Management of hypertension and renin-angiotensin-aldosterone system blockade in adults with diabetic kidney disease: Association of British Clinical Diabetologists and the Renal Association UK guideline update 2021.

People with type 1 and type 2 diabetes are at risk of developing progressive chronic kidney disease (CKD) and end-stage kidney failure. Hypertension is a major, reversible risk factor in people with diabetes for development of albuminuria, impaired kidney function, end-stage kidney disease and cardiovascular disease. Blood pressure control has been shown to be beneficial in people with diabetes in slowing progression of kidney disease and reducing cardiovascular events. However, randomised controlled trial evidence differs in type 1 and type 2 diabetes and different stages of CKD in terms of target blood pressure. Activation of the renin-angiotensin-aldosterone system (RAAS) is an important mechanism for the development and progression of CKD and cardiovascular disease. Randomised trials demonstrate that RAAS blockade is effective in preventing/ slowing progression of CKD and reducing cardiovascular events in people with type 1 and type 2 diabetes, albeit differently according to the stage of CKD. Emerging therapy with sodium glucose cotransporter-2 (SGLT-2) inhibitors, non-steroidal selective mineralocorticoid antagonists and endothelin-A receptor antagonists have been shown in randomised trials to lower blood pressure and further reduce the risk of progression of CKD and cardiovascular disease in people with type 2 diabetes. This guideline reviews the current evidence and makes recommendations about blood pressure control and the use of RAAS-blocking agents in different stages of CKD in people with both type 1 and type 2 diabetes.

Management of adults with diabetes on the haemodialysis unit: summary of guidance from the Joint British Diabetes Societies and the Renal Association.

Diabetic nephropathy remains the principal cause of end-stage renal failure in the UK and its prevalence is set to increase. People with diabetes and end-stage renal failure on maintenance haemodialysis are highly vulnerable, with complex comorbidities, and are at high risk of adverse cardiovascular outcomes, the leading cause of mortality in this population. The management of people with diabetes receiving maintenance haemodialysis is shared between diabetes and renal specialist teams and the primary care team, with input from additional healthcare professionals providing foot care, dietary support and other aspects of multidisciplinary care. In this setting, one specialty may assume that key aspects of care are being provided elsewhere, which can lead to important components of care being overlooked. People with diabetes and end-stage renal failure require improved delivery of care to overcome organizational difficulties and barriers to communication between healthcare teams. No comprehensive guidance on the management of this population has previously been produced. These national guidelines, the first in this area, bring together in one document the disparate needs of people with diabetes on maintenance haemodialysis. The guidelines are based on the best available evidence, or on expert opinion where there is no clear evidence to inform practice. We aim to provide clear advice to clinicians caring for this vulnerable population and to encourage and improve education for clinicians and people with diabetes to promote empowerment and self-management.

Elevated plasma il-8 concentration is related to severity of systemic inflammation in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is associated with activation of acute phase response. Questions arise regarding its association with other inflammatory mediators. To determine plasma IL-8 concentration in CSU patients and its association with C-reactive protein (CRP) concentration, a nonspecific inflammatory marker of the disease activity, concentrations of plasma IL-8 and serum CRP were measured in CSU patients and compared with healthy controls. IL-8 and CRP concentrations were significantly higher in CSU patients as compared with the healthy subjects. In addition, there were significant differences in IL-8 and CRP concentrations between CSU patients with moderate-severe symptoms and the healthy subjects. Plasma IL-8 and serum CRP concentrations showed a significant correlation with urticaria activity score (UAS). Additionally, a significant positive correlation was observed between IL-8 and CRP concentrations. Up-regulations of IL-8 and its association with the marker of clinical and inflammatory activity suggest a role of this cytokine in the pathogenesis of CSU.

Acute dissociative reaction to spontaneous delivery in a case of total denial of pregnancy: Diagnostic and forensic aspects.

