Membrane-Localized Orientation of NONPHOTOTROPIC HYPOCOTYL3 Affects the Necessity of Its Phosphorylation for Phototropism.

NONPHOTOTROPIC HYPOCOTYL3 (NPH3) is a key regulator of hypocotyl phototropism under both low- and high-intensity blue light (LBL/HBL), mediating phototropin1 (phot1) and phot2 signaling. NPH3 undergoes dephosphorylation and is released from the plasma membrane (PM) upon blue light irradiation. However, how its phosphorylation status and PM localization mediate phot1 and phot2 signaling in Arabidopsis (Arabidopsis thaliana) remains elusive. In this study, we found that fusing NPH3 with GFP at its C terminus (N3G) impaired its release from the PM, a defect exacerbated by a phosphorylation-deficient mutation, resulting in a dephosphorylated NPH3-GFP (N3AG). Unlike N3G, transgenic lines expressing N3AG exhibited defective hypocotyl phototropism under HBL, which could be rescued by myristoylation at the N-terminus of N3AG (mN3AG), indicating that NPH3 phosphorylation is not essential for HBL-induced phototropic responses when it is artificially anchored at the PM via its N terminus. Furthermore, genetic analysis revealed that N3AG anchored to the PM by its N terminus (as in mN3AG) only rescues phot1-mediated HBL responses, which require RPT2. However, N3AG failed to regulate phot2-mediated HBL signaling, regardless of its PM orientation. Taken together, our results revealed that NPH3 phosphorylation is essential for phot2-mediated hypocotyl phototropism under HBL, but is not required for phot1-mediated HBL signaling when the NPH3 N terminus is PM-anchored.

BTB domains: A structural view of evolution, multimerization, and protein-protein interactions.

Broad-complex, Tramtrack, and Bric-à-brac/poxvirus and zinc finger (BTB/POZ) is a conserved domain found in many eukaryotic proteins with diverse cellular functions. Recent studies revealed its importance in multiple developmental processes as well as in the onset and progression of oncological diseases. Most BTB domains can form multimers and selectively interact with non-BTB proteins. Structural studies of BTB domains delineated the presence of different interfaces involved in various interactions mediated by BTBs and provided a basis for the specific inhibition of distinct protein-interaction interfaces. BTB domains originated early in eukaryotic evolution and progressively adapted their structural elements to perform distinct functions. In this review, we summarize and discuss the structural principles of protein-protein interactions mediated by BTB domains based on the recently published structural data and advances in protein modeling. We propose an update to the structure-based classification of BTB domain families and discuss their evolutionary interconnections.

Safety and Efficacy of Insulins in Critically Ill Patients Receiving Continuous Enteral Nutrition.

OBJECTIVE: There is a relative lack of consensus regarding the optimal management of hyperglycemia in patients receiving continuous enteral nutrition (EN), with or without a diagnosis of diabetes. METHODS: This retrospective study examined 475 patients (303 with known diabetes) hospitalized in critical care setting units in 2019 in a single center who received continuous EN. Rates of hypoglycemia, hyperglycemia, and glucose levels within the target range (70-180 mg/dL) were compared between patients with and without diabetes, and among patients treated with intermediate-acting (IA) biphasic neutral protamine Hagedorn 70/30, long-acting (LA) insulin, or rapid-acting insulin only. RESULTS: Among those with type 2 diabetes mellitus, IA and LA insulin regimens were associated with a significantly higher proportion of patient-days in the target glucose range and fewer hyperglycemic days. Level 1 (<70 mg/dL) and level 2 (<54 mg/dL) hypoglycemia occurred rarely, and there were no significant differences in level 2 hypoglycemia frequency across the different insulin regimens. CONCLUSION: Administration of IA and LA insulin can be safe and effective for those receiving insulin doses for EN-related hyperglycemia.

Profiling iNPH features through cluster analysis: an aid for clinical suspicion and diagnosis.

