Discovery and Optimization of Pyridazinones as PI3Kδ Selective Inhibitors for Administration by Inhalation.

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2H)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved. Intratracheal administration of lead compound 26 resulted in a promising pharmacokinetic profile, thus demonstrating that the optimization strategy of in vitro profiles successfully translated to an in vivo setting.

[Polytrauma and Acute Kidney Injury: A Multidisciplinary Approach].

The development of acute kidney injury (AKI) in polytrauma patients is a common and serious complication, with an incidence ranging from 6% to 50%. Polytrauma is a complex pathological condition that involves the collaboration of various specialists. On one hand, hemodynamic stabilization through fluid therapy and aminic support, with specific attack protocols, managed by anesthetists. On the other hand, if necessary, the initiation of renal replacement therapy such as Continuous Renal Replacement Therapy (CRRT), managed by nephrologists. CRRT is chosen both for managing fluid balance and ensuring the removal of toxic substances, as well as for proper control of electrolytes and acid-base balance.

Use of CFTR Modulators for Cystic Fibrosis in a Patient with Liver Transplant and ESRD on Hemodialysis.

Cystic fibrosis is an autosomal recessive disorder caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most recent therapeutic approach to cystic fibrosis aims to correct structural and functional abnormalities of CFTR protein. CFTR modulators including ivacaftor-tezacaftor-elexacaftor are used in patients with F508del mutation, with clinical improvement. To date, there are no experiences of CFTR modulator therapy in cystic fibrosis patients with organ transplantation and severe renal impairment. We report the case of a patient diagnosed with cystic fibrosis with F508del mutation, who underwent liver transplantation at the age of 19 and started hemodialysis at the age of 24 due to end-stage renal disease secondary to membranous glomerulonephritis. She was treated with Kaftrio (ivacaftor-tezacaftor-elexacaftor) with clinical benefits on appetite, improvement of body mass index, and reduction of pulmonary exacerbations. A reduction of dosage to 75% of the standard dose was required due to alterations of the liver function. Conclusions. Use of CFTR modulators in patient with cystic fibrosis, liver transplant and end-stage renal disease could be considered safe but a clinical and laboratoristic monitoring of hepatic function is needed.

[Acute kidney injury in severely burned patient: prevention and treatment].

Acute Kidney Injury (AKI) is associated with a great increase in morbidity and mortality in severely burned patients and occurs as a complication in more than 25% of these cases. The onset of ARF may be early or late. Early AKI depends mainly on reduced cardiac output resulting from fluid loss, rhabdomyolysis, or hemolysis. Late AKI, instead, is usually a consequence of sepsis and is often associated with multiorgan failure (MOF). The first sign of AKI is the contraction of diuresis despite adequate volemic filling, which is followed by elevation of serum urea and creatinine. Fluid therapy is the main treatment in the burned victim: in the first few hours after injury, it aims to avoid hypovolemic shock and the possible related MOF, while later it becomes the cornerstone of treatment, besides antibiotic therapy in the case of sepsis onset. Particular care must also be taken in the choice of administered drugs in order to avoid possible nephrotoxic damage in addition to burning injury. Hemodialytic renal replacement therapy is used both for water balance management in patients requiring massive fluid infusions and for blood purification purposes to control the metabolic state, acid-base balance, and electrolytes abnormality. Our team has been collaborating for over 25 years in the management of severely burned patients admitted to the Centro Grandi Ustionati at the Bufalini Hospital in Cesena.

Application of an "inhalation by design" approach to the identification and in-vitro evaluation of novel purine based PI3Kδ inhibitors.

PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kδ selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates.

Antibody Responses after Two Doses of COVID-19 mRNA Vaccine in Dialysis and Kidney Transplantation Patients Recovered from SARS-CoV-2 Infection.