This article presents the history of a 21-year-old female college student with total denial of pregnancy who experienced an acute dissociative reaction during the spontaneous delivery at home without medical assistance where the newborn died immediately. Psychiatric examination, self-report questionnaires, legal documents, and witness reports have been reviewed in evaluation of the case. Evidence pointed to total denial of pregnancy, that is, until delivery. The diagnoses of an acute dissociative reaction to stress (remitted) and a subsequent PTSD were established in a follow-up examination conducted 7 months after the delivery. Notwithstanding the inherently dissociative nature of total denial of pregnancy, no other evidence has been found about pre-existing psychopathology. For causing the newborn's death, the patient faced charges for "aggravated murder," which were later on reduced into "involuntary manslaughter." Given the physical incapacity to perform voluntary acts due to the loss of control over her actions during the delivery, and the presence of an acute dissociative reaction to unexpected delivery, the legal case represents an intricate overlap between "insanity" and "incapacitation" defenses. The rather broad severity spectrum of acute dissociative conditions requires evaluation of the limits and conditions of appropriate legal defenses by mental health experts and lawyers. Denial of pregnancy as a source of potential stress has attracted little interest in psychiatric literature although solid research exists which documented that it is not infrequent. Arguments are presented to introduce this condition as a diagnostic category of female reproductive psychiatry with a more neutral label: "unperceived pregnancy."

Assessment of complex dissociative disorder patients and simulated dissociation in forensic contexts.

Few assessors receive training in assessing dissociation and complex dissociative disorders (DDs). Potential differential diagnoses include anxiety, mood, psychotic, substance use, and personality disorders, as well as exaggeration and malingering. Individuals with DDs typically elevate on many clinical and validity scales on psychological tests, yet research indicates that they can be distinguished from DD simulators. Becoming informed about the testing profiles of DD individuals and DD simulators can improve the accuracy of differential diagnoses in forensic settings. In this paper, we first review the testing profiles of individuals with complex DDs and contrast them with DD simulators on assessment measures used in forensic contexts, including the Minnesota Multiphasic Personality Inventory-2 (MMPI-2), Personality Assessment Inventory (PAI), and the Structured Inventory of Reported Symptoms (SIRS), as well as dissociation-specific measures such as the Dissociative Experiences Scale (DES) and Structured Clinical Interview for DSM-IV Dissociative Disorders (SCID-D-R). We then provide recommendations for assessing complex trauma and dissociation through the aforementioned assessments.

Foundation doctors working at night: what training opportunities exist?

INTRODUCTION: Foundation Training is designed for doctors in their first two years of post-graduation. The number of foundation doctors (FD) in the UK working nights has reduced because of a perception that clinical supervision at night is unsatisfactory and that minimal training opportunities exist. We aimed to assess the value of night shifts to FDs and hypothesised that removing FDs from nights may be detrimental to training. METHODS: Using a survey, we assessed the number of FDs working nights in London, FDs views on working nights and their supervision at night. We evaluated whether working at night, compared to daytime working provided opportunities to achieve foundation competencies. RESULTS: 83% (N = 2157/2593) of FDs completed the survey. Over 90% of FDs who worked nights felt that the experience they gained improved their ability to prioritise, make decisions and plan. FDs who worked nights reported higher scores for achieving competencies in history taking (2.67 vs. 2.51; p = 0.00), examination (2.72 vs. 2.59; p = 0.01) and resuscitation (2.27 vs. 1.96; p = 0.00). The majority (65%) felt adequately supervised. CONCLUSIONS: Our survey has demonstrated that FDs find working nights a valuable experience, providing important training opportunities, which are additional to those encountered during daytime working.

Improved blood pressure, nitric oxide and asymmetric dimethylarginine are independent after bariatric surgery.

