate patient-reported health-related quality of life (QOL) of patients receiving HPN and its development over time in particular. METHODS: We assessed QOL of HPN patients in a prospective multicenter observational study (SWISSHPN II study). We designed a questionnaire to record symptoms and negative impacts of HPN and completed the validated Optum® SF-36v2® Health Survey with the patients. RESULTS: Seventy patients (50% women) on HPN were included. HPN commonly affected feelings of dependency (n = 49, 70%), traveling/leaving home (n = 37, 53%), attending cultural and social events (n = 25, 36%), and sleep (n = 22, 31%). Most frequently reported symptoms were diarrhea (n = 30, 43%), polyuria (n = 28, 40%), nausea/emesis (n = 27, 39%), dysgeusia (n = 23, 33%), and cramps (n = 20, 29%). At baseline, mean (standard deviation) SF-36v2® physical and mental health component summary scores (PCS and MCS) were 45 (20) and 57 (19), respectively, and there was a trend toward improvement in PCS over the study period, while MCS remained stable. Satisfaction with health care professionals involved in HPN care was high. CONCLUSION: QOL is a crucial and decisive aspect of HPN patient care. Symptoms related to the underlying disease and PN are frequent. Impaired social life and an ambivalent attitude toward the life-saving therapy are major concerns for these patients and should be addressed in their care.

Attitudes and expectations of patients on home parenteral nutrition towards eHealth: A multicenter survey.

BACKGROUND & AIMS: Advances in technology enable patients on home parenteral nutrition (HPN) to manage their treatment more independently and safely. eHealth is a promising application of electronic means in healthcare, aimed at improving and simplifying processes and connecting the different parties involved. A thorough understanding of the attitudes and expectations of patients on HPN towards eHealth is a prerequisite for a successful implementation. However, to the best of our knowledge, such a survey preceding the implementation of HPN specific eHealth care has never been conducted. The objective of this preliminary survey is the acquisition of insights on the attitudes and expectations of patients on HPN towards eHealth. Resulting findings then serve as the basis for the design of an eHealth platform to facilitate communication among those involved in HPN care, improve the HPN management, and safeguard and monitor the treatment. METHODS: We conducted a survey on the attitudes and expectations of patients towards an envisioned eHealth platform for HPN. Patients were recruited from large Swiss hospitals by their treating physician or directly by the research team. The surveys were conducted between September 2020 and October 2021 by structured personal interviews based on a questionnaire. RESULTS: We included 35 patients on HPN (21 [60%] females) treated in ambulant care of 4 hospitals. They had a median (interquartile range) age of 55 (18) years and a median (interquartile range) duration of parenteral nutrition of 1.3 (3.1) years. Most patients (n = 30, 86%) were equipped with a smartphone, tablet, or computer and 22 (63%) used apps and rated themselves as proficient with the corresponding digital device. A majority of patients rated the following aspects and features of the platform as important: Data collection and storage (n = 29, 83%), checklists for PN, catheter, and infusion pump handling (n = 28, 80%), video instructions (n = 27, 77%), and videoconferencing with physicians (n = 25, 71%). Most patients (n = 26, 74%) were willing to enter data into the platform themselves. The type of data to be entered should be defined on an individual basis. CONCLUSIONS: Patients on HPN are open to videoconference consultations and using an eHealth platform. Two-thirds have the necessary technical skills including suitable digital devices for an eHealth care. We identified key features of an eHealth platform to improve HPN management.

Discovery and Structure-Activity Relationship Studies of Novel Adenosine A1 Receptor-Selective Agonists.

A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists N6-cyclopentyl adenosine (CPA) and N6-cyclopentyl 5'-N-ethylcarboxamidoadenosine (CP-NECA) were synthesized, and their potency and selectivity were assessed. We observed that the most potent were the compounds with a halogen in the meta position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed greater A1R selectivity than the adenosine-based compounds, with N6-2-(3-bromobenzyloxy)cyclopentyl-NECA and N6-2-(3-methoxyphenoxy)cyclopentyl-NECA showing ∼1500-fold improved A1R selectivity compared to NECA. In addition, we quantified the compounds' affinity and kinetics of binding at both human and rat A1R using a NanoBRET binding assay and found that the halogen substituent in the benzyloxy- or phenoxycyclopentyl moiety seems to confer high affinity for the A1R. Molecular modeling studies suggested a hydrophobic subpocket as contributing to the A1R selectivity displayed. We believe that the identified selective potent A1R agonists are valuable tool compounds for adenosine receptor research.

Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression.

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A1 receptors (A1Rs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists. We have discovered that the A1R-selective agonist, benzyloxy-cyclopentyladenosine (BnOCPA), is a potent and powerful analgesic but does not cause sedation, bradycardia, hypotension or respiratory depression. This unprecedented discrimination between native A1Rs arises from BnOCPA's unique and exquisitely selective activation of Gob among the six Gαi/o subtypes, and in the absence of ß-arrestin recruitment. BnOCPA thus demonstrates a highly-specific Gα-selective activation of the native A1R, sheds new light on GPCR signalling, and reveals new possibilities for the development of novel therapeutics based on the far-reaching concept of selective Gα agonism.

Management of Home Parenteral Nutrition: Complications and Survival.

BACKGROUND AND AIMS: Parenteral nutrition (PN) has become an efficient, safe, and convenient treatment over years for patients suffering from intestinal failure. Home PN (HPN) enables the patients to have a high quality of life in their own environment. The therapy management however implies many restrictions and potentially severe lethal complications. Prevention and therapy of the latter are therefore of utmost importance. This study aims to assess and characterize the situation of patients with HPN focusing on prevalence of catheter-related complications and mortality. METHODS: Swiss multicentre prospective observational study collecting demographic, anthropometric, and catheter-related data by means of questionnaires every sixth month from 2017 to 2019 (24 months), focusing on survival and complications. Data were analysed using descriptive statistics. Logistic regression models were fitted to investigate association between infection and potential co-factors. RESULTS: Seventy adult patients (50% women) on HPN were included (≈5 patients/million adult inhabitants/year). The most common underlying diseases were cancer (23%), bariatric surgery (11%), and Crohn's disease (10%). The most prevalent indication was short bowel syndrome (30%). During the study period, 47% of the patients were weaned off PN; mortality rate reached 7% for a median treatment duration of 1.31 years. The rate of catheter-related infection was 0.66/1,000 catheter-days (0.28/catheter-year) while the rate of central venous thrombosis was 0.13/1,000 catheter-days (0.05/catheter-year). CONCLUSION: This prospective study gives a comprehensive overview of the adult Swiss HPN patient population. The collected data are prerequisite for evaluation, comparison, and improvement of recommendations to ensure best treatment quality and safety.

Characterization of Novel Fluorescent Bile Salt Derivatives for Studying Human Bile Salt and Organic Anion Transporters.

Bile salts, such as cholate, glycocholate, taurocholate, and glycochenodeoxycholate, are taken up from the portal blood into hepatocytes via transporters, such as the Na+-taurocholate-cotransporting polypeptide (NTCP) and organic anion-transporting polypeptides (OATPs). These bile salts are later secreted into bile across the canalicular membrane, which is facilitated by the bile salt export pump (BSEP). Apart from bile salt transport, some of these proteins (e.g., OATPs) are also key transporters for drug uptake into hepatocytes. In vivo studies of transporter function in patients by using tracer compounds have emerged as an important diagnostic tool to complement classic liver parameter measurements by determining dynamic liver function both for diagnosis and monitoring progression or improvement of liver diseases. Such approaches include use of radioactively labeled bile salts (e.g., for positron emission tomography) and fluorescent bile salt derivatives or dyes (e.g., indocyanine green). To expand the list of liver function markers, we synthesized fluorescent derivatives of cholic and chenodeoxycholic acid by conjugating small organic dyes to the bile acid side chain. These novel fluorescent probes were able to block substrate transport in a concentration-dependent manner of NTCP, OATP1B1, OATP1B3, OATP2B1, BSEP, and intestinal apical sodium-dependent bile salt transporter (ASBT). Whereas the fluorescent bile acid derivatives themselves were transported across the membrane by OATP1B1, OATP1B3, and OATP2B1, they were not transport substrates for NTCP, ASBT, BSEP, and multidrug resistance-related protein 2. Accordingly, these novel fluorescent bile acid probes can potentially be used as imaging agents to monitor the function of OATPs. SIGNIFICANCE STATEMENT: Synthetic modification of common bile acids by attachment of small organic fluorescent dyes to the bile acid side chain resulted in bright, fluorescent probes that interact with hepatic and intestinal organic anion [organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, OATP2B1], bile salt uptake (Na+-taurocholate-cotransporting polypeptide, apical sodium-dependent bile salt transporter), and bile salt efflux (bile salt export pump, multidrug resistance-related protein 2) transporters. Although the fluorescent bile salt derivatives are taken up into cells via the OATPs, the efflux transporters do not transport any of them but one.