PURPOSE: Idiopathic Normal Pressure Hydrocephalus (iNPH) is a neurological syndrome defined by gait disturbance, cognitive impairment and urinary incontinence. However, its clinical presentation can vary widely due to overlapping syndromes and common comorbidities in older adults. This study aims to provide practical guidance to aid in the clinical suspicion and support the diagnostic and therapeutic processes for these patients. METHODS: Six quantitative variables regarding clinical, functional, and demographic aspects were considered for a large sample of patients with diagnosed iNPH. Principal component analysis (PCA) was adopted to define the main dimensions explaining the variability of the phenomenon. Then, two clusters of iNPH patients were described. RESULTS: 178 patients were included in the analysis. The PCA produced two dimensions covering 61.8% of the total variability. The first one relied mainly on both clinical (mRS, iNPHGs) and functional (TUG, Tinetti) variables, while the second one was represented mainly on the demographic pattern (age and education). Cluster analysis depicted two main groups of patients. Cluster n.1 is composed of individuals who are older, more disabled, with poor functional performances, and highly symptomatic. Cluster n.2 patients are slightly younger, more educated, fitter, and with more nuanced clinical aspects. CONCLUSIONS: Profiling iNPH patients using quantitative variables and cluster analysis can help identify distinct characteristics of these patients, aiding in the guidance of both medical and surgical interventions.

Spinal cord motion and CSF flow in the cervical spine of 70 healthy participants.

Pulsatile spinal cord and CSF velocities related to the cardiac cycle can be depicted by phase-contrast MRI. Among patients with spontaneous intracranial hypotension, we have recently described relevant differences compared with healthy controls in segment C2/C3. The method might be a promising tool to solve clinical and diagnostic ambiguities. Therefore, it is important to understand the physiological range and the effects of clinical and anatomical parameters in healthy volunteers. Within a prospective study, 3D T2 -weighted MRI for spinal canal anatomy and cardiac-gated phase-contrast MRI adapted to CSF flow and spinal cord motion for time-resolved velocity data and derivatives were performed in 70 participants (age 20-79 years) in segments C2/C3 and C5/C6. Correlations were analyzed by multiple linear regression models; p < 0.01 was required to assume a significant impact of clinical or anatomical data quantified by the regression coefficient B. Data showed that in C2/C3, the CSF and spinal cord craniocaudal velocity ranges were 4.5 ± 0.9 and 0.55 ± 0.15 cm/s; the total displacements were 1.1 ± 0.3 and 0.07 ± 0.02 cm, respectively. The craniocaudal range of the CSF flow rate was 8.6 ± 2.4 mL/s; the CSF stroke volume was 2.1 ± 0.7 mL. In C5/C5, physiological narrowing of the spinal canal caused higher CSF velocity ranges and lower stroke volume (C5/C6 B = +1.64 cm/s, p < 0.001; B = -0.4 mL, p = 0.002, respectively). Aging correlated to lower spinal cord motion (e.g., B = -0.01 cm per 10 years of aging, p < 0.001). Increased diastolic blood pressure was associated with lower spinal cord motion and CSF flow parameters (e.g., C2/C3 CSF stroke volume B = -0.3 mL per 10 mmHg, p < 0.001). Males showed higher CSF flow and spinal cord motion (e.g., CSF stroke volume B = +0.5 mL, p < 0.001; total displacement spinal cord B = +0.016 cm, p = 0.002). We therefore propose to stratify data for age and sex and to adjust for diastolic blood pressure and segmental narrowing in future clinical studies.