BACKGROUND: Obesity is associated with hypertension, but the exact mechanism is not fully understood. Bariatric surgery significantly decreases weight and blood pressure (BP). Low plasma nitric oxide (NO) and raised asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO, concentrations are associated with both obesity and hypertension. Correlations between the changes in these parameters were studied after bariatric surgery. METHODS: Weight, BP, plasma ADMA and NO were measured in 29 obese patients (24 female, 5 male) before and six weeks after bariatric surgery. RESULTS: Patients were 39.2 ± 1.2 (mean ± SEM) years old and weighed 126 ± 3 kg. Six weeks after the surgery, patients had lost 10 ± 0.7 kg (P < 0.0001) and mean arterial pressure (MAP) decreased by 11 ± 1.0 mmHg (P < 0.0001). The plasma ADMA concentration decreased by 24 ± 2% from 5 ± 0.4 to 4.0 ± 0.3 µmol/L (P < 0.0001). The plasma total nitrite concentration increased by 15 ± 1% from 51.4 ± 2.6 to 60 ± 3 µmol/L (P < 0.0001). The correlation between the decrease of ADMA and increase of NO subsequent to weight loss was significant (P < 0.0001). However, MAP was not correlated to the changes in ADMA or NO. CONCLUSIONS: After bariatric surgery, beneficial changes in BP, NO and ADMA occur, but our findings suggest that these BP changes are independent of changes in the NO-ADMA axis. Other causes for the changes in BP should therefore be considered.

A new context-based approach to assess marine mammal behavioral responses to anthropogenic sounds.

Acute effects of anthropogenic sounds on marine mammals, such as from military sonars, energy development, and offshore construction, have received considerable international attention from scientists, regulators, and industry. Moreover, there has been increasing recognition and concern about the potential chronic effects of human activities (e.g., shipping). It has been demonstrated that increases in human activity and background noise can alter habitats of marine animals and potentially mask communications for species that rely on sound to mate, feed, avoid predators, and navigate. Without exception, regulatory agencies required to assess and manage the effects of noise on marine mammals have addressed only the acute effects of noise on hearing and behavior. Furthermore, they have relied on a single exposure metric to assess acute effects: the absolute sound level received by the animal. There is compelling evidence that factors other than received sound level, including the activity state of animals exposed to different sounds, the nature and novelty of a sound, and spatial relations between sound source and receiving animals (i.e., the exposure context) strongly affect the probability of a behavioral response. A more comprehensive assessment method is needed that accounts for the fact that multiple contextual factors can affect how animals respond to both acute and chronic noise. We propose a three-part approach. The first includes measurement and evaluation of context-based behavioral responses of marine mammals exposed to various sounds. The second includes new assessment metrics that emphasize relative sound levels (i.e., ratio of signal to background noise and level above hearing threshold). The third considers the effects of chronic and acute noise exposure. All three aspects of sound exposure (context, relative sound level, and chronic noise) mediate behavioral response, and we suggest they be integrated into ecosystem-level management and the spatial planning of human offshore activities.

Renal cytokines improve early after bariatric surgery.

BACKGROUND: Bariatric surgery has been suggested to improve arterial hypertension and renal function. This prospective controlled observational study aimed to investigate changes in renal inflammation, renal function and arterial blood pressure before and after bariatric surgery. METHODS: Blood pressure was measured, and urine and blood samples were collected from 34 morbidly obese patients before and 4 weeks after bariatric surgery. Serum levels of cystatin C, creatinine, albumin, cholesterol and C-reactive protein (CRP) were measured, along with urinary cytokine/creatinine ratios for macrophage migration inhibitory factor (MIF), monocyte chemotactic protein (MCP) 1, chemokine ligand (CCL) 18 and CCL-15. RESULTS: Mean(s.e.m.) bodyweight dropped from 124·1(2·6) to 114·8(2·4) kg (P < 0·001) and mean arterial blood pressure decreased from 105·7(1·8) to 95·5(1·2) mmHg (P < 0·001) in 4 weeks. Systemic and urinary inflammatory markers improved, with a reduction in serum CRP level (P < 0·001), and decreased urinary MIF/creatinine (P < 0·001), MCP-1/creatinine (P < 0·001) and CCL-18/creatinine (P = 0·003) ratios. In contrast, urinary CCL-15/creatinine ratios did not change and the glomerular filtration rate, measured by serum cystatin C, was unchanged (P = 0·615). CONCLUSION: Surgically induced weight loss contributed to a decrease in blood pressure and markers of renal inflammation. The reduced levels of CRP and urinary cytokines suggest that bariatric surgery attenuates systemic and renal inflammatory status.