Deciphering the Agonist Binding Mechanism to the Adenosine A1 Receptor.

Despite being among the most characterized G protein-coupled receptors (GPCRs), adenosine receptors (ARs) have always been a difficult target in drug design. To date, no agonist other than the natural effector and the diagnostic regadenoson has been approved for human use. Recently, the structure of the adenosine A1 receptor (A1R) was determined in the active, Gi protein complexed state; this has important repercussions for structure-based drug design. Here, we employed supervised molecular dynamics simulations and mutagenesis experiments to extend the structural knowledge of the binding of selective agonists to A1R. Our results identify new residues involved in the association and dissociation pathway, they suggest the binding mode of N6-cyclopentyladenosine (CPA) related ligands, and they highlight the dramatic effect that chemical modifications can have on the overall binding mechanism, paving the way for the rational development of a structure-kinetics relationship of A1R agonists.

Mapping the Orthosteric Binding Site of the Human 5-HT3 Receptor Using Photo-cross-linking Antagonists.

The serotonin-gated 5-HT3 receptor is a ligand-gated ion channel. Its location at the synapse in the central and peripheral nervous system has rendered it a prime pharmacological target, for example, for antiemetic drugs that bind with high affinity to the neurotransmitter binding site and prevent the opening of the channel. Advances in structural biology techniques have led to a surge of disclosed three-dimensional receptor structures; however, solving ligand-bound high-resolution 5-HT3 receptor structures has not been achieved to date. Ligand binding poses in the orthosteric binding site have been largely predicted from mutagenesis and docking studies. We report the synthesis of a series of photo-cross-linking compounds whose structures are based on the clinically used antiemetic drug granisetron (Kytril). These displaced [3H]granisetron from the orthosteric binding site with low nanomolar affinities and showed specific photo-cross-linking with the human 5-HT3 receptor. Detailed analysis by protein-MS/MS identified a residue (Met-228) near the tip of binding loop C as the covalent modification site.

The binding orientations of structurally-related ligands can differ; A cautionary note.

Crystal structures can identify ligand-receptor interactions and assist the development of novel therapeutics, but experimental challenges sometimes necessitate the use of homologous proteins. Tropisetron is an orthosteric ligand at both 5-HT3 and α7 nACh receptors and its binding orientation has been determined in the structural homologue AChBP (pdbid: 2WNC). Co-crystallisation with a structurally-related ligand, granisetron, reveals an almost identical orientation (pdbid; 2YME). However, there is a >1000-fold difference in the affinity of tropisetron at 5-HT3 versus α7 nACh receptors, and α7 nACh receptors do not bind granisetron. These striking pharmacological differences prompt questions about which receptor the crystal structures most closely represent and whether the ligand orientations are correct. Here we probe the binding orientation of tropisetron and granisetron at 5-HT3 receptors by in silico modelling and docking, radioligand binding on cysteine-substituted 5-HT3 receptor mutants transiently expressed in HEK 293 cells, and synthetic modification of the ligands. For 15 of the 23 cysteine substitutions, the effects on tropisetron and granisetron were different. Structure-activity relationships on synthesised derivatives of both ligands were also consistent with different orientations, revealing that contrary to the crystallographic evidence from AChBP, the two ligands adopt different orientations in the 5-HT3 receptor binding site. Our results show that even quite structurally similar molecules can adopt different orientations in the same binding site, and that caution may be needed when using homologous proteins to predict ligand binding.

Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes.

Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-Benzylated l-threo-ß-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy.

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.

A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.

Management of Home Parenteral Nutrition: A Prospective Multicenter Observational Study.

BACKGROUND: There are no specific Swiss home parenteral nutrition (HPN) data showing patient characteristics, quality of life (QoL) and complications. The goal of this study was to collect representative nationwide data on current adult HPN patients in Switzerland for international comparability and benchmarking. METHODS: This was a multicenter, nationwide, observational study. We conducted interviews for demographics, PN characteristics, QoL and complications. The data were assessed at baseline and after a follow-up of 3 months using a questionnaire. RESULTS: Thirty-three adult patients were included. The most common underlying diseases were cancer, radiation enteritis and state after bariatric surgery, and the most prevalent indication was short bowel syndrome. During the 3-month observation period, significant increase or stabilization of body weight occurred in the patients, physical activity scores improved from 34.0 to 39.4 and mental scores improved from 41.9 to 46.4. HPN dependency and traveling restrictions were of the greatest concern. Diarrhea, xerostomia and/or thirst were frequent complaints. CONCLUSION: Anthropometric parameters and QoL improved during the observational period in this HPN cohort. These Swiss HPN data are prerequisite for evaluation and comparison of HPN recommendations and best clinical practice, status of professional care instructions related to HPN effectiveness, quality of treatment and patient safety.

[The overheated lunch]. / Das hitzige Mittagessen.

We report about three patients consulting a general practitioner with acute onset of allergy-like clinical signs after having consumed tuna fish salad in the same restaurant. The treatment with antihistamines and steroids was effective and induced a quick regression of the symptoms. We look at considerations regarding the differential diagnosis and explain the pathophysiologic and the biochemical mechanisms of scombrotoxicosis.

Nous rapportons le cas de trois patients qui se présentent dans un cabinet médical souffrant de symptômes de type allergique après la consommation d'une salade de thon dans le même restaurant. Un traitement d'antihistaminiques et de stéroïdes s'est révélé efficace avec une rapide régression des symptômes. Nous proposons une réflexion sur le diagnostic différentiel et ses conséquences. En autre nous expliquons les mécanismes pathophysiologiques et biochimiques de la scombrotoxicose.

Safe refeeding management of anorexia nervosa inpatients: an evidence-based protocol.

OBJECTIVE: Anorexia nervosa is associated with several serious medical complications related to malnutrition, severe weight loss, and low levels of micronutrients. The refeeding phase of these high-risk patients bears a further threat to health and potentially fatal complications. The objective of this study was to examine complications due to refeeding of patients with anorexia nervosa, as well as their mortality rate after the implementation of guidelines from the European Society of Clinical Nutrition and Metabolism. METHODS: We analyzed retrospective, observational data of a consecutive, unselected anorexia nervosa cohort during a 5-y period. The sample consisted of 65 inpatients, 14 were admitted more than once within the study period, resulting in 86 analyzed cases. RESULTS: Minor complications associated with refeeding during the first 10 d (replenishing phase) were recorded in nine cases (10.5%), four with transient pretibial edemas and three with organ dysfunction. In two cases, a severe hypokalemia occurred. During the observational phase of 30 d, 16 minor complications occurred in 14 cases (16.3%). Six infectious and 10 non-infectious complications occurred. None of the patients with anorexia nervosa died within a follow-up period of 3 mo. CONCLUSIONS: Our data demonstrate that the seriousness and rate of complications during the replenishment phase in this high-risk population can be kept to a minimum. The findings indicate that evidence-based refeeding regimens, such as our guidelines are able to reduce complications and prevent mortality. Despite anorexia nervosa, our sample were affected by serious comorbidities, no case met the full diagnostic criteria for refeeding syndrome.

[Practical scores for the detection of malnutrition]. / Praxisnahe Scores für die Erfassung der Mangelernährung.

Malnutrition occurs in 30 - 60 % of hospitalized medical or surgical patients, as well as out-patients. Serious consequences at various levels were observed. Malnutrition influences negatively the quality of life, the immune system, muscle strength and worsens the prognosis of the patient. Interventions for a rapid and simple identification and effective treatment of this condition are essential and cost saving. Screening tools for the identification of patients at nutritional risk are very useful in daily practice. The systematic identification of patients with potential or apparent malnutrition is very important allowing an effective nutritional treatment at an early time. The medical team in charge should perform the nutritional risk screening and the following assessment to recognize the nutritional problems and to solve them in an interdisciplinary and -professional team.

Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport.