Background and Objectives: Hemodialysis patients (HD) and kidney transplant recipients (KTRs) have been heavily impacted by COVID-19, showing increased risk of infection, worse clinical outcomes, and higher mortality rates than the general population. Although mass vaccination remains the most successful measure in counteracting the pandemic, less evidence is available on vaccine effectiveness in immunodepressed subjects previously infected and recovered from COVID-19. Materials and Methods: This study aimed at investigating the ability to develop an adequate antibody response after vaccination in a 2-dose series against SARS-CoV-2 in HD patients and KTR that was administered after laboratory and clinical recovery from COVID-19. Results: Comparing SARS-CoV-2 S1/S2 IgG levels measured before and after 2 doses of mRNA vaccine (BNT162b2 vaccine, Comirnaty, Pfizer-BioNTech or mRNA-1273 vaccine, Spikevax, Moderna), highly significant increases of antibody titers were observed. The antibody peak level was reached at 3 months following second dose administration, regardless of the underlying cause of immune depression and the time of pre-vaccine serology assessment after negativization. Conclusions: Our data indicate that HD patients and KTR exhibit a satisfying antibody response to a 2-dose series of mRNA vaccine, even in cases when infection-induced humoral immunity was poor or rapidly fading. Further studies are needed to evaluate the role of booster doses in conferring effective and durable protection in weak patient categories.

Persistence of Antibody Responses to the SARS-CoV-2 in Dialysis Patients and Renal Transplant Recipients Recovered from COVID-19.

Nephropathic subjects with impaired immune responses show dramatically high infection rates of coronavirus disease 2019 (COVID-19). This work evaluated the ability to acquire and maintain protective antibodies over time in 26 hemodialysis patients and 21 kidney transplant recipients. The subjects were followed-up through quantitative determination of circulating SARS-CoV-2 S1/S2 IgG and neutralizing antibodies in the 6-month period after clinical and laboratory recovery. A group of 143 healthcare workers with no underlying chronic pathologies or renal diseases recovered from COVID was also evaluated. In both dialysis and transplanted patients, antibody titers reached a zenith around the 3rd month, and then a decline occurred on average between the 270th and 300th day. Immunocompromised patients who lost antibodies around the 6th month were more common than non-renal subjects, although the difference was not significant (38.5% vs. 26.6%). Considering the decay of antibody levels below the positivity threshold (15 AU/mL) as "failure", a progressive loss of immunisation was found in the overall population starting 6 months after recovery. A longer overall antibody persistence was observed in severe forms of COVID-19 (p = 0.0183), but within each group, given the small number of patients, the difference was not significant (dialysis: p = 0.0702; transplant: p = 0.1899). These data suggest that immunocompromised renal patients recovered from COVID-19 have weakened and heterogeneous humoral responses that tend to decay over time. Despite interindividual variability, an association emerged between antibody persistence and clinical severity, similar to the subjects with preserved immune function.

COVID-19 Infection: Viral Clearance and Antibody Response in Dialysis Patients and Renal Transplant Recipients.

BACKGROUND/AIMS: The coronavirus disease 2019 (CO-VID-19) pandemic is the major current health emergency worldwide, adding a significant burden also to the community of nephrologists for the management of their patients. Here, we analyzed the impact of COVID-19 infection in renal patients to assess the time to viral clearance, together with the production and persistence of IgG and IgM antibody response, in consideration of the altered immune capacity of this fragile population. METHODS: Viral clearance and antibody kinetics were investigated in 49 renal patients recovered from COVID-19 infection: 7 of them with chronic decompensated renal failure, 31 under dialysis treatment, and 11 kidney transplant recipients. RESULTS: The time span between the diagnosis of infection and recovery based on laboratory testing (2 negative nasopharyngeal swabs in consecutive days) was 31.7 ± 13.3 days. Three new positive cases were detected from 8 to 13 days following recovery. At the first serological determination after swab negativization, all the patients developed IgG and IgM antibodies. The semiquantitative analysis showed a progressive increase in IgG and a slow reduction in IgM. DISCUSSION/CONCLUSION: In subjects with decompensated chronic kidney disease, under dialysis and in transplant recipients, viral clearance is lengthened compared to the general population. However, in spite of their common status of immunodepression, all of them were able to produce specific antibodies. These data might provide useful insights for monitoring and planning health-care activities in the weak category of patients with compromised renal function recovered from COVID-19.

