Management of colonic complications of type IV Ehlers-Danlos syndrome: a systematic review and evidence-based management strategy.

AIM: Type IV Ehlers Danlos Syndrome (EDS) is a connective tissue disorder affecting approximately 1 per 100,000-200,000 people. Life expectancy is reduced secondary to spontaneous vascular rupture or colonic perforation. Surgery carries significant morbidity and mortality. While strategies to manage colonic perforation include primary repair with or without a defunctioning stoma, Hartmann's procedure, total abdominal colectomy with end ileostomy and ileorectal anastomosis, evidence is contradictory and has not previously been evaluated in order to form a treatment strategy. We aim to review the published literature and identify outcome data relating to operative management of colonic perforation in type IV EDS. METHODS: Pubmed, EM-BASE, Cochrane library and Google Scholar were searched with the following details: Ehlers Danlos Syndrome AND colonic surgery. The main outcome measure was re-perforation rates following colonic surgery on patients with type IV EDS. If the nature of surgery and follow up were reported, data were recorded in a SPSS database according to PRISMA guidelines. RESULTS: One hundred and nine operations have been described in 51 patients in 44 case series. There were 26 visceral re-perforations, 2 affecting the small intestine and 24 colonic. Survival analysis favoured total abdominal colectomy compared with operations where the colon was left in situ. CONCLUSIONS: Total abdominal colectomy with end ileostomy or ileorectal anastomosis are the safest strategies after colonic perforation in type IV EDS. Anastomotic leak rates are high. End colostomy is high risk for colonic re-perforation and anastomotic leak rates are extremely high. Restoration of colonic continuity should be avoided.

Avoiding, diagnosing and treating well leg compartment syndrome after pelvic surgery.

BACKGROUND: Patients undergoing prolonged pelvic surgery may develop compartment syndrome of one or both lower limbs in the absence of direct trauma or pre-existing vascular disease (well leg compartment syndrome). This condition may have devastating consequences for postoperative recovery, including loss of life or limb, and irreversible disability. METHODS: These guidelines represent the collaboration of a multidisciplinary group of colorectal, vascular and orthopaedic surgeons, acting on behalf of their specialty associations in the UK and Ireland. A systematic analysis of the available peer-reviewed literature was undertaken to provide an evidence base from which these guidelines were developed. RESULTS: These guidelines encompass the risk factors (both patient- and procedure-related), diagnosis and management of the condition. Key recommendations for the adoption of perioperative strategies to facilitate prevention and effective treatment of well leg compartment syndrome are presented. CONCLUSION: All surgeons who carry out abdominopelvic surgical procedures should be aware of well leg compartment syndrome, and instigate policies within their own institution to reduce the risk of this potentially life-changing complication.

Outcome of open abdominal management following military trauma.

BACKGROUND: Temporary abdominal closure (TAC) is increasingly common after military and civilian major trauma. Primary fascial closure cannot be achieved after TAC in 30 per cent of civilian patients; subsequent abdominal wall reconstruction carries significant morbidity. This retrospective review aimed to determine this morbidity in a UK military cohort. METHODS: A prospectively maintained database of all injured personnel from the Iraq and Afghanistan conflicts was searched from 1 January 2003 to 31 December 2014 for all patients who had undergone laparotomy in a deployed military medical treatment facility. This database, the patients' hospital notes and their primary care records were searched. RESULTS: Laparotomy was performed in a total of 155 patients who survived to be repatriated to the UK; records were available for 150 of these patients. Seventy-seven patients (51·3 per cent) had fascial closure at first laparotomy, and 73 (48·7 per cent) had a period of TAC. Of the 73 who had TAC, two died before closure and two had significant abdominal wall loss from blast injury and were excluded from analysis. Of the 69 remaining patients, 65 (94 per cent) were able to undergo delayed primary fascial closure. The median duration of follow-up from injury was 1257 (range 1-4677) days for the whole cohort. Nine (12 per cent) of the 73 patients who underwent TAC subsequently developed an incisional hernia, compared with ten (13 per cent) of the 77 patients whose abdomen was closed at the primary laparotomy (P = 1·000). CONCLUSION: Rates of delayed primary closure of abdominal fascia after temporary abdominal closure appear high. Subsequent rates of incisional hernia formation were similar in patients undergoing delayed primary closure and those who had closure at the primary laparotomy.

