Investigating the Generic Features of the Sudanese Judicial Precedents

This study aims at investigating the Sudanese criminal and civil judicial precedents so as to gain a better understanding of the communicative purposes of each subgenre and the variation in demands across the two subgenres using genre analysis. It adopted the mixed approach, using Maxqda application, to investigate the generic features, the moves, the sub-moves; as well as how problems are solved and decisions arrived at. The investigation shows that the law practitioners should know the intrinsic nature of these judicial precedents by examining their generic features, concepts, functions and approaches. Also, the analysis of the typical generic moves and sub-moves clearly reveals that the judicial precedents across the two subgenres have some overlapping generic structures at all levels.  Most of the judicial precedents in the corpus seem to have the typical generic move structures. The analysis of the specific generic move structures reveals slight generic differences of judicial precedents. Finally, there are still evidences of slight variation across the two subgenres at sub-move level

Management aspects of congenital adrenal hyperplasia during adolescence and transition to adult care

The adolescent period is characterised by fundamental hormonal changes, which affect sex steroid production, cortisol metabolism and insulin sensitivity. These physiological changes have a significant impact on patients with congenital adrenal hyperplasia (CAH). An essential treatment aim across the lifespan in patients with CAH is to replace glucocorticoids sufficiently to avoid excess adrenal androgen production but equally to avoid cardiometabolic risks associated with excess glucocorticoid intake. The changes to the hormonal milieu at puberty, combined with poor adherence to medical therapy, often result in unsatisfactory control exacerbating androgen excess and increasing the risk of metabolic complications due to steroid over‐replacement. With the physical and cognitive maturation of the adolescent with CAH, fertility issues and sexual function become a new focus of patient care in the paediatric clinic. This requires close surveillance for gonadal dysfunction, such as irregular periods/hirsutism or genital surgery‐associated symptoms in girls and central hypogonadism or testicular adrenal rest tumours in boys. To ensure good health outcomes across the lifespan, the transition process from paediatric to adult care of patients with CAH must be planned carefully and early from the beginning of adolescence, spanning over many years into young adulthood. Its key aims are to empower the young person through education with full disclosure of their medical history, to ensure appropriate follow‐up with experienced physicians and facilitate access to multispecialist teams addressing the complex needs of patients with CAH

One week of step reduction lowers myofibrillar protein synthesis rates in young men

Purpose Across the lifespan, physical activity levels decrease and time spent sedentary typically increases. However, little is known about the impact that these behavioral changes have on skeletal muscle mass regulation. The primary aim of this study was to use a step reduction model to determine the impact of reduced physical activity and increased sedentary time on daily myofibrillar protein synthesis rates in healthy young men. Methods Eleven men (22 ± 2 yr) completed 7 d of habitual physical activity (HPA) followed by 7 d of step reduction (SR). Myofibrillar protein synthesis rates were determined during HPA and SR using the deuterated water (2H2O) method combined with the collection of skeletal muscle biopsies and daily saliva samples. Gene expression of selected proteins related to muscle mass regulation and oxidative metabolism were determined via real time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results Daily step count was reduced by approximately 91% during SR (from 13,054 ± 2763 steps per day to 1192 ± 330 steps per day; P < 0.001) and this led to an increased contribution of sedentary time to daily activity (73% ± 6% to 90% ± 3%; P < 0.001). Daily myofibrillar protein synthesis decreased by approximately 27% from 1.39 ± 0.32%·d−1 during HPA to 1.01 ± 0.38%·d−1 during SR (P < 0.05). Muscle atrophy F-box and myostatin mRNA expression were upregulated, whereas mechanistic target of rapamycin, p53, and PDK4 mRNA expression were downregulated after SR (P < 0.05). Conclusions One week of reduced physical activity and increased sedentary time substantially lowers daily myofibrillar protein synthesis rates in healthy young men

Inflammation-based scores in patients with pheochromocytoma

Background: Pheochromocytoma is associated with systemic inflammation, but the underlying mechanisms are unclear. Therefore, we investigated the relationship between plasma metanephrine levels and haematological parameters – as a surrogate of inflammation – in patients with pheochromocytoma and the influence of preoperative α-blockade treatment.Design and Methods: We retrospectively studied 68 patients with pheochromocytoma who underwent adrenalectomy (median age 53 years, 64.7% females) and two control groups matched for age, sex, and body mass index (BMI): 68 patients with non-functioning adrenocortical tumors (NFAT) and 53 with essential hypertension (EAH). The complete blood count (CBC) and several inflammation-based scores [Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), Lymphocyte-to-Monocyte Ratio (LMR), Systemic-Immune-Inflammation Index (SII), Prognostic-Nutrition Index (PNI)] were assessed in all patients and, in a subset of pheochromocytomas, after adrenalectomy (n=26) and before and after preoperative α-blockade treatment (n=29).Results: A higher inflammatory state, as indicated by both CBC and inflammation-based scores, was observed in patients with pheochromocytoma compared to NFAT and EAH. Plasma metanephrine levels showed a positive correlation with NLR (r=0.4631), PLR (r=0.3174), SII (r=0.3709), and a negative correlation with LMR (r=0.4368) and PNI (r=0.3741), even after adjustment for age, sex, ethnicity, BMI and tumor size (except for PLR). After adrenalectomy, we observed a reduction in NLR (p=0.001), PLR (p=0.003), SII (p=0.004) and a concomitant increase in LMR (p=0.0002). Similarly, α-blockade treatment led to a reduction in NLR (p=0.007) and SII (p=0.03).Conclusions: Inflammation-based scores in patients with pheochromocytoma showed pro-inflammatory changes that correlated with plasma metanephrine levels and are ameliorated by adrenalectomy and α-blockade

Pheochromocytomas Most Commonly Present As Adrenal Incidentalomas:A Large Tertiary Center Experience

Context: Pheochromocytomas are increasingly diagnosed in incidentally detected adrenal masses. However, the characteristics of incidental pheochromocytomas are unclear.Objective: We aimed to assess the proportion and clinical, biochemical, radiological, genetic, histopathological, and follow-up characteristics of incidental pheochromocytomas.Methods: A retrospective review was conducted of patients with pheochromocytoma seen between January 2010 and October 2022 at a large UK tertiary care center. The diagnosis was confirmed histologically or by the combined presence of increased plasma and/or urinary metanephrines (MN), indeterminate adrenal mass on cross-sectional imaging, and metaiodobenzylguanidine avidity.Results: We identified 167 patients with pheochromocytoma; 144 (86.2%) underwent adrenalectomy, for 23 (13.8%) surgery was either awaited, deemed unsuitable due to frailty or other metastatic malignancy, or declined by the patients. Excluding pheochromocytomas diagnosed via screening genetically predisposed individuals (N = 20), 37 of 132 (28.0%) presented with adrenergic symptoms and/or uncontrolled hypertension, while 91 of 132 (69.0%) patients presented with an incidentally detected adrenal mass. Incidentally detected patients were older (median age 62 years) than those detected due to clinical suspicion (aged 42 years) or after genetic screening (aged 33 years) (all P &lt; .05). Incidentally detected pheochromocytomas were smaller (median 42 mm) than tumors detected due to adrenergic symptoms/uncontrolled hypertension (60 mm), but larger than tumors identified by genetic screening (30 mm) (all P &lt; .05). Increased MN excretion showed a similar pattern (symptomatic/uncontrolled hypertension &gt; incidental &gt; genetic screening) (all P &lt; .05). Hereditary predisposition was detected in 20.4% of patients (incidental, 15.3%; symptomatic/uncontrolled hypertension, 42.9%).Conclusion: The majority of pheochromocytomas are diagnosed incidentally and have distinct clinical, radiological, biochemical, and genetic features. Their detection at older age but smaller size may point to a different underlying tumor biology

Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BM) for prognostication and monitoring of ACC.We investigated 34 patients with ACC and 23 healthy subjects (HS) as controls. ccfDNA was extracted by commercial kits and ccfDNA concentrations quantified by fluorimeter (BM1). Targeted sequencing was performed using a customised panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging.ccfDNA concentrations were higher in ACC than HS (mean±SD, 1.15±1.56 vs 0.05±0.05 ng/µl, P&lt;0.0001), 96% of them being above the cut-off of 0.146 ng/µl (mean HS+2SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least one somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (HR=2.63, 95%CI=1.13-6.13, P=0.010, and HR=5.98, 95%CI=2.29-15.6, P=0.0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared to BM1.In conclusion, ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up

Induction of the nicotinamide riboside kinase NAD⁺ salvage pathway in a model of sarcoplasmic reticulum dysfunction

Background Hexose-6-Phosphate Dehydrogenase (H6PD) is a generator of NADPH in the Endoplasmic/Sarcoplasmic Reticulum (ER/SR). Interaction of H6PD with 11 beta-hydroxysteroid dehydrogenase type 1 provides NADPH to support oxo-reduction of inactive to active glucocorticoids, but the wider understanding of H6PD in ER/SR NAD(P)(H) homeostasis is incomplete. Lack of H6PD results in a deteriorating skeletal myopathy, altered glucose homeostasis, ER stress and activation of the unfolded protein response. Here we further assess muscle responses to H6PD deficiency to delineate pathways that may underpin myopathy and link SR redox status to muscle wide metabolic adaptation. Methods We analysed skeletal muscle from H6PD knockout (H6PDKO), H6PD and NRK2 double knockout (DKO) and wild-type (WT) mice. H6PDKO mice were supplemented with the NAD(+) precursor nicotinamide riboside. Skeletal muscle samples were subjected to biochemical analysis including NAD(H) measurement, LC-MS based metabolomics, Western blotting, and high resolution mitochondrial respirometry. Genetic and supplement models were assessed for degree of myopathy compared to H6PDKO. Results H6PDKO skeletal muscle showed adaptations in the routes regulating nicotinamide and NAD(+) biosynthesis, with significant activation of the Nicotinamide Riboside Kinase 2 (NRK2) pathway. Associated with changes in NAD(+) biosynthesis, H6PDKO muscle had impaired mitochondrial respiratory capacity with altered mitochondrial acylcarnitine and acetyl-CoA metabolism. Boosting NAD(+) levels through the NRK2 pathway using the precursor nicotinamide riboside elevated NAD(+)/NADH but had no effect to mitigate ER stress and dysfunctional mitochondrial respiratory capacity or acetyl-CoA metabolism. Similarly, H6PDKO/NRK2 double KO mice did not display an exaggerated timing or severity of myopathy or overt change in mitochondrial metabolism despite depression of NAD(+) availability. Conclusions These findings suggest a complex metabolic response to changes in muscle SR NADP(H) redox status that result in impaired mitochondrial energy metabolism and activation of cellular NAD(+) salvage pathways. It is possible that SR can sense and signal perturbation in NAD(P)(H) that cannot be rectified in the absence of H6PD. Whether NRK2 pathway activation is a direct response to changes in SR NAD(P)(H) availability or adaptation to deficits in metabolic energy availability remains to be resolved