48 research outputs found
CFU-S(11) activity does not localize solely with the aorta in the aorta-gonad-mesonephros region
The aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site in
the midgestation mouse conceptus and first contains colony-forming
units-spleen day 11 (CFU-S(11)) at embryonic day 10 (E10). Because
CFU-S(11) activity is present in the AGM region before the onset of
hematopoietic stem cell (HSC) activity, CFU-S(11) activity in the complex
developing vascular and urogenital regions of the AGM was localized. From
E10 onward, CFU-S(11) activity is associated with the aortic vasculature,
and is found also in the urogenital ridges (UGRs). Together with data
obtained from organ explant cultures, in which up to a 16-fold increase in
CFU-S(11) activity was observed, it was determined that CFU-S(11) can be
increased autonomously both in vascular sites and in UGRs. Furthermore,
CFU-S(11) activity is present in vitelline and umbilical vessels. This,
together with the presence of CFU-S(11) in the UGRs 2 days before HSC
activity, suggests both temporally and spatially distinct emergent sources
of CFU-S(11). (Blood. 2000;96:2902-2904
Detecting functional decline from normal aging to dementia: Development and validation of a short version of the Amsterdam IADL Questionnaire
Introduction Detecting functional decline from normal aging to dementia is relevant for diagnostic and prognostic purposes. Therefore, the Amsterdam IADL Questionnaire (A-IADL-Q) was developed: a 70-item proxy-based tool with good psychometric properties. We aimed to design a short version while preserving its psychometric quality. Methods Study partners of subjects (n = 1355), ranging from cognitively normal to dementia subjects, completed the original A-IADL-Q. We selected the short version items using a stepwise procedure combining missing data, Item Response Theory, and input from respondents and experts. We investigated internal consistency of the short version and concordance with the original version. To assess its construct validity, we additionally investigated concordance between the short version and the Mini–Mental State Examination (MMSE) and Disability Assessment for Dementia (DAD). Finally, we investigated differences in instrumental activities of daily living (IADL) scores between diagnostic groups across the dementia spectrum. Results We selected 30 items covering the entire spectrum of IADL functioning. Internal consistency (0.98) and concordance with the original version (0.97) were very high. Concordance with the MMSE (0.72) and DAD (0.87) scores was high. IADL impairment scores increased across the spectrum from normal cognition to dementia. Discussion The A-IADL-Q short version (A-IADL-Q-SV) consists of 30 items and has maintained the psychometric quality of the original A-IADL-Q. As such, the A-IADL-Q-SV is a concise measure of functional decline
New rat model that phenotypically resembles autosomal recessive polycystic kidney disease
Numerous murine models of polycystic kidney disease (PKD) have been
described. While mouse models are particularly well suited for
investigating the molecular pathogenesis of PKD, rats are well established
as an experimental model of renal physiologic processes. Han:SPRD-CY: rats
have been proposed as a model for human autosomal dominant PKD. A new
spontaneous rat mutation, designated wpk, has now been identified. In the
mutants, the renal cystic phenotype resembles human autosomal recessive
PKD (ARPKD). This study was designed to characterize the clinical and
histopathologic features of wpk/wpk mutants and to map the wpk locus.
Homozygous mutants developed nephromegaly, hypertension, proteinuria,
impaired urine-concentrating capacity, and uremia, resulting in death at 4
wk of age. Early cysts were present in the nephrogenic zone at embryonic
day 19. These were localized, by specific staining and electron
microscopy, to differentiated proximal tubules, thick limbs, distal
tubules, and collecting ducts. In later stages, the cysts were largely
confined to collecting ducts. Although the renal histopathologic features
are strikingly similar to those of human ARPKD, wpk/wpk mutants exhibited
no evidence of biliary tract abnormalities. The wpk locus maps just
proximal to the CY: locus on rat chromosome 5, and complementation studies
demonstrated that these loci are not allelic. It is concluded that the
clinical and renal histopathologic features of this new rat model strongly
resemble those of human ARPKD. Although homology mapping indicates that
rat wpk and human ARPKD involve distinct genes, this new rat mutation
provides an excellent experimental model to study the molecular
pathogenesis and renal pathophysiologic features of recessive PKD
Developmental defects and male sterility in mice lacking the ubiquitin-like DNA repair gene mHR23B.