Lymph node metastasis of medulloblastoma in a young adult.

Medulloblastoma is the commonest primary central nervous system malignancy in childhood, but is rare in adults. Rarer still is metastasis of such a tumour to a lymph node. This report describes such a case, and briefly discusses relevant pathophysiology and epidemiology.

Anti-CD3 recombinant diphtheria immunotoxin therapy of cutaneous T cell lymphoma.

The recombinant CD3 immunotoxin, A-dmDT(390)-bisFv(UCHT1), composed of the catalytic and translocation domains of diphtheria toxin fused to two single chain Fv fragments of an anti-CD3epsilon monoclonal antibody was administered to five patients with cutaneous T cell lymphoma (CTCL) by eight 15 min intravenous infusions over four days. Side effects were fever, chills, nausea, hypoalbuminemia, transaminasemia and reactivation of EBV and CMV. Half-life of drug was 40 min. Anti-immunotoxin antibodies developed in all patients after two weeks. Two patients had partial remissions lasting 1 and 6+ months. The agent is undergoing further dose escalation and shows promising results in this disease.

Sequence assembly.

Despite the rapidly increasing number of sequenced and re-sequenced genomes, many issues regarding the computational assembly of large-scale sequencing data have remain unresolved. Computational assembly is crucial in large genome projects as well for the evolving high-throughput technologies and plays an important role in processing the information generated by these methods. Here, we provide a comprehensive overview of the current publicly available sequence assembly programs. We describe the basic principles of computational assembly along with the main concerns, such as repetitive sequences in genomic DNA, highly expressed genes and alternative transcripts in EST sequences. We summarize existing comparisons of different assemblers and provide a detailed descriptions and directions for download of assembly programs at: http://genome.ku.dk/resources/assembly/methods.html.

Autophagy regulates selective HMGB1 release in tumor cells that are destined to die.

Macroautophagy (hereafter referred to as autophagy) can increase or decrease the amount of cell death in response to various stimuli. To test whether autophagy also controls the characteristics associated with dying cells, we studied tumor cell killing by epidermal growth factor receptor-targeted diphtheria toxin (DT-EGF). DT-EGF kills epithelial and glioblastoma tumor cells with similar efficiency but by different mechanisms that depend on whether the cells activate autophagy when treated with the drug. Dying cells in which autophagy is induced selectively release the immune modulator high-mobility group B1 (HMGB1) without causing lysis of the cell membrane and classical necrosis. Conversely, cells that are killed by DT-EGF where autophagy is blocked, activate caspases but retain HMGB1. These data suggest that it may be feasible to manipulate the immunogenicity of dying cells by increasing or decreasing autophagy.

Temporary access and central venous catheters.

The use of central venous catheters for temporary vascular access is a vital part of modern medicine and has an important role in the management of patients with renal failure. Attention to detail when addressing issues relating to temporary venous access, will pay dividends, with significant reductions in morbidity and mortality in both the short and long term.

Induction of apoptosis by tumor cell-targeted toxins.

Targeted toxins are fusion proteins that combine a targeting molecule that selectively binds to and enters tumor cells with a protein toxin that kills the target cells. These molecules represent an exciting approach to develop effective cancer-specific therapeutics that have few side effects on normal tissues and numerous such toxins are in various stages of pre-clinical and clinical development to treat a wide variety of tumors. In this review, we discuss this strategy, describe ways that the toxins activate the apoptosis machinery and discuss future developments in this field.

Diphtheria toxin-interleukin-3 fusion protein (DT(388)IL3) prolongs disease-free survival of leukemic immunocompromised mice.

The novel fusion protein DT(388)IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT(388)) fused with a Met-His linker to human interleukin 3 (IL-3), was tested for anti-leukemia efficacy in an in vivo model of differentiated human acute myeloid leukemia (AML). Six-week-old female SCID mice were irradiated with 350 cGy, inoculated 24 h later with 20 million (i.v., i.p., or s.c.) TF1 cells transfected with the v-SRC oncogene, and treated i.p., starting 24 h later, with up to five daily injections of saline, DT(388)IL3 (2 microg), DT(388)GMCSF (2 microg), DAB(389)IL2 (2 microg), or cytarabine (80 microg) or two weekly injections of anti-CD33-calicheamicin conjugate (5 microg). Animals were monitored twice daily, and moribund animals killed and necropsied. Control animals had a median disease-free survival (DFS) of 37 days (i.v., n = 45), 35 days (i.p., n = 20), and 21 days (s.c., n = 20), respectively. Only 5/49 (10%) of the DT(388)IL3 treated i.v. inoculated animals died with leukemia. Median DFS with i.v., i.p. and s.c. tumor inoculated animals was prolonged by fusion protein treatment to >120 days, 66 days and 31 days (P < 0.001, = 0.0003, and = 0.0006), respectively. Median DFS with s.c. tumor inoculated animals was also prolonged by other active anti-leukemia agents (DT(388)GMCSF, cytarabine and anti-CD33-calicheamicin) relative to controls by 67%, 172% and 47% (P < 0.0001, <0.0001, and =0.0004), respectively. In contrast, median DFS with s.c. tumor inoculated animals treated with DAB(389)IL2 non-significantly reduced by 13% relative to controls (P = 0.21). Thus, DT(388)IL3 fusion protein demonstrates in vivo anti-leukemia efficacy and warrants further preclinical development for treatment of chemo-resistant, IL-3 receptor positive AML patients.

Efficacy and safety of gemtuzumab ozogamicin in patients with poor-prognosis acute myeloid leukemia.

The objective of this work was to determine the safety and efficacy of gemtuzumab ozogamicin in patients with poor prognosis acute myeloid leukemia (AML). Patients with the following diagnoses/characteristics were treated with 1-3 infusions of gemtuzumab ozogamicin at a dose of 9 mg/m2: (1) relapse of AML < or = 6 months of first complete remission (CR); (2) AML refractory to chemotherapy at initial induction or at first relapse; (3) AML in second or greater relapse; (4) myeloid blast crisis of chronic myeloid leukemia (CML); (5) untreated patients > or = 70 years or > or = 55 years with abnormal cytogenetics (excluding inv 16, t(15;17) and t(8;21)) and/or an antecedent hematologic disorder; (6) refractory anemia with excess blasts in transformation (RAEBT). Forty-three patients, ages 19-84 (mean 62), were treated, including 7 patients with untreated AML age > 70 years, 2 with untreated RAEBT, 14 with AML first salvage (first remission 0-6 months), 15 with AML > or = second salvage and 14 with myeloid blast phase of CML. The overall response rate was 14%, with 4/43 (9%) patients achieving CR and 2/43 (5%) achieving CR without platelet recovery. The most significant toxicity was neutropenic fever, which occurred in 84% of patients. In conclusion, in patients with relapsed/refractory AML, gemtuzumab ozogamicin has a comparable response rate to single-agent chemotherapy and may offer a more favorable toxicity profile.

Chimeric fusion proteins--diphtheria toxin-based.

Most cancer patients receive chemotherapy drugs that target DNA or the cell division apparatus. Many of these patients develop multidrug-resistant tumor cells, thus, novel methods to overcome drug resistance are needed. One approach is to target tumor cell protein synthesis. Peptide toxins, which catalytically inactivate protein synthesis, have been re-engineered to selectively bind and intoxicate tumor cells. Diphtheria toxin (DT), a member of the class of peptide toxins, has been subjected to structural and genetic analysis and protein engineering for several decades. In this review, we will examine the structure, function, synthesis and pharmacology of anticancer DT conjugates.