Change in Morphological Features of Enlarged Subarachnoid Spaces Following Treatment in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Focally enlarged sulci (FES) are areas of proposed extraventricular fluid entrapment that may occur within idiopathic normal pressure hydrocephalus (iNPH) with radiographic evidence of disproportionately enlarged subarachnoid-space hydrocephalus (DESH), and should be differentiated from atrophy. PURPOSE: To evaluate for change in FES size and pituitary height after shunt placement in iNPH. STUDY TYPE: Retrospective. SUBJECTS: A total of 125 iNPH patients who underwent shunt surgery and 40 age-matched controls. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T. Axial T2w FLAIR, 3D T1w MPRAGE, 2D sagittal T1w. ASSESSMENT: FES were measured in three dimensions and volume was estimated by assuming an ellipsoid shape. Pituitary gland height was measured in the mid third of the gland in iNPH patients and controls. STATISTICAL TESTS: Wilcoxon signed-rank test for comparisons between MRI measurements; Wilcoxon rank sum test for comparison of cases/controls. Significance level was P < 0.05. RESULTS: Fifty percent of the patients had FES. FES volume significantly decreased between the pre and first postshunt MRI by a median of 303 mm3 or 30.0%. Pituitary gland size significantly increased by 0.48 mm or 14.4%. FES decreased significantly by 190 mm3 or 23.1% and pituitary gland size increased significantly by 0.25 mm or 6% between the first and last postshunt MRI. DATA CONCLUSION: Decrease in size of FES after shunt placement provides further evidence that these regions are due to disordered cerebrospinal fluid (CSF) dynamics and should not be misinterpreted as atrophy. A relatively smaller pituitary gland in iNPH patients that normalizes after shunt is a less-well recognized feature of altered CSF dynamics. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Pharmacokinetic and pharmacodynamic equivalence of Biocon's biosimilar insulin N with US-licensed Humulin® N formulation in healthy subjects: Results from the RHINE-2 (Recombinant Human INsulin Equivalence-2) study.

AIM: To establish the pharmacokinetic (PK) and pharmacodynamic (PD) equivalence of proposed biosimilar Insulin N (Biocon's Insulin-N; Biocon Biologics Ltd., Bangalore, India) and US-licensed Humulin® N (Humulin-N; Eli Lilly and Company, Indianapolis, IN, USA) in healthy subjects. MATERIALS AND METHODS: This was a phase-1, single-centre, double-blind, randomized, three-period, six-sequence, partially replicated, crossover, 24-h euglycaemic clamp study. Overall, 90 healthy subjects were randomized, of whom 85 completed the study. The subjects received either two single doses of Biocon's Insulin-N and a single dose of Humulin-N or two single doses of Humulin-N and a single dose of Biocon's Insulin-N subcutaneously at a dose of 0.4 IU/kg. The primary PK endpoints were the area under the insulin concentration-time curve from 0 to 24 h (AUCins.0-24h ) and the maximum insulin concentration (Cins.max ). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 h (AUCGIR.0-24h ) and the maximum GIR (GIRmax ). RESULTS: Biocon's Insulin-N was found to be equivalent to Humulin-N for the primary PK (geometric 90% confidence interval for the least squares mean ratio: AUCins.0-24h , 100.98%-115.66% and Cins.max , 95.91%-110.16%) and PD endpoints (intra-subject variability ≥0.294; 95% upper confidence interval [(µT - µR)2 - θσ2 WR] <0; point estimates of geometric least squares mean ratio: AUCGIR.0-24h , 104.61% and GIRmax , 100.81%). The safety profile of Biocon's Insulin-N was similar to that of Humulin-N, and no serious adverse events were reported. CONCLUSION: PK and PD equivalence was shown between Biocon's Insulin-N and Humulin-N in healthy subjects, and both treatments were well tolerated and considered safe.

The efficacy of insulin degludec and insulin glargine over NPH insulin among toddlers and preschoolers with type 1 diabetes using glycemic variability and time in range.

Optimizing glycemic control without risking hypoglycemia is crucial in toddlers and preschoolers with type 1 diabetes (T1D) to avoid cognitive impairment later in life. Hence, this study aims to compare glycemic parameters among toddlers and preschoolers with T1D in relation to different basal insulins. Sixty toddlers and preschoolers with T1D with mean age of 3.53 ± 1.17 years (range, 2-6) and mean diabetes duration of 9.37 ± 1.85 months were randomly assigned into three equal groups; group A received insulin degludec, group B received insulin glargine, and group C were on NPH. At baseline, the three groups were matched regarding clinical and laboratory parameters (p > 0.05). They were followed up at 3 and 6 months for insulin daily dose (IDD), hypoglycemia and severe-hypoglycemia frequency, and glycated hemoglobin (HbA1c). At the study endpoint, continuous glucose monitoring (CGM) was assessed in a random sample of 10 patients from each group. The mean time in range (TIR) of the studied cohort was 55.07 ± 24.05%, and their mean coefficient of variation (CV) was 42.82 ± 11.69%. The TIR was significantly higher in the degludec group (69.36 ± 18.54) and the glargine group (55.43 ± 26.51) than the NPH group (32.56 ± 9.11), p < 0.001. Meanwhile, the CV was significantly lower in the degludec group (35.12 ± 6.47) than the gargine (44.1 ± 13.13) and the NPH (53.8 ± 7.54) groups, p < 0.001. The insulin degludec and glargine groups had significantly lower HbA1c (p = 0.002), hypoglycemia (p = 0.006), severe hypoglycemia (p = 0.029), and IDD (p = 0.015) than the NPH group. CONCLUSION: Insulin degludec and glargine resulted in better HbA1c and TIR with reduced hypoglycemia and IDD than NPH among toddlers and preschoolers with T1D. Moreover, CV was lowest in the insulin degludec group. WHAT IS KNOWN: • Insulin therapy is the mainstay of T1D management. • Optimal insulin therapy for young children with T1D should provide effective glycemic. WHAT IS NEW: • Insulin degludec and insulin glargine have better efficacy than NPH insulin among toddlers and preschoolers with T1D in the term of significantly lower coefficient of variation, HbA1c and IDD and significantly higher time in range. • Insulin degludec and insulin glargine have better safety in the term of less hypoglycemia and severe hypoglycemia episodes than NPH insulin among toddlers and preschoolers with T1D.

The benefits of automated CSF drainage in normal pressure hydrocephalus.

BACKGROUND: The commonly used cerebrospinal fluid (CSF) drainage system remains the manual drip-chamber drain. The LiquoGuard (Möller Medical GmbH, Germany) is an automated CSF management device with dual functionality, measuring intracranial pressure and automatic pressure- or volume-led CSF drainage. There is limited research for comparison of devices, particularly in the neurosurgical field, where it has potential to reshape care. OBJECTIVE: This study aims to compare manual drip-chamber drain versus LiquoGuard system, by assessing accuracy of drainage, associated morbidity and impact on length of stay. METHOD: Inclusion criteria consisted of suspected normal pressure hydrocephalus (NPH) patients undergoing extended lumbar drainage. Patients were divided into manual drain group versus automated group. RESULTS: Data was analysed from 42 patients: 31 in the manual group versus 11 in the LiquoGuard group. Volumetric over-drainage was seen in 90.3% (n = 28) versus 0% (p < 0.05), and under-drainage in 38.7% (n = 12) versus 0% (p < 0.05), in the manual and automatic group, respectively. Symptoms of over-drainage were noted in 54.8% (n = 17) of the manual group, all of which had episodes of volumetric over-drainage, versus 18.2% (n = 2) in automated group, of which neither had actual over-drainage (p < 0.05). Higher over-drainage symptoms of manual drain is likely due to increased fluctuation of CSF drainage, instead of smooth CSF drainage seen with LiquoGuard system. An increased length of stay was seen in 38.7% (n = 12) versus 9% (n = 1) (p < 0.05) in the manual and LiquoGuard group, respectively. CONCLUSION: The LiquoGuard device is a more superior way of CSF drainage in suspected NPH patients, with reduced morbidity and length of stay.

Radiological predictors of shunt response in the diagnosis and treatment of idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis.