[Resilience in COVID-19 times: general considerations on the recovery of a 93-year-old patient on haemodialysis treatment].

We report the case of a 93-year-old woman on haemodialysis treatment for more than 30 months and with multiple comorbidities who recovered from a Covid-19 infection without any significant clinical problems. The patient has shown a delay in viral clearance with swab test negativization (confirmed) after 33 days; after testing positive again, she has resulted persistently negative, (confirmed after 49 days). After the first negative swab, IgG and IgM antibodies have been found; these have remained persistently positive after a month. As well as highlighting an unexpected resilience in an extremely fragile context, the analysis of this case draws attention to patients' management and, potentially, to the need to arrange dialysis treatments in isolation for some time after their "laboratory recovery".

Bloodstream infections and patient survival with tunneled-cuffed catheters for hemodialysis: A single-center observational study.

BACKGROUND: In hemodialysis patients, a tunneled-cuffed permanent catheter is mandatory when the arteriovenous fistula is not feasible. The major risks of the use of tunneled-cuffed permanent catheter are bloodstream infections. The aim of this study is to analyze bloodstream infections from tunneled-cuffed permanent catheter in hemodialysis patients. METHODS: An observational prospective study was carried out and 79 hemodialysis patients with tunneled-cuffed permanent catheter were enrolled. Patients were divided into those with bloodstream infections from tunneled-cuffed permanent catheter and those without. Their clinical and laboratory characteristics were compared. An original tunneled-cuffed permanent catheter lock therapy sequence was carried out combined with systemic antibiotic therapy. In case of antibiotic resistance, the tunneled-cuffed permanent catheter was removed. RESULTS: The patients affected by bloodstream infections from tunneled-cuffed permanent catheter were 16/79 (20.3%). The bloodstream infection from tunneled-cuffed permanent catheter's incidence rate was 0.52 per 1000 catheter days. Twenty-three bloodstream infections from tunneled-cuffed permanent catheter were found in 16/79 patients who used tunneled-cuffed permanent catheter. Staphylococcus aureus was the cause of bloodstream infection from tunneled-cuffed permanent catheter in 35% of the cases and Staphylococcus epidermidis in 30% of the cases. Risk factors were infection located in other organs and the presence of peripheral obstructive arterial disease. CONCLUSION: The enrolled cohort showed a reduced bloodstream infection from tunneled-cuffed permanent catheter incidence rate in comparison with the reference value (1 per 1000 catheter days). To reduce the number of bloodstream infections from tunneled-cuffed permanent catheter, hand hygiene and asepsis management of the tunneled-cuffed permanent catheter during the connection to the extracorporeal circuit and an original tunneled-cuffed permanent catheter lock therapy sequence seem to be the most efficient measures. Infections of other organs and the presence of peripheral obstructive arterial disease are the most important risk factors for bloodstream infections from tunneled-cuffed permanent catheter.

Dissecting the structure of thiopeptides: assessment of thiazoline and tail moieties of baringolin and antibacterial activity optimization.

Several analogues of baringolin (1) were prepared to evaluate the role of its characteristic thiazoline ring and pentapeptidic tail with the aim of defining structure-activity relationships for these moieties. The thiazoline ring appeared as a crucial moiety to maintain a broad scope of activities against different Gram-positive bacteria. Further modifications were performed to simplify the structure of the natural product and assess the role of its tail, resulting in an enhanced in vitro performance. Analogue 25, with the thiazole-containing macrocycle and a 4-aminocyclohexane-1-carboxylic acid moiety in place of the pentapeptidic tail, was identified as a much more potent analogue, capable of overcoming the absence of the thiazoline ring and performing extraordinarily well against all strains tested. This is the first library of thiopeptide analogues produced by chemical synthesis alone, which demonstrates the robustness and convenience of the synthetic strategy used.

The champion: Conquering the challenges of bipolar disorders

@#<p style="text-align: justify;">Bipolar Disorder has been one of the leading psychiatric conditions here in the Philippines. . It is characterized by mood swings from profound depression to extreme euphoria (mania), with intervening period of normal mood (euthymia). The frequency, duration, and severity of manic and/or depressive episodes varies and is unique to each individual (Haber, 1997). In general, there are five in every 100 Filipinos who are suffering from some form of depression, and other may have a different reaction such as hyperactivity or swinging from depression to euphoria, unable to function normally, and in real danger of hurting themselves and others. Sadly, many of those with bipolar illness are left undiagnosed and, consequently, untreated. This case study presents how nurses play a role in helping patients overcome the challenges of having a psychiatric illness particularly those with Bipolar Disorder. </p>

Total synthesis and stereochemical assignment of baringolin.

The thiopeptide antibiotic baringolin has been synthesized, and its structure and stereochemistry have been confirmed. The use of a strategy based on palladium-catalyzed cross-couplings permitted a modular construction of this natural product.

Stereodivergent strategy for neurofuran synthesis via palladium-catalyzed asymmetric allylic cyclization: total synthesis of 7-epi-ST-Δ(8)-10-neurofuran.

Neurofurans are formed in vivo in the human brain as a consequence of an increased oxidative stress, and they could be valuable biomarkers of the neuronal oxidative stress. In this paper, an enantioselective stereodivergent approach to two key neurofuran precursors, belonging to the AC and ST classes, has been developed starting from a single achiral precursor, the meso-diol 11. The absolute configuration of the THF cores was secured by a Pd-catalyzed asymmetric allylic alkylation using (S,S)-L1 and (R,R)-L2 ligands, respectively.

Total synthesis of aeruginazole A.

The first total synthesis of Aeruginazole A, prepared via a convergent strategy that involved both solid-phase peptide synthesis and solution phase chemistry and that enabled conservation of the stereochemistry of the intermediates, is reported.

Improved synthesis of (E)-12-nitrooctadec-12-enoic acid, a potent PPARγ activator. Development of a "buffer-free" enzymatic method for hydrolysis of methyl esters.

Endogenous nitro-fatty acids, acting as partial agonist of PPARγ, are able to lower the insulin and glucose levels without the side effects associated with common antidiabetic drugs. (E)-12-Nitrooctadec-12-enoic acid, a potent activator of this peroxisome receptor, was synthesized in a very efficient sequence via a Henry-retro-Claisen ring fragmentation, followed by a novel enzymatic cleavage of methyl esters. The latter method was then applied in the last step of the synthesis of a few labile natural products, such as prostaglandins, isoprostanes, and phytoprostanes.

Primer reporte de Phoneutrismo en el Perú. Presentación de dos casos / First case reports of phoneutrism in Peru. Presentation of two cases

Se presentan dos casos de mordedura de la araña Phoneutria spp. atendidos en el Hospital Nacional Cayetano Heredia (HNCH) en los años 2005 y 2008. En ambos casos la mordedura fue de sintomatología leve y de buena evolución, y se debió a un accidente laboral en personas que trabajan en mercados de venta de fruta al extraerplátanos de cajas procedentes de Tingo María (Selva central). El phoneutrismo es un accidente por arácnidos poco común; sin embargo, sería un problema importante de salud pública sobretodo en las zonas rurales en donde el comercio de plátanos es una de las principales fuente de ingresos de la población. El personal médico no conoce del todo a esta araña, así como la clínica de sus mordeduras, por ello presentamos estos casos que permitirán reconocer estos accidentes para su adecuado manejo y control.