mHR23B encodes one of the two mammalian homologs of Saccharomyces cerevisiae RAD23, a ubiquitin-like fusion protein involved in nucleotide excision repair (NER). Part of mHR23B is complexed with the XPC protein, and this heterodimer functions as the main damage detector and initiator of global genome NER. While XPC defects exist in humans and mice, mutations for mHR23A and mHR23B are not known. Here, we present a mouse model for mHR23B. Unlike XPC-deficient cells, mHR23B(-/-) mouse embryonic fibroblasts are not UV sensitive and retain the repair characteristics of wild-type cells. In agreement with the results of in vitro repair studies, this indicates that mHR23A can functionally replace mHR23B in NER. Unexpectedly, mHR23B(-/-) mice show impaired embryonic development and a high rate (90%) of intrauterine or neonatal death. Surviving animals display a variety of abnormalities, including retarded growth, facial dysmorphology, and male sterility. Such abnormalities are not observed in XPC and other NER-deficient mouse mutants and point to a separate function of mHR23B in development. This function may involve regulation of protein stability via the ubiquitin/proteasome pathway and is not or only in part compensated for by mHR23A
Generalized glycogen storage and cardiomegaly in a knockout mouse model of Pompe disease
Glycogen storage disease type II (GSDII; Pompe disease), caused by
inherited deficiency of acid alpha-glucosidase, is a lysosomal disorder
affecting heart and skeletal muscles. A mouse model of this disease was
obtained by targeted disruption of the murine acid alpha-glucosidase gene
(Gaa) in embryonic stem cells. Homozygous knockout mice (Gaa -/-) lack Gaa
mRNA and have a virtually complete acid alpha-glucosidase deficiency.
Glycogen-containing lysosomes are detected soon after birth in liver,
heart and skeletal muscle cells. By 13 weeks of age, large focal deposits
of glycogen have formed. Vacuolar spaces stain positive for acid
phosphatase as a sign of lysosomal pathology. Both male and female
knockout mice are fertile and can be intercrossed to produce progeny. The
first born knockout mice are at present 9 months old. Overt clinical
symptoms are still absent, but the heart is typically enlarged and the
electrocardiogram is abnormal. The mouse model will help greatly to
understand the pathogenic mechanism of GSDII and is a valuable instrument
to explore the efficacy of different therapeutic interventions
Reduced Vitamin K Status as a Potentially Modifiable Risk Factor of Severe Coronavirus Disease 2019
BACKGROUND: Respiratory failure and thromboembolism are frequent in SARS-CoV-2-infected patients. Vitamin K activates both hepatic coagulation factors and extrahepatic endothelial anticoagulant protein S, required for thrombosis prevention. In times of vitamin K insufficiency, hepatic procoagulant factors are preferentially activated over extrahepatic proteins. Vitamin K also activates matrix Gla protein (MGP), which protects against pulmonary and vascular elastic fiber damage. We hypothesized that vitamin K may be implicated in coronavirus disease 2019 (COVID-19), linking pulmonary and thromboembolic disease. METHODS: 135 hospitalized COVID-19 patients were compared with 184 historical controls. Poor outcome was defined as invasive ventilation and/or death. Inactive vitamin K-dependent MGP (dp-ucMGP) and prothrombin (PIVKA-II) were measured, inversely related to extrahepatic and hepatic vitamin K status, respectively. Desmosine was measured to quantify the rate of elastic fiber degradation. Arterial calcification severity was assessed by computed tomography. RESULTS: Dp-ucMGP was elevated in COVID-19 patients compared to controls (p<0.001), with even higher dp-ucMGP in patients with poor outcomes (p<0.001). PIVKA-II was normal in 82.1% of patients. Dp-ucMGP was correlated with desmosine (p<0.001), and coronary artery (p=0.002) and thoracic aortic (p<0.001) calcification scores. CONCLUSIONS: Dp-ucMGP was severely increased in COVID-19 patients, indicating extrahepatic vitamin K insufficiency, which was related to poor outcome while hepatic procoagulant factor II remained unaffected. These data suggest a mechanism of pneumonia-induced extrahepatic vitamin K depletion leading to accelerated elastic fiber damage and thrombosis in severe COVID-19 due to impaired activation of MGP and endothelial protein S, respectively. A clinical trial could assess whether vitamin K administration improves COVID-19 outcomes
When Limb Surgery Has Become the Only Life-Saving Therapy in FOP: A Case Report and Systematic Review of the Literature
Fibrodysplasia ossificans progressiva (FOP) is a rare disease in which heterotopic ossification (HO) is formed in muscles, tendons and ligaments. Traumatic events, including surgery, are discouraged as this is known to trigger a flare-up with risk of subsequent HO. Anesthetic management for patients with FOP is challenging. Cervical spine fusion, ankylosis of the temporomandibular joints, thoracic insufficiency syndrome, restrictive chest wall disease, and sensitivity to oral trauma complicate airway management and anesthesia and pose life-threatening risks. We report a patient with FOP suffering from life-threatening antibiotic resistant bacterial infected ulcers of the right lower leg and foot. The anