Purine nucleoside phosphorylase (PNP) is an intracellular enzyme crucial for purine degradation. PNP defects result in metabolic abnormalities and fatal T cell immunodeficiency. Protein transduction domains (PTD) transfer molecules across biological membranes. We hypothesized that fusion of PTD to PNP (PTD-PNP) would be an effective method for treating PNP deficiency. We find that PTD-PNP rapidly enters PNP-deficient lymphocytes and increases intracellular enzyme activity for 96 h. Similar to endogenous PNP, PTD-PNP is predominantly distributed in the cytoplasm. PTD-PNP improve viability and correct abnormal functions of PNP-deficient T lymphocytes including their response to stimulation and IL-2 secretion. Intracellular transduction protects PTD-PNP from antibody neutralization and from elimination, which may also provide significant in vivo therapeutic advantages to PNP. In conclusion, PTD fusion is an attractive method for extended PNP intracellular enzyme replacement therapy for PNP-deficient patients as well as for the intracellular delivery of other proteins.

Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro.

Cellular Immunology

Management of type 2 diabetes is advancing beyond glycemic control and is increasingly based on cardiovascular risk stratification. This review summarizes recent advances in the field and identifies existing knowledge gaps and areas of ongoing research.

A bibliographic search was carried out in PubMed for recently published cardiorenal outcome trials, relevant guidelines, and studies on antidiabetic agents in the pipeline.

Findings from cardiovascular outcome trials support the use of glucagon-like peptide 1 (GLP-1) receptor agonists or sodium-glucose cotransporter 2 (SGLT-2) inhibitors for patients with established cardiovascular disease or multiple risk factors, although it as yet remains uncertain whether the benefits are transferable to patients at lower absolute cardiovascular risk. Additionally, robust evidence suggests that SGLT-2 inhibitors improve clinical outcomes for people with concomitant heart failure or chronic kidney disease. Gut hormone multiagonists will likely represent another major addition to the therapeutic armamentarium for morbidly obese individuals with diabetes. Moreover, nonalcoholic fatty liver disease is a common comorbidity and several liver outcome trials are awaited with great interest. Use of insulin as first-line injectable therapy has been displaced by GLP-1 receptor agonists. Once-weekly formulations of basal insulins along with combinations with GLP-1 receptor agonists are also under development and could increase patient convenience. Technologies of glucose sensors are rapidly evolving and have the potential to reduce the burden of frequent blood glucose measurements, mainly for patients treated with intensified insulin regimens.

Management of type 2 diabetes requires a holistic approach and recent breakthroughs are expected to improve the quality of care.

Management of type 2 diabetes in the new era.

Hormones : International Journal of Endocrinology and Metabolism

Most of the evidences for beneficial effects of beta-blockers in patients with acute myocardial infarction (AMI) were from the clinical studies published in the pre-reperfusion era when anti-platelet drugs, statins or inhibitors of renin-angiotensin-aldosterone system which are known to reduce cardiovascular mortality of patients with AMI were not introduced. In the reperfusion era, beta-blockers' benefit has not been clearly shown except in patients with reduced ejection fraction (EF; &#x2264;40%). In the era of the early reperfusion therapy for AMI, a number of patients with mildly reduced EF (&gt;40%, &lt;50%) or preserved EF (&#x2265;50%) become increasing. However, because no randomized clinical trials are available until now, the benefit and the optimal duration of oral treatment with beta-blockers in patients with mildly reduced or preserved EF are questionable. Registry data have not showed the association of oral beta-blocker therapy with decreased mortality in survivors without heart failure or left ventricular systolic dysfunction after AMI. In the Korea Acute Myocardial Infarction Registry-National Institute of Health of in-hospital survivors after AMI, the benefit of beta-blocker therapy at discharge was shown in patients with reduced or mildly reduced EF, but not in those with preserved EF, which provides new information about beta-blocker therapy in patients without reduced EF. However, clinical practice can be changed when the results of appropriate randomized clinical trials are available. Ongoing clinical trials may help to answer the unresolved issues of beta-blocker therapy in patients with AMI.

Beta-blocker therapy in patients with acute myocardial infarction: not all patients need it.

Acute and critical care.

The International Society on Thrombosis and Haemostasis (ISTH) released overt disseminated intravascular coagulation (DIC) diagnostic criteria in 2001. Since then, DIC has been understood as the end-stage consumptive coagulopathy and not the therapeutic target. However, DIC is not merely a decompensated coagulation disorder, but also includes early stages with systemic activation in coagulation. Thus, the ISTH has recently released sepsis-induced coagulopathy (SIC) criteria that can diagnose compensated-phase of coagulopathy with readily available biomarkers.

DIC is a laboratory-based diagnosis due to various critical conditions, although sepsis is the most common underlying disease. The pathophysiology of sepsis-associated DIC is multifactorial, and in addition to coagulation activation with suppressed fibrinolysis, multiple inflammatory responses are initiated by activated leukocytes, platelets, and vascular endothelial cells as part of thromboinflammation. Although overt DIC diagnostic criteria were established by ISTH to diagnose the advanced stage of DIC, additional criteria that can detect an earlier stage of DIC were needed for potential therapeutic considerations. Accordingly, the ISTH introduced SIC criteria in 2019 that are easy to use and require only platelet count, prothrombin time-international normalized ratio, and Sequential Organ Failure Assessment Score. SIC score can be used to evaluate disease severity and determine the timing of potential therapeutic interventions. One of the major disadvantages in treating sepsis-associated DIC is the lack of availability of specific therapeutic approaches beyond treating the underlying infection. Clinical trials to date have failed because included patients who were not coagulopathic. Nevertheless, in addition to infection control, anticoagulant therapy will be the choice for sepsis-associated DIC. Therefore, the efficacy of heparin, antithrombin, and recombinant thrombomodulin has to be proven in future clinical studies.

It is necessary to develop a novel therapeutic strategy against sepsis-associated DIC and improve the outcomes. Consequently, we recommend screening and monitoring DIC using SIC scoring system.

The pathophysiology, diagnosis, and management of sepsis-associated disseminated intravascular coagulation.

Journal of Intensive Care

Abdominal wall closure.

British Journal of Surgery

This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and&#xa0;aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies.

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement.

Nature Reviews. Endocrinology

Hyperkalemia (HK) is a life-threatening condition that often occurs in patients with chronic kidney disease (CKD). High serum potassium (sKsK) is responsible for a higher risk of end-stage renal disease, arrhythmias and mortality. This risk increases in patients that discontinue cardio-nephroprotective renin-angiotensin-aldosterone system inhibitor (RAASi) therapy after developing HK. Hence, the management of HK deserves the attention of the clinician in order to optimize the therapeutic strategies of chronic treatment of HK in the CKD patient. The adoption in clinical practice of the new hypokalaemic agents patiromer and sodium zirconium cyclosilicate (SZC) for the prevention and chronic treatment of HK could allow patients, suffering from heart failure and chronic renal failure, to continue to benefit from RAASi therapy. We have updated a narrative review of the clear variables, correct definition, epidemiology, pathogenesis, etiology and classifications for HK among non-dialysis CKD (ND CKD) patients. Furthermore, by describing the prognostic impact on mortality and on the progression of renal damage, we want to outline the strategies currently available for the control of potassium (K+) plasma levels.

Hyperkalemia in CKD: an overview of available therapeutic strategies.

Frontiers in Medicine

Sodium glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like-peptide-1 receptor (GLP-1-R) agonists are novel therapeutic agents used for the management of type 2 diabetes mellitus (T2DM). Recently, large-scale randomized clinical trials have been conducted to assess the cardiovascular safety of these medications. The findings of these trials have revealed that both SGLT2 inhibitors and GLP-1-R agonists exhibit favorable cardioprotective effects, including reduction in cardiovascular and all-cause mortality, a decreased risk of chronic kidney disease progression, a decrease in hospitalization for heart failure (HF), an effect shown by SGLT2 inhibitors, and stroke prevention, an effect shown by GLP-1-R agonists. Based on the results from above studies, the European and American Diabetes Associations have issued new recommendations strongly endorsing the use of SGLT2 inhibitors and GLP-1-R agonists in combination with metformin for patients with T2DM who have additional cardiovascular (CV) comorbidities or risk factors. The primary aim of this combined therapy is to prevent CV events. Although both medication groups offer beneficial effects, they demonstrate slightly different profiles. SGLT2 inhibitors have exhibited better effects regarding a reduced incidence of HF, whereas GLP-1-R agonists have shown a reduced risk of CV events, particularly stroke. Moreover, recent European Society of Cardiology as well as American College of Cardiology and American Heart Association guidelines of HF treatment stressed the importance of SGLT2 inhibitor administration in patients with HF regardless of T2DM. In this context, we present and discuss the outcomes of the most recent trials investigating the impact of SGLT2 inhibitors and GLP-1-R agonists on renal and cardiovascular outcomes in patients, both with and without T2DM. Additionally, we explore the synergistic effects of combining SGLT2 inhibitors and GLP-1-R agonists in patients with cardiovascular disease.

SGLT2 Inhibitors vs. GLP-1 Agonists to Treat the Heart, the Kidneys and the Brain.

Journal of Cardiovascular Development and Disease

To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD).

One hundred and seven patients with diagnosis of prion disease (60 with definite sCJD, 33 with probable sCJD and 14 with genetic prion disease) and 40 non-prion related RPD patients (npRPD) underwent brain MRI including DWI and FLAIR. MRIs were evaluated with a semiquantitative rating score, which separately considered abnormal signal extent and intensity in 22 brain regions. Clinical findings at onset, disease duration, cerebrospinal-fluid 14-3-3 and t-tau protein levels, and EEG data were recorded.

Among patients with definite/probable diagnosis of CJD or genetic prion disease, 2/107 had normal DWI-MRI: in one patient a 2-months follow-up DWI-MRI showed CJD-related changes while the other had autopsy-proven CJD despite no DWI abnormalities 282&#xa0;days after clinical onset. CJD-related cortical changes were detected in all lobes and involvement of thalamus was common. In the npRPD groups, 6/40 patients showed DWI alterations that clustered in three different patterns: (1) minimal/doubtful signal alterations (limbic encephalitis, dementia with Lewy bodies); (2) clearly suggestive of alternative diagnoses (status epilepticus, Wernicke or metabolic encephalopathy); (3) highly suggestive of CJD (mitochondrial disease), though cortical swelling let exclude CJD.

In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. The pulvinar sign is not exclusive of the variant form.

Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro.

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Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro.

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