Recent developments in the surgical management of complex intra-abdominal infection.

BACKGROUND: Current guidance on the management of sepsis often applies to infection originating from abdominal or pelvic sources, which presents specific challenges and opportunities for efficient and rapid source control. Advances made in the past decade are presented in this article. METHODS: A qualitative systematic review was undertaken by searching standard literature databases for English-language studies presenting original data on the clinical management of abdominal and pelvic complex infection in adults over the past 10 years. High-quality studies relevant to five topical themes that emerged during review were included. RESULTS: Important developments and promising preliminary work are presented, relating to: imaging and other diagnostic modalities; antimicrobial therapy and the importance of antimicrobial stewardship; the particular challenges posed by fungal sepsis; novel techniques in percutaneous and endoscopic source control; and current issues relating to surgical source control and managing the abdominal wound. Logistical challenges relating to rapid access to cross-sectional imaging, interventional radiology and operating theatres need to be addressed so that international benchmarks can be met. CONCLUSION: Important advances have been made in the diagnosis, non-operative and surgical control of abdominal or pelvic sources, which may improve outcomes in the future. Important areas for continued research include the diagnosis and therapy of fungal infection and the challenges of managing the open abdomen.

Disruptive mood dysregulation disorder at the age of 6 years and clinical and functional outcomes 3 years later.

BACKGROUND: Little is known about the predictive validity of disruptive mood dysregulation disorder (DMDD). This longitudinal, community-based study examined associations of DMDD at the age of 6 years with psychiatric disorders, functional impairment, peer functioning and service use at the age of 9 years. METHOD: A total of 473 children were assessed at the ages of 6 and 9 years. Child psychopathology and functional impairment were assessed at the age of 6 years with the Preschool Age Psychiatric Assessment with parents and at the age of 9 years with the Kiddie-Schedule of Affective Disorders and Schizophrenia (K-SADS) with parents and children. At the age of 9 years, mothers, fathers and youth completed the Child Depression Inventory (CDI) and the Screen for Child Anxiety Related Disorders, and teachers and K-SADS interviewers completed measures of peer functioning. Significant demographic covariates were included in all models. RESULTS: DMDD at the age of 6 years predicted a current diagnosis of DMDD at the age of 9 years. DMDD at the age of 6 years also predicted current and lifetime depressive disorder and attention-deficit/hyperactivity disorder (ADHD) at the age of 9 years, after controlling for all age 6 years psychiatric disorders. In addition, DMDD predicted depressive, ADHD and disruptive behavior disorder symptoms on the K-SADS, and maternal and paternal reports of depressive symptoms on the CDI, after controlling for the corresponding symptom scale at the age of 6 years. Last, DMDD at the age of 6 years predicted greater functional impairment, peer problems and educational support service use at the age of 9 years, after controlling for all psychiatric disorders at the age of 6 years. CONCLUSIONS: Children with DMDD are at high risk for impaired functioning across childhood, and this risk is not accounted for by co-morbid conditions.

Personality diatheses and Hurricane Sandy: effects on post-disaster depression.