2-Aminoethyl diphenylborinate (2-APB) is a known modulator of the IP3 receptor, the calcium ATPase SERCA, the calcium release-activated calcium channel Orai and TRP channels. More recently, it was shown that 2-APB is an efficient inhibitor of the epithelial calcium channel TRPV6 which is overexpressed in prostate cancer. We have conducted a structure-activity relationship study of 2-APB congeners to understand their inhibitory mode of action on TRPV6. Whereas modifying the aminoethyl moiety did not significantly change TRPV6 inhibition, substitution of the phenyl rings of 2-APB did. Our data show that the diaryl borinate moiety is required for biological activity and that the substitution pattern of the aryl rings can influence TRPV6 versus SOCE inhibition. We have also discovered that 2-APB is hydrolyzed and transesterified within minutes in solution.

The SLC1 high-affinity glutamate and neutral amino acid transporter family.

Glutamate transporters play important roles in the termination of excitatory neurotransmission and in providing cells throughout the body with glutamate for metabolic purposes. The high-affinity glutamate transporters EAAC1 (SLC1A1), GLT1 (SLC1A2), GLAST (SLC1A3), EAAT4 (SLC1A6), and EAAT5 (SLC1A7) mediate the cellular uptake of glutamate by the co-transport of three sodium ions (Na(+)) and one proton (H(+)), with the counter-transport of one potassium ion (K(+)). Thereby, they protect the CNS from glutamate-induced neurotoxicity. Loss of function of glutamate transporters has been implicated in the pathogenesis of several diseases, including amyotrophic lateral sclerosis and Alzheimer's disease. In addition, glutamate transporters play a role in glutamate excitotoxicity following an ischemic stroke, due to reversed glutamate transport. Besides glutamate transporters, the SLC1 family encompasses two transporters of neutral amino acids, ASCT1 (SLC1A4) and ASCT2 (SLC1A5). Both transporters facilitate electroneutral exchange of amino acids in neurons and/or cells of the peripheral tissues. Some years ago, a high resolution structure of an archaeal homologue of the SLC1 family was determined, followed by the elucidation of its structure in the presence of the substrate aspartate and the inhibitor d,l-threo-benzyloxy aspartate (d,l-TBOA). Historically, the first few known inhibitors of SLC1 transporters were based on constrained glutamate analogs which were active in the high micromolar range but often also showed off-target activity at glutamate receptors. Further development led to the discovery of l-threo-ß-hydroxyaspartate derivatives, some of which effectively inhibited SLC1 transporters at nanomolar concentrations. More recently, small molecule inhibitors have been identified whose structures are not based on amino acids. Activators of SLC1 family members have also been discovered but there are only a few examples known.

[Sausage or carrot--spoilt for choice]. / Cervelat oder rüebli--die qual der wahl!

As far as healthy food is concerned, it cannot be categorized simply as "good" or "bad" since its effect on health depends mainly on the amount and method consumed. Today's recommendations include a diversified diet, a diet which targets energy-balance and provides all nutrients necessary. Living in an affluent society aggravates healthy choices because of a constantly available, large assortment of food items. In general, the way food is prepared these days has changed a lot: mainly, the energy content has constantly increased, while the fiber and natural micronutrient concentrations decreased. Food items with a high energy yield, containing a lot of fat and sugar, affects our energy balance, which may lead to diseases of affluence such as type 2 diabetes, cardiovascular diseases, and some kinds of tumors.

Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk.

PURPOSE: The hypothesis of this clinical study was to determine whether glucocorticoid use and immobility were associated with in-hospital nutritional risk. METHODS: One hundred and one patients consecutively admitted to the medical wards were enrolled. Current medical conditions, symptoms, medical history, eating and drinking habits, diagnosis, laboratory findings, medications, and anthropometrics were recorded. The Nutrition Risk Score 2002 (NRS-2002) was used as a screening instrument to identify nutritional risk. RESULTS: The results confirmed that glucocorticoid use and immobility are independently associated with nutritional risk determined by the NRS-2002. Constipation could be determined as an additional cofactor independently associated with nutritional risk. CONCLUSIONS: Glucocorticoid treatment, immobility, and constipation are associated with nutritional risk in a mixed hospitalized population. The presence of long-time glucocorticoid use, immobility, or constipation should alert the clinician to check for nutritional status, which is an important factor in mortality and morbidity.