A rating scale for drug-induced akathisia has been derived that incorporates diagnostic criteria for pseudoakathisia, and mild, moderate, and severe akathisia. It comprises items for rating the observable, restless movements which characterise the condition, the subjective awareness of restlessness, and any distress associated with the akathisia. In addition, there is an item for rating global severity. A standard examination procedure is recommended. The inter-rater reliability for the scale items (Cohen's kappa) ranged from 0.738 to 0.955. Akathisia was found in eight of 42 schizophrenic in-patients, and nine had pseudoakathisia, where the typical sense of inner restlessness was not reported.

A rating scale for drug-induced akathisia

Diabetic kidney disease is the leading cause of kidney failure worldwide; in the USA, it accounts for over 50% of individuals entering dialysis or transplant programmes. Unlike other complications of diabetes, the prevalence of diabetic kidney disease has failed to decline over the past 30 years. Hyperglycaemia is the primary aetiological factor responsible for the development of diabetic kidney disease. Once hyperglycaemia becomes established, multiple pathophysiological disturbances, including hypertension, altered tubuloglomerular feedback, renal hypoxia, lipotoxicity, podocyte injury, inflammation, mitochondrial dysfunction, impaired autophagy and increased activity of the sodium–hydrogen exchanger, contribute to progressive glomerular sclerosis and the decline in glomerular filtration rate. The quantitative contribution of each of these abnormalities to the progression of diabetic kidney disease, as well as their role in type 1 and type 2 diabetes mellitus, remains to be determined. Sodium–glucose co-transporter 2 (SGLT2) inhibitors have a beneficial impact on many of these pathophysiological abnormalities; however, as several pathophysiological disturbances contribute to the onset and progression of diabetic kidney disease, multiple agents used in combination will likely be required to slow the progression of disease effectively. Multiple pathophysiological disturbances contribute to the onset and progression of diabetic kidney disease (DKD). This Review describes these pathogenic processes and discusses the ability of sodium–glucose co-transporter 2 (SGLT2) inhibitors to correct or improve many of these processes, which are likely to underlie the ability of these agents to slow progression of established diabetic kidney disease.

http://www-nature-com-443.webvpn.bjmu.tsg211.com/articles/s41581-021-00393-8.pdf

Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors.

In animals, physical activity has been shown to induce functional and structural changes especially in the hippocampus and to improve memory, probably by upregulating the release of neurotrophic factors. In humans, results on the effect of acute exercise on memory are inconsistent so far. Therefore, the aim of the present study was to assess the effects of a single bout of physical exercise on memory consolidation and the underlying neuroendocrinological mechanisms in young adults. Participants encoded a list of German-Polish vocabulary before exercising for 30 minutes with either high intensity or low intensity or before a relaxing phase. Retention of the vocabulary was assessed 20 minutes after the intervention as well as 24 hours later. Serum BDNF and salivary cortisol were measured at baseline, after learning, and after the intervention. The high-intensity exercise group showed an increase in BDNF and cortisol after exercising compared to baseline. Exercise after learning did not enhance the absolute number of recalled words. Participants of the high-intensity exercise group, however, forgot less vocabulary than the relaxing group 24 hours after learning. There was no robust relationship between memory scores and the increase in BDNF and cortisol, respectively, suggesting that further parameters have to be taken into account to explain the effects of exercise on memory in humans.

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The Effects of Acute Physical Exercise on Memory, Peripheral BDNF, and Cortisol in Young Adults

Background Globally, diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. As the most common microvascular complication of diabetes, DKD is a thorny, clinical problem in terms of its diagnosis and management. Intensive glucose control in DKD could slow down but not significantly halt disease progression. Revisiting the tremendous advances that have occurred in the field would enhance recognition of DKD pathogenesis as well as improve our understanding of translational science in DKD in this new era. Scope of review In this review, we summarize advances in the understanding of the local microenvironmental changes in diabetic kidneys and discuss the involvement of genetic and epigenetic factors in the pathogenesis of DKD. We also review DKD prevalence changes and analyze the challenges in optimizing the diagnostic approaches and management strategies for DKD in the clinic. As we enter the era of ‘big data’, we also explore the possibility of linking systems biology with translational medicine in DKD in the current healthcare system. Major conclusion Newer understanding of the structural changes of diabetic kidneys and mechanisms of DKD pathogenesis, as well as emergent research technologies will shed light on new methods of dealing with the existing clinical challenges of DKD.