BACKGROUND: According to diathesis-stress models, personality traits, such as negative emotionality (NE) and positive emotionality (PE), may moderate the effects of stressors on the development of depression. However, relatively little empirical research has directly examined whether NE and PE act as diatheses in the presence of stressful life events, and no research has examined whether they moderate the effect of disaster exposure on depressive symptoms. Hurricane Sandy, the second costliest hurricane in US history, offers a unique opportunity to address these gaps. METHOD: A total of 318 women completed measures of NE and PE 5 years prior to Hurricane Sandy. They were also assessed for lifetime depressive disorders on two occasions, the latter occurring an average of 1 year before the hurricane. Approximately 8 weeks after the disaster (mean = 8.40, s.d. = 1.48 weeks), participants completed a hurricane stress exposure questionnaire and a measure of current depressive symptoms. RESULTS: Adjusting for lifetime history of depressive disorders, higher levels of stress from Hurricane Sandy predicted elevated levels of depressive symptoms, but only in participants with high levels of NE or low levels of PE. CONCLUSIONS: These findings support the role of personality in the development of depression and suggest that personality traits can be useful in identifying those most vulnerable to major stressors, including natural disasters.

European Society of Coloproctology consensus on the surgical management of intestinal failure in adults.

Intestinal failure (IF) is a debilitating condition of inadequate nutrition due to an anatomical and/or physiological deficit of the intestine. Surgical management of patients with acute and chronic IF requires expertise to deal with technical challenges and make correct decisions. Dedicated IF units have expertise in patient selection, operative risk assessment and multidisciplinary support such as nutritional input and interventional radiology, which dramatically improve the morbidity and mortality of this complex condition and can beneficially affect the continuing dependence on parenteral nutritional support. Currently there is little guidance to bridge the gap between general surgeons and specialist IF surgeons. Fifteen European experts took part in a consensus process to develop guidance to support surgeons in the management of patients with IF. Based on a systematic literature review, statements were prepared for a modified Delphi process. The evidence for each statement was graded using Oxford Centre for Evidence-Based Medicine Levels of Evidence. The current paper contains the statements reflecting the position and practice of leading European experts in IF encompassing the general definition of IF surgery and organization of an IF unit, strategies to prevent IF, management of acute IF, management of wound, fistula and stoma, rehabilitation, intestinal and abdominal reconstruction, criteria for referral to a specialist unit and intestinal transplantation.

Protein kinetics in human endotoxaemia and their temporal relation to metabolic, endocrine and proinflammatory cytokine responses.

BACKGROUND: Sepsis is associated with profound alterations in protein metabolism. The unpredictable time course of sepsis and the multiplicity of confounding factors prevent studies of temporal relations between the onset of endocrine and proinflammatory cytokine responses and the onset of protein catabolism. This study aimed to determine the time course of whole-body protein catabolism, and relate it to the endocrine, metabolic and cytokine responses in a human endotoxaemia model of early sepsis. METHODS: Six healthy male volunteers were studied twice in random order, before and for 600 min after administration of either an intravenous bolus of Escherichia coli lipopolysaccharide (LPS) or sterile saline. Whole-body protein synthesis, breakdown and net protein breakdown were measured by amino acid tracer infusion, and related to changes in plasma levels of growth hormone, glucagon, cortisol, insulin-like growth factor (IGF) 1, tumour necrosis factor (TNF) α and interleukin (IL) 6. RESULTS: Protein synthesis, breakdown and net protein breakdown increased and peaked 120 min after LPS administration (P < 0·001), the alterations persisting for up to 480 min. These peaks coincided with peaks in plasma growth hormone, TNF-α and IL-6 concentrations (P = 0·049, P < 0·001 and P < 0·001 for LPS versus saline), whereas plasma cortisol concentration peaked later. No alterations in plasma insulin or glucagon concentrations, or in the IGF axis were observed during the period of abnormalities of protein metabolism. CONCLUSION: LPS administration induced an early protein catabolic response in young men and this coincided with changes in plasma growth hormone, TNF-α and IL-6 concentrations, rather than changes in cortisol, glucagon, insulin or the IGF axis. Surgical relevance Sepsis in surgical patients is common and remains associated with substantial mortality. Although sepsis is a heterogeneous condition and its pathophysiology therefore difficult to study, a universal and profound clinical problem is protein catabolism not responsive to nutritional support. Human experimental endotoxaemia is a promising model of clinical sepsis that can be used to elucidate underlying pathophysiology and explore novel therapeutic approaches. This study demonstrates that human experimental endotoxaemia replicates the changes in whole-body protein turnover seen in clinical sepsis. Frequent measurements allowed identification of tumour necrosis factor (TNF) α, interleukin (IL) 6 and growth hormone as putative mediators. Human experimental endotoxaemia is a valid model for further study of mechanisms and putative therapies of catabolism associated with sepsis. In particular, effects of TNF-α and IL-6 blockade should be evaluated.