We present two cases of Phoneutria spp. spiderbite seen at the Hospital Nacional Cayetano Heredia (HNCH) in 2005 and 2008 respectively. In both cases, the bite had few symptoms with a good evolution, and occured as work related accidents in fruit market sales people while extracting bananas from Tingo Maria (central peruvian jungle).Phoneutrism is a relatively common accidental bite; nevertheless it can become an important public health problem in the rural zones where banana trade is one of main income sources for the local population. Medical personnel in the area is mostly unaware of this spider or of the clinical picture its bite produces We hope, by presenting these two cases, to allow them to recognize these accidents for its appropriate diagnosis, management and control.

Determination of polycyclic aromatic hydrocarbons (PAHs) in particulate matter collected with low volume samplers.

The determination of polycyclic aromatic hydrocarbons (PAHs) contained in samples of particulate matter (PM), collected with low volume pumps, were carried out with an high sensitivity method that comes from several revisions of a previous method. The present work describes how, by using programmable temperature vaporization (PTV) and a mass selective detector with inert ionic source for the GC-MS analysis and the modifications of microwave-assisted extraction (MAE), the sensitivity of the method can be increased. The PAHs chosen for testing the method are: benzo[a]anthracene (BaA), benzo[b]fluoranthene (BbF), benzo[k]fluoranthene (BkF), benzo[a]pyrene (BaP), indeno[1,2,3-cd]pyrene (Ip) and dibenzo[a,h]anthracene (DbA). They, in fact, belong to that group of substances that are the most harmful for human health for their carcinogenicity. PAHs recoveries for spiked standard solutions at different concentrations were between 95 and 100% with relative standard deviation ranging from 1 to 3%. The revised method was validated using a 1649a urban dust standard reference material (SRM). The results obtained were in good agreement with certified values. The high sensitivity of the method allows to carry out analyses using only a half of the sampled filter (usually 47mm diameter membranes). In this way, the other half can be used for the characterization of the other components of PM (heavy metals, organic carbon, ions, etc). The last step has been constituted by application of the optimized method on real samples collected in two cities located in Southern Italy (Bari and Taranto).

Multiregion bicentric-spheres models of the head for the simulation of bioelectric phenomena.

Equations are derived for the electric potentials [electroencephalogram (EEG)] produced by dipolar sources in a multiregion bicentric-spheres volume-conductor head model. Being the equations valid for an arbitrary number of regions, our proposal is a generalization of many spherical models presented so far in literature, each of those regarded as a particular case of our multiregion model. Moreover, our approach allows considering new features of the head volume-conductor to better approximate electrical properties of the real head.

Head model extension for the study of bioelectric phenomena.

Bioelectrical phenomena spread within the whole body (the conductor medium) independently of electrical source position within the body. However, under certain circumstances, it is possible to limit the volume within which the study can be done. Given its high resistivity, the skull limits the spread of bioelectrical currents due to brain sources and it leaves only few holes for current flow, namely the occipital hole and the openings for the optic nerves. This is a simulation study performed adopting realistic head models extended to different percentages of the whole head volume conductor to determine the possibility of limiting the model volume for bioelectric field analysis. A realistic head model extended to the chin was used as reference model to analyze three reduced model extensions: 80% of the volume of the reference model (including the neck upper part), 70% (including all the skull but not the neck) and 60% (cutting the head at cerebellum level). The lower limit of the reduced model was named "cut-plane". We simulated the head electrical potential generated by various dipole current sources within the brain, either far from or near the cut-plane and either orthogonal or parallel to it. The scalp potential distributions were compared between each reduced model and the reference model by means of relative-difference measure (RDM). The larger differences were found for sources near the cut-plane and for sources orthogonal to it. The differences increased non linearly with model volume reduction, dramatically augmenting as the skull was intercepted by the cut-plane. The same model performed differently according to source position relative to the particular head structure.