BACKGROUND: Patients with the dementia subtype idiopathic normal pressure hydrocephalus (iNPH) may improve clinically following cerebrospinal fluid (CSF) diversion (shunt) surgery, though the predictors of shunt response remain debated. Currently, radiological features play an important role in the diagnosis of iNPH, but it is not well established which radiological markers most precisely predict shunt responsive iNPH. OBJECTIVE: To conduct a systematic review and meta-analysis to identify radiological predictors of shunt responsiveness, evaluate their diagnostic effectiveness, and recommend the most predictive radiological features. METHODS: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR were searched for original studies investigating radiological predictors of shunt response in iNPH patients. Included studies were assessed using the ROBINS-1 tool, and eligible studies were evaluated using a univariate meta-analysis. RESULTS: Overall, 301 full-text papers were screened, of which 28 studies were included, and 26 different radiological features were identified, 5 of these met the inclusion criteria for the meta-analysis: disproportionately enlarged subarachnoid space (DESH), callosal angle, periventricular white matter changes, cerebral blood flow (CBF), and computerized tomography cisternography. The meta-analysis showed that only callosal angle and periventricular white matter changes significantly differentiated iNPH shunt responders from non-responders, though both markers had a low diagnostic odds ratio (DOR) of 1.88 and 1.01 respectively. None of the other radiological markers differentiated shunt responsive from shunt non-responsive iNPH. CONCLUSION: Callosal angle and periventricular changes are the only diagnostically effective radiological predictors of shunt responsive iNPH patients. However, due to the DORs approximating 1, they are insufficient as sole predictors and are advised to be used only in combination with other diagnostic tests of shunt response. Future research must evaluate the combined use of multiple radiological predictors, as it may yield beneficial additive effects that may allow for more robust radiological shunt response prediction.

Quantitative Evans index estimation using ultrasonographic measurement of the optic nerve sheath diameter in supine and upright position.

OBJECTIVES: We aimed to quantitatively assess Evans index (EI) using ultrasonographic optic nerve sheath diameter (ONSD) measurements in supine and upright position in normal pressure hydrocephalus (NPH) patients. METHODS: Ultrasonographically ONSD was measured in a supine and upright position before and 4-5 days after the ventriculoperitoneal shunt surgery. The changes of the ONSD between supine and upright positions were calculated as ∆ONSD = sONSD-uONSD and as the variation ONSD_V = 100% × [(sONSD - uONSD)/sONSD]. Multiple linear regression analyses were conducted to assess associations between EI and the variation of ONSD. We derived the mathematical function to predict EI. Bland-Altman analysis was applied to evaluate the accuracy and precision of the EI prediction. RESULTS: Thirteen adult patients (mean age 61.8 ± 11.1 (SD) years; 6 (46%) female) undergone VP shunt implantation for NPH. The mean EI was 0.432 (95% CI, 0.393-0.471) preoperatively and 0.419 (95% CI, 0.373-0.466) postoperatively (p = 0.066). There is a decrease of the ONSD during positional changes from supine to upright position and pre- and postoperative EI correlated with preoperative variation ONSD_V1 (r = - 0.610 and - 0.648, p < 0.05). The mathematical function for preoperative EI estimation was EIpreop = 0.504 - 0.022 × ONSD_V1 + 0.101 × gender (M = 0; W = 1), (Durbin-Watson value = 1.94), and for postoperative was EIpostop = 0.487 - 0.022 × ONSD_V1 + 0.117 × gender; (Durbin-Watson value 2.23). CONCLUSIONS: Ultrasonographic ONSD measurements in supine and upright position provide a potential method to quantify EI that can be conducted at the bedside.

Endoscopic third ventriculostomy compared to ventriculoperitoneal shunt as treatment for idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis.

BACKGROUND: The accepted treatment for idiopathic normal pressure hydrocephalus (iNPH) is the insertion of a ventriculoperitoneal shunt (VPS). Recently, some studies examined endoscopic third ventriculostomy (ETV) for the treatment of iNPH with controversial results. The aim of this systematic review and meta-analysis was to compare ETV to VPS regarding complications and outcome for the treatment of iNPH. METHODS: We searched Medline, Embase and Scopus. Due to the scarcity of data, we did not include only randomized controlled trials, but also retro- and prospective studies. The primary outcome was failure of cerebrospinal fluid diversion method. Secondary endpoints were clinical postoperative improvement rate, morbidity and mortality. RESULTS: Out of 311 screened studies, three were included in the quantitative analysis including one RCT and two retrospective cohort studies. No statistically significant difference concerning failure rate of CSF diversion method (ETV 27.5% vs. VPS 33.2%, RR 1.19, 95% CI [0.69-2.04], p = 0.52) or postoperative improvement was found (68% for ETV vs. 72.8% for VPS, RR 0.81, 95% CI [0.57-1.16], p = 0.26). ETV showed a significantly lower complication rate compared to VPS (7.5% vs. 51.1%, RR 0.25, 95% CI [0.08-0.76], p = 0.02). CONCLUSION: ETV and VPS did not differ significantly regarding their failure rate for iNPH, while ETV showed a significantly lower complication rate than VPS. However, the data available is scarce with only one RCT investigating this important matter. Further well-designed trials are necessary to investigate the clinical outcome of ETV in iNPH. TRIAL REGISTRATION NUMBER: PROSPERO (ID: CRD42020199173).