Systematic review of preoperative, intraoperative and postoperative risk factors for colorectal anastomotic leaks.

BACKGROUND: Anastomotic leak (AL) represents a dreaded complication following colorectal surgery, with a prevalence of 1-19 per cent. There remains a lack of consensus regarding factors that may predispose to AL and the relative risks associated with them. The objective was to perform a systematic review of the literature, focusing on the role of preoperative, intraoperative and postoperative factors in the development of colorectal ALs. METHODS: A systematic review was performed to identify adjustable and non-adjustable preoperative, intraoperative and postoperative factors in the pathogenesis of AL. Additionally, a severity grading system was proposed to guide treatment. RESULTS: Of 1707 papers screened, 451 fulfilled the criteria for inclusion in the review. Significant preoperative risk factors were: male sex, American Society of Anesthesiologists fitness grade above II, renal disease, co-morbidity and history of radiotherapy. Tumour-related factors were: distal site, size larger than 3 cm, advanced stage, emergency surgery and metastatic disease. Adjustable risk factors were: smoking, obesity, poor nutrition, alcohol excess, immunosuppressants and bevacizumab. Intraoperative risk factors were: blood loss/transfusion and duration of surgery more than 4 h. Stomas lessen the consequences but not the prevalence of AL. In the postoperative period, CT is the most commonly used imaging tool, with or without rectal contrast, and a C-reactive protein level exceeding 150 mg/l on day 3-5 is the most sensitive biochemical marker. A five-level classification system for AL severity and appropriate management is presented. CONCLUSION: Specific risk factors and their potential correction or indications for stoma were identified. An AL severity score is proposed to aid clinical decision-making.

Anal acoustic reflectometry predicts the outcome of percutaneous nerve evaluation for faecal incontinence.

BACKGROUND: Sacral nerve stimulation (SNS) is effective for some patients with faecal incontinence. Before insertion of a costly implant, percutaneous nerve evaluation (PNE) is undertaken to identify patients likely to report success from SNS. The aim of this study was to determine whether variables of anal sphincter function measured by anal acoustic reflectometry (AAR) could predict the outcome of PNE for faecal incontinence. METHODS: Women with faecal incontinence undergoing PNE were recruited. AAR, followed by anal manometry, was performed on the day of surgery, immediately before PNE. The outcome of PNE was determined by bowel diary results and incontinence severity score. Patients with a successful PNE outcome were compared with those with an unsuccessful outcome; logistic regression analysis was used to identify any independent predictors of success. RESULTS: Fifty-two patients were recruited, of whom 32 (62 per cent) had a successful PNE outcome and 20 (38 per cent) an unsuccessful outcome. The AAR variable opening pressure was significantly greater in patients who subsequently had a successful PNE result compared with the pressure in patients who did not (28 versus 17 cmH2 O; P = 0·008). No difference was seen in the manometric equivalent, maximum resting pressure. Opening pressure was an independent predictor of success with an odds ratio of 1·08 (95 per cent confidence interval 1·01 to 1·16; P = 0·018). CONCLUSION: AAR is a sensitive test of sphincter function and can identify differences between patients who respond to PNE and those who do not. Opening pressure is an independent predictor of success in PNE, and may be of value in the selection of patients for this expensive treatment option.

DSM-5 disruptive mood dysregulation disorder: correlates and predictors in young children.