Diabetic kidney diseases revisited: A new perspective for a new era.

BackgroundAccumulating evidence shows that a propensity towards a pro-inflammatory status in the brain plays an important role in schizophrenia. Anti-inflammatory drugs might compensate this propensity. This study provides an update regarding the efficacy of agents with some anti-inflammatory actions for schizophrenia symptoms tested in randomized controlled trials (RCTs).MethodsPubMed, Embase, the National Institutes of Health website (http://www.clinicaltrials.gov), and the Cochrane Database of Systematic Reviews were systematically searched for RCTs that investigated clinical outcomes.ResultsOur search yielded 56 studies that provided information on the efficacy of the following components on symptom severity: aspirin, bexarotene, celecoxib, davunetide, dextromethorphan, estrogens, fatty acids, melatonin, minocycline, N-acetylcysteine (NAC), pioglitazone, piracetam, pregnenolone, statins, varenicline, and withania somnifera extract. The results of aspirin [mean weighted effect size (ES): 0.30; n = 270; 95% CI (CI) 0.06-0.54], estrogens (ES: 0.78; n = 723; CI 0.36-1.19), minocycline (ES: 0.40; n = 946; CI 0.11-0.68), and NAC (ES: 1.00; n = 442; CI 0.60-1.41) were significant in meta-analysis of at least two studies. Subgroup analysis yielded larger positive effects for first-episode psychosis (FEP) or early-phase schizophrenia studies. Bexarotene, celecoxib, davunetide, dextromethorphan, fatty acids, pregnenolone, statins, and varenicline showed no significant effect.ConclusionsSome, but not all agents with anti-inflammatory properties showed efficacy. Effective agents were aspirin, estrogens, minocycline, and NAC. We observed greater beneficial results on symptom severity in FEP or early-phase schizophrenia.

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An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis

Introduction: Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in diabetes and is the most common cause of proteinuric and non-proteinuric forms of end-stage renal disease (ESRD). Control of risk factors such as blood glucose and blood pressure is not always achievable or effective. Significant research efforts have attempted to understand the pathophysiology of DKD and develop new therapies. Areas covered: We review DKD pathophysiology in the context of existing and emerging therapies that affect hemodynamic and metabolic pathways. Renin-angiotensin system (RAS) inhibition has become standard care. Recent evidence for renoprotective activity of SGLT2 inhibitors and GLP-1 agonists is an exciting step forward while endothelin receptor blockade shows promise. Multiple metabolic pathways of DKD have been evaluated with varying success; including mitochondrial function, reactive oxygen species, NADPH oxidase (NOX), transcription factors (NF-B and Nrf2), advanced glycation, protein kinase C (PKC), aldose reductase, JAK-STAT, autophagy, apoptosis-signaling kinase 1 (ASK1), fibrosis and epigenetics. Expert opinion: There have been major advances in the understanding and treatment of DKD. SGLT2i and GLP-1 agonists have demonstrated renoprotection, with novel therapies under evaluation. Addressing the interaction between hemodynamic and metabolic pathways may help achieve prevention, attenuation or even reversal of DKD.

Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies

A systematic review of the impact of oral contraceptives on cognition.

Combined oral contraceptives (OCs) are the most commonly prescribed medication in women of reproductive age, but despite widespread use, their effect on cognitive performance remains controversial. Given strong evidence for the neurological impact of reproductive hormones, a clear rationale for investigation exists. This systematic review sought to identify, collate and critically appraise studies assessing the impact of OCs on cognition in healthy premenopausal women. Ovid MEDLINE, PsychINFO and EMBASE were comprehensively searched using relevant keywords for original peer-reviewed observational studies or randomised trials published after 1960. Of 1289 references screened, 22 studies were eligible for inclusion. Assembled evidence supports a cognitive impact of OCs restricted to specific domains; however, the quality of evidence is poor. The most consistent finding is improved verbal memory with OC use. Evidence is also emerging that differing progestin androgenicity may lead diverse OC formulations to differentially impact certain cognitive domains, such as visuospatial ability. At present, evidence is inconclusive, contradictory and limited by methodological inconsistencies. There is scope for further research in this area to definitively determine the cognitive impact of OCs.

Review article A systematic review of the impact of oral contraceptives on cognition

Importance A substantial proportion of women with schizophrenia experience debilitating treatment-refractory symptoms. The efficacy of estrogen in modulating brain function in schizophrenia has to be balanced against excess exposure of peripheral tissue. Raloxifene hydrochloride is a selective estrogen receptor modulator (mixed estrogen agonist/antagonist) with potential psychoprotective effects and fewer estrogenic adverse effects. Objective To determine whether adjunctive raloxifene therapy reduces illness severity in women with refractory schizophrenia. Design, Setting, and Participants This 12-week, double-blind, placebo-controlled, randomized clinical trial with fortnightly assessments was performed at an urban tertiary referral center and a regional center from January 1, 2006, to December 31, 2014. Participants included 56 women with schizophrenia or schizoaffective disorder and marked symptom severity despite substantial and stable antipsychotic doses. Data were analyzed using intention to treat as the basis. Interventions Adjunctive raloxifene hydrochloride, 120 mg/d, or placebo for 12 weeks. Main Outcomes and Measures The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score. Clinical response (defined as a ≥20% decrease in PANSS total score from baseline) and change in PANSS subscale scores, mood, cognition, reproductive hormone levels, and adverse events were also assessed. Results Of the 56 participants (mean [SD] age, 53 [7.7] years; age range, 40-70 years; mean [SD] duration of psychotic illness, 24 [11] years), 26 were randomized to raloxifene and 30 were randomized to placebo. Raloxifene produced a greater reduction in the PANSS total score relative to placebo (β = −6.37; 95% CI, −11.64 to −1.10;P = .02) and resulted in an increased probability of a clinical response (hazard ratio, 5.79; 95% CI, 1.46 to 22.97;P = .01). A significant reduction was found in the PANSS general symptom scores for the raloxifene compared with the placebo (β = −3.72; 95% CI, −6.83 to −0.61;P = .02) groups. For patients who completed the full 12-week trial, there was not a statistically significant treatment effect on PANSS positive symptom scores (β for change in raloxifene vs placebo, −1.92; 95% CI, −3.83 to 0.00;P = .05). Change in mood, cognition, and reproductive hormone levels and the rate of adverse events did not differ between groups. Conclusions and Relevance Raloxifene hydrochloride, 120 mg/d, reduces illness severity and increases the probability of a clinical response in women with refractory schizophrenia. This large trial of raloxifene in this patient population offers a promising, well-tolerated agent that has potential application in clinical practice. Trial Registration clinicaltrials.gov Identifier:NCT00361543

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Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial

Oral contraceptives (OCs) containing estrogen and progesterone analogues are widely used amongst reproductive-aged women, but their neurocognitive impact is poorly understood. Preliminary studies suggest that OCs improve verbal memory and that OCs with greater androgenic activity may improve visuospatial ability. We sought to explore the cognitive impact of OCs by assessing performance of OC users at different stages of the OC cycle, and comparing this performance between users of different OC formulations according to known androgenic activity. We conducted a prospective, observational trial of OC users, evaluating cognitive performance with CogState software on two occasions: days 7-10 of active hormonal pill phase, and days 3-5 of the inactive pill phase (coinciding with the withdrawal bleed resembling menstruation). Thirty-five OC users (18 taking androgenic formulations, 17 taking anti-androgenic) were assessed. Analysis by androgenic activity showed superior performance by users of androgenic OCs, as compared to anti-androgenic OCs, in visuospatial ability and facial affect discrimination tasks. A growing understanding of cognitive effects of OC progestin androgenicity may have implications in choice of OC formulation for individuals and in future OC development.

https://www.mdpi.com/2076-3425/10/4/194/pdf

Annabelle M. Warren

Papers

Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies

A systematic review of the impact of oral contraceptives on cognition.

Review article A systematic review of the impact of oral contraceptives on cognition

Effect of Adjunctive Raloxifene Therapy on Severity of Refractory Schizophrenia in Women: A Randomized Clinical Trial

Effects of Oral Contraceptive Androgenicity on Visuospatial and Social-Emotional Cognition: A Prospective Observational Trial.