The topology of ventricle surfaces and its application in the analysis of hydrocephalic ventricles: a proof-of-concept study.

PURPOSE: The cerebral ventricles deform in a non-uniform fashion in response to increased CSF volume and/or pressure in hydrocephalic syndromes. Current research is focused on volumetric analyses, while topological analysis of ventricular surfaces remains understudied. We developed a method of quantitatively modeling the curvature of ventricular surfaces to analyze changes in ventricular surfaces in normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD), using the left frontal horn as an example. METHODS: Twenty-one patients with NPH were recruited from our institution, and 21 healthy controls (HC) and patients with Alzheimer's disease (AD) were identified from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. On T1-weighted fine-cut magnetic resonance sequences, 3D Slicer was used to segment the left frontal horn. Next, the mean curvatures at a set of points on the ventricular surface were determined. The frontal horns were scaled and centered into normalized volumes, allowing for pooling across the study subjects. The frontal horn was divided into superolateral, superomedial, inferolateral, and inferomedial surfaces, and locoregional mean curvatures were analyzed. Statistical comparisons were made between NPH, AD, and HC groups. RESULTS: Significant differences in the mean curvature of lateral surfaces of the ventricles distinguished patterns of distortion between all three cohorts. Significant flattening of the superomedial surface discriminated NPH from HC and AD. However, significant rounding of the inferomedial surface compared to controls was a distinguishing feature of NPH alone. CONCLUSION: NPH ventricles deform non-uniformly. The pattern of surface distortion may be used as an additional tool to differentiate between these hydrocephalic conditions.

Is DAT imaging abnormality in normal pressure hydrocephalus always suggestive of degeneration?

Idiopathic normal pressure hydrocephalus (iNPH) is a debated entity with controversial pathogenesis, diagnostic criteria, and predictors of response after ventriculoperitoneal shunt (VPS). Parkinsonian signs are frequently reported in the clinical picture, sometimes due to the coexistence of an underlying neurodegenerative parkinsonism and sometimes in the absence thereof. To distinguish these two scenarios is crucial, since they may carry different long-term response to CSF drainage. 123I-FP-CIT-SPECT was believed to be helpful in this regard, however its role in predicting surgical outcome has been disputed. We illustrate a patient presented with gait disturbance, urinary incontinence, and asymmetrical parkinsonian signs, who underwent a 3T brain MRI and a 123I-FP-CIT-SPECT. VPS was performed. The patient repeated a 123I-FP-CIT-SPECT, 18 months after the operation, and was clinically followed up for 24 months. Our patient displayed clinical and radiological criteria for iNPH and an abnormal asymmetrical uptake in 123I-FP-CIT-SPECT, consistent with her asymmetrical parkinsonism. However, the organization of the substantia nigra studied with iron-sensitive sequences in 3T brain MRI scan appeared intact. The patient revealed an improvement both clinically and in 123I-FP-CIT-SPECT at postsurgical follow-up. Our report suggests that abnormal 123I-FP-CIT-SPECT may not necessarily reveal an overlap with neurodegenerative parkinsonism; its partial reversibility may suggest that the mechanical effect exerted on the striatum by ventriculomegaly ultimately leads to downregulation of dopaminergic transporters which may improve after VPS.

Analysis of Intracranial Pressure Pulse-Pressure Relationship: Experimental Validation.

The slope of linear relationship between the amplitude of pulsations in intracranial pressure (ICP) versus mean ICP has recently been suggested as a useful guide for selecting patients for shunt surgery in normal pressure hydrocephalus (NPH). To better understand how the pathophysiology of cerebral circulation influences this parameter, we aimed to study the relationship between mean pressure and pulsation amplitude in a wide range of conditions affecting cerebrovascular tone and ICP in experimental conditions.We retrospectively analysed experimental material collected previously. Three physiological manoeuvres were studied in 29 New Zealand white rabbits: lumbar infusion with an infusion rate ≤0.2 mL/min to induce mild intracranial hypertension (n = 43), sympathetic blockade to induce arterial hypotension (n = 19), and modulation of the ventilator tidal volume, simultaneously influencing arterial carbon dioxide partial pressure (PaCO2) to induce hypocapnia or hypercapnia (n = 17). We investigated whether the slope of the pulse amplitude (AMP)-ICP line depended on PaCO2 and arterial blood pressure (ABP) changes.We found a linear correlation between AMP-ICP and ICP with positive slope. Regression of slope against mean ABP showed a negative dependence (p = 0.03). In contrast, the relationship between slope and PaCO2 was positive, although not reaching statistical significance (p = 0.18).The slope of amplitude-pressure line is strongly modulated by systemic vascular variables and therefore should be taken as a descriptor of cerebrospinal fluid dynamics with great care.

The continuing arc toward phototropic enlightenment.

Phototropism represents a simple physiological mechanism-differential growth across the growing organ of a plant-to respond to gradients of light and maximize photosynthetic light capture (in aerial tissues) and water/nutrient acquisition (in roots). The phototropin blue light receptors, phot1 and phot2, have been identified as the essential sensors for phototropism. Additionally, several downstream signal/response components have been identified, including the phot-interacting proteins NON-PHOTOTROPIC HYPOCOTYL 3 (NPH3) and PHYTOCHROME SUBSTRATE 4 (PKS4). While the structural and photochemical properties of the phots are quite well understood, much less is known about how the phots signal through downstream regulators. Recent advances have, however, provided some intriguing clues. It appears that inactive receptor phot1 is found dispersed in a monomeric form at the plasma membrane in darkness. Upon light absorption dimerizes and clusters in sterol-rich microdomains where it is signal active. Additional studies showed that the phot-regulated phosphorylation status of both NPH3 and PKS4 is linked to phototropic responsiveness. While PKS4 can function as both a positive (in low light) and a negative (in high light) regulator of phototropism, NPH3 appears to function solely as a key positive regulator. Ultimately, it is the subcellular localization of NPH3 that appears crucial, an aspect regulated by its phosphorylation status. While phot1 activation promotes dephosphorylation of NPH3 and its movement from the plasma membrane to cytoplasmic foci, phot2 appears to modulate relocalization back to the plasma membrane. Together these findings are beginning to illuminate the complex biochemical and cellular events, involved in adaptively modifying phototropic responsiveness under a wide varying range of light conditions.

Myotonic dystrophy type 1 accompanied with normal pressure hydrocephalus: a case report and literature review.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is the most common disease that can cause muscle weakness and atrophy among adults. Normal pressure hydrocephalus (NPH) is characterized by the triad of gait disturbance, cognitive impairment and urinary incontinence. The association between DM1 and NPH is extremely rare. We report a Chinese female patient with DM1 in association with NPH. CASE PRESENTATION: The patient presented with a history of 3-year of walking instability and cognitive impairment. Her brain MRI showed ventriculomegaly with normal cerebrospinal fluid (CSF) pressure and the CSF tap-test was positive, which indicated the diagnosis of probable NPH. DM1 was confirmed by genetic testing. CONCLUSIONS: Four patients with DM1-NPH association were found before. The association between NPH and DM1 may not be just a coincidence, NPH may occur in DM1 later in life and it is vital to recognize the association as a shunt surgery may improve patients' quality of life.

Study rationale and design of the EANITIATE study (EmpAgliflozin compared to NPH Insulin for sTeroId diAbeTEs) - a randomized, controlled, multicenter trial of safety and efficacy of treatment with empagliflozin compared with NPH-insulin in patients with newly onset diabetes following initiation of glucocorticoid treatment.

BACKGROUND: A well-known metabolic side effect from treatment with glucocorticoids is glucocorticoid-induced diabetes mellitus (GIDM). Guidelines on the management of GIDM in hospitalized patients (in the non-critical care setting), recommend initiation of insulin therapy. The scientific basis and evidence for superiority of insulin therapy over other glucose lowering therapies is however poor and associated with episodes of both hypo- and hyperglycaemia. There is an unmet need for an easier, safe and convenient therapy for glucocorticoid-induced diabetes. METHODS: EANITIATE is a Danish, open, prospective, multicenter, randomized (1:1), parallel group study in patients with new-onset diabetes following treatment with glucocorticoids (> 20 mg equivalent prednisolone dose/day) with blinded endpoint evaluation (PROBE design). Included patients are randomized to either a Sodium-Glucose-Cotransporter 2 (SGLT2) inhibitor or neutral protamin Hagedorn (NPH) insulin and followed for 30 days. Blinded continuous glucose monitoring (CGM) will provide data for the primary endpoint (mean daily blood glucose) and on glucose fluctuations in the two treatment arms. Secondary endpoints are patient related outcomes, hypoglycaemia, means and measures of variation for all values and for time specific glucose values. This is a non-inferiority study with the intent to demonstrate that treatment with empagliflozin is not inferior to treatment with NPH insulin when it comes to glycemic control and side effects. DISCUSSION: This novel approach to management of glucocorticoid-induced hyperglycemia has not been tested before and if SGLT2 inhibition with empaglifozin compared to NPH-insulin is a safe, effective and resource sparing treatment for GIDM, it has the potential to improve the situation for affected patients and have health economic benefits. TRIAL REGISTRATION: www.clinicaltrialsregister.eu no.: 2018-002640-82. Prospectively registered November 20th. 2018. Date of first patient enrolled: June 4th. 2019. This protocol article is based on the EANITATE protocol version 1.3, dated 29. January 2018.

Hippo signaling-a central player in cystic kidney disease?

Cystic transformation of kidney tissue is a key feature of various disorders including autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive polycystic kidney disease (ARPKD), and disorders of the nephronophthisis spectrum (NPH). While ARPKD and NPH typically affect children and adolescents, pediatric onset of ADPKD is less frequently found. While both ADPKD and ARPKD are characterized by formation of hundreds of cysts accompanied by hyperproliferation of tubular epithelia with massive renal enlargement, NPH patients usually show kidneys of normal or reduced size with cysts limited to the corticomedullary border. Recent results suggest the hippo pathway to be a central regulator at the crossroads of the renal phenotype in both diseases. Hippo signaling regulates organ size and proliferation by keeping the oncogenic transcriptional co-activators Yes associated protein 1 (YAP) and WW domain containing transcription regulator 1 (TAZ) in check. Once this inhibition is released, nuclear YAP/TAZ interacts with TEAD family transcription factors and the consecutive transcriptional activation of TEA domain family members (TEAD) target genes mediates an increase in proliferation. Here, we review the current knowledge on the impact of NPHP and ADPKD mutations on Hippo signaling networks. Furthermore, we provide an outlook towards potential future therapeutic strategies targeting Hippo signaling to alleviate cystic kidney disease.

Normal pressure hydrocephalus-an overview of pathophysiological mechanisms and diagnostic procedures.

Normal pressure hydrocephalus (NPH) is an important differential diagnosis of neurodegenerative diseases. The prevalence of dementia is increasing in line with the worldwide increase in life expectancy. NPH can be divided into idiopathic (iNPH) and secondary (sNPH) which is important in terms of clinical symptoms, future progress, and the outcome of possible treatment. The full clinical triad is not prevalent in all of the cases and the pathophysiology of iNPH remains unclear. Diagnosis is based on the evaluation of clinical symptoms (Hakim's triad) combined with an MRI assessment, evaluation of CSF dynamic parameters by different methods such as a tap test, lumbar infusion test (LIT), and external lumbar drainage (ELD). Despite the development of diagnostic techniques and strategies in management, NPH remains to be a challenge for the specialists despite more than 50 years of research. However, results of this research have brought new opportunities in the diagnosis, therapy, and quality of life as well as survival time of NPH patients with improved symptoms. The aim of this article is to present the pathophysiological hypotheses of NPH and an overview of the diagnostic techniques used for the evaluation of NPH patients.