BACKGROUND: Despite the inclusion of disruptive mood dysregulation disorder (DMDD) in DSM-5, little empirical data exist on the disorder. We estimated rates, co-morbidity, correlates and early childhood predictors of DMDD in a community sample of 6-year-olds. METHOD: DMDD was assessed in 6-year-old children (n = 462) using a parent-reported structured clinical interview. Age 6 years correlates and age 3 years predictors were drawn from six domains: demographics; child psychopathology, functioning, and temperament; parental psychopathology; and the psychosocial environment. RESULTS: The 3-month prevalence rate for DMDD was 8.2% (n = 38). DMDD occurred with an emotional or behavioral disorder in 60.5% of these children. At age 6 years, concurrent bivariate analyses revealed associations between DMDD and depression, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, functional impairment, poorer peer functioning, child temperament (higher surgency and negative emotional intensity and lower effortful control), and lower parental support and marital satisfaction. The age 3 years predictors of DMDD at age 6 years included child attention deficit hyperactivity disorder, oppositional defiant disorder, the Child Behavior Checklist - Dysregulation Profile, poorer peer functioning, child temperament (higher child surgency and negative emotional intensity and lower effortful control), parental lifetime substance use disorder and higher parental hostility. CONCLUSIONS: A number of children met DSM-5 criteria for DMDD, and the diagnosis was associated with numerous concurrent and predictive indicators of emotional and behavioral dysregulation and poor functioning.

Management of large bowel obstruction with self-expanding metal stents. A multicentre retrospective study of factors determining outcome.

AIM: UK cancer guidelines recommend patients with colonic obstruction due to suspected malignancy be considered for stenting with a self-expanding metal stent (SEMS). Considerable variation in practice exists due to a lack of expertise, technical difficulties and other, as yet ill-defined features. This retrospective multi-centre study aims to determine the outcome following colonic stenting for large bowel obstruction and identify factors associated with successful intervention. METHOD: A regional programme of colonic stenting for large bowel obstruction, in five UK centres from 2005 to 2010 was evaluated for outcome including technical and clinical success, survival, complications and reoperation. RESULTS: A SEMS was inserted in 334 patients, including 264 (79.0%) for palliation and 52 (15.6%) as a bridge to surgery. Technical success was achieved in 292 (87.4%) patients, with 46 (13.8%) experiencing a complication or technical failure. Reoperation was required in 39 (14.8%) patients stented for palliation of colorectal cancer of whom 16 (6.1%) subsequently required a colostomy. A one-stage primary anastomosis was achieved in 35 (67.3%) of the 52 patients undergoing stenting as a bridge to resection. Technical success did not vary by indication or site of obstruction (P = 0.60) but was higher for operators who had performed more than 10 procedures (OR 3.34, P = 0.001). ASA grade ≥3 predicted a worse clinical outcome (OR 0.43, P = 0.04). The through-the-scope (TTS) endoscopy technique was more successful than radiological placement alone (90.3% vs 74.8%, P < 0.001). CONCLUSION: Experienced operators using a TTS technique achieved a better outcome for the emergency management of large bowel obstruction. Older, sicker patients and those with extracolonic and benign strictures fared less well.

Blood glucose levels in children with Type 1 diabetes attending a residential diabetes camp: a 2-year review.

AIMS: The objective of this retrospective analysis of blood glucose values at a week-long residential summer camp for children with Type 1 diabetes was to provide experiential data to reinforce current summer camp guidelines and to determine if specific interventions implemented between 2009 and 2010 were effective in lowering average blood glucose among our campers without increasing risk of hypoglycaemia. METHODS: Blood glucose records were obtained from a random selection of children who attended six 1-week camp sessions, three each in 2009 and 2010. Five values per day: pre-meal breakfast, lunch and dinner, pre-evening snack and midnight values were analysed. RESULTS: A total of 13,267 blood glucose values were included. There were no severe hypoglycaemic episodes, seizures or need for full-dose glucagon or intravenous glucose in either year. Mean blood glucose was significantly lower in 2010 compared with 2009 (9.22 vs. 10.06 mmol/l, P < 0.001). Older age and camp year were associated with lower mean blood glucose, even when controlling for gender and duration of diabetes. CONCLUSIONS: This analysis is the largest so far conducted at a residential diabetes camp. Mean blood glucose levels were lower than other published studies. Although we cannot attribute a cause-and-effect relationship between our interventions and the improvement in blood glucose between 2009 and 2010, the use of pre-meal insulin bolus doses, low glycaemic meals and highlighting blood glucose levels in logs before being reviewed by endocrinologists are strongly encouraged. From this study we hope to establish benchmarks for comparison among camps and begin to identify best practices.

Absolute abundance and function of intestinal drug transporters: a prerequisite for fully mechanistic in vitro-in vivo extrapolation of oral drug absorption.

The use of whole body physiological-based pharmacokinetic (PBPK) models linked with in vitro-in vivo extrapolation (IVIVE) of kinetic parameters from laboratory experiments, has become embedded within many of the pharmaceutical industry and is used even as part of regulatory submissions. These include the influence of transporter proteins on drug disposition, a subject for which we have witnessed an increasing awareness. A combination of the development of high-powered analytical techniques and antibody-based technology, together with a realization that an understanding of absolute transporter protein abundances together with activity can potentially enhance the modelling of transporter kinetics by PBPK-IVIVE link models. This review summarizes the mechanistic approaches to integrate suitable non-biased in vitro transporter kinetic data relevant to the intestine (i.e. 'intrinsic' K(i) , 'intrinsic' K(m) ), by in vitro system modelling for these kinetic inputs with the advantages of, and challenges for, generating these data for input into PBPK models. This step is considered as a prerequisite for mechanistic modelling of the oral absorption for drugs that are substrates for transporters. Various approaches are provided to integrate intestinal transporter expression into PBPK models with a perspective on the incorporation of the absolute abundance/activity of transporters to enhance the predictive power of the models. We define the key intestinal tissue and functional expression-based scaling factors required. The objective is to use these for facilitating the extrapolation from in vitro intestinal transporter assays to the in vivo system, using absolute quantification methodologies. The models could be used to elucidate the complex relationship and relative importance of metabolizing enzymes and transporters in drug disposition and toxicity.

Theoretical and empirical issues for marker-assisted breeding of congenic mouse strains.

Congenic breeding strategies are becoming increasingly important as a greater number of complex trait linkages are identified. Traditionally, the development of a congenic strain has been a time-consuming endeavour, requiring ten generations of backcrosses. The recent advent of a dense molecular genetic map of the mouse permits methods that can reduce the time needed for congenic-strain production by 18-24 months. We present a theoretical evaluation of marker-assisted congenic production and provide the empirical data that support it. We present this 'speed congenic' method in a user-friendly manner to encourage other investigators to pursue this or similar methods of congenic production.

Comparative study of anal acoustic reflectometry and anal manometry in the assessment of faecal incontinence.

BACKGROUND: Anal acoustic reflectometry (AAR) is a reproducible technique providing a novel physiological assessment of anal sphincter function. It may have advantages over conventional anal manometry. The aims of this study were to determine the ability of AAR and anal manometry to identify changes in anal sphincter function in patients with faecal incontinence (FI) and to relate these changes to the severity of FI. METHODS: Women with FI underwent assessment with AAR and anal manometry. All patients completed the Vaizey FI questionnaire and were classified according to symptom type (urge, passive or mixed) and integrity of the anal sphincters. The ability of AAR and anal manometry to correlate with symptom severity was evaluated. AAR was compared with anal manometry in detecting differences in anal sphincter function between symptomatic subgroups, and patients with and without a sphincter defect. RESULTS: One hundred women with FI were included in the study. The AAR variables opening pressure, opening elastance, closing elastance and squeeze opening pressure correlated with symptom severity, whereas the manometric measurements maximum resting pressure and maximum squeeze pressure did not. Unlike anal manometry, AAR was able to detect differences in anal sphincter function between different symptomatic subgroups. [corrected]. An anal sphincter defect was not associated with a significant change in anal sphincter function determined by either AAR or anal manometry. CONCLUSION: In the assessment of women with FI, AAR variables correlated with symptom severity and could distinguish between different symptomatic subgroups. AAR may help to guide management in these patients.

Autologous reconstruction of massive enteroatmospheric fistulation with a pedicled subtotal lateral thigh flap.

BACKGROUND: Reconstruction of massive contaminated abdominal wall defects associated with enteroatmospheric fistulation represents a technical challenge. An effective technique that allows closure of intestinal fistulas and reconstruction of the abdominal wall, with a good functional and cosmetic result, has yet to be described. The present study is a retrospective review of simultaneous reconstruction of extensive gastrointestinal tract fistulation and large full-thickness abdominal wall defects, using a novel pedicled subtotal thigh flap. METHODS: The flap, based on branches of the lateral circumflex femoral artery, was used to reconstruct the abdominal wall in six patients who were dependent on artificial nutritional support, with a median (range) of 4·5 (3-23) separate intestinal fistulas, within open abdominal wounds with a surface area of 564·5 (204-792) cm2. Intestinal reconstruction was staged, with delayed closure of a loop jejunostomy. Median follow-up was 93·5 (10-174) weeks. RESULTS: Successful healing occurred in all patients, with no flap loss or gastrointestinal complications. One patient died from complications of sepsis unrelated to the surgical treatment. All surviving patients gained complete nutritional autonomy following closure of the loop jejunostomy. CONCLUSION: Replacement of almost the entire native abdominal wall in patients with massive contaminated abdominal wall defects is possible, without the need for prosthetic material or microvascular free flaps. The subtotal pedicled thigh flap is a safe and effective method of providing definitive treatment for patients with massive enteroatmospheric fistulation.

Joint Inversion of GNSS and GRACE for Terrestrial Water Storage Change in California.

Global Navigation Satellite System (GNSS) vertical displacements measuring the elastic response of Earth's crust to changes in hydrologic mass have been used to produce terrestrial water storage change (∆TWS) estimates for studying both annual ∆TWS as well as multi-year trends. However, these estimates require a high observation station density and minimal contamination by nonhydrologic deformation sources. The Gravity Recovery and Climate Experiment (GRACE) is another satellite-based measurement system that can be used to measure regional TWS fluctuations. The satellites provide highly accurate ∆TWS estimates with global coverage but have a low spatial resolution of ∼400 km. Here, we put forward the mathematical framework for a joint inversion of GNSS vertical displacement time series with GRACE ∆TWS to produce more accurate spatiotemporal maps of ∆TWS, accounting for the observation errors, data gaps, and nonhydrologic signals. We aim to utilize the regional sensitivity to ∆TWS provided by GRACE mascon solutions with higher spatial resolution provided by GNSS observations. Our approach utilizes a continuous wavelet transform to decompose signals into their building blocks and separately invert for long-term and short-term mass variations. This allows us to preserve trends, annual, interannual, and multi-year changes in TWS that were previously challenging to capture by satellite-based measurement systems or hydrological models, alone. We focus our study in California, USA, which has a dense GNSS network and where recurrent, intense droughts put pressure on freshwater supplies. We highlight the advantages of our joint inversion results for a tectonically active study region by comparing them against inversion results that use only GNSS vertical deformation as well as with maps of ∆TWS from hydrological models and other GRACE solutions. We find that our joint inversion framework results in a solution that is regionally consistent with the GRACE ∆TWS solutions at different temporal scales but has an increased spatial resolution that allows us to differentiate between regions of high and low mass change better than using GRACE alone.

Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.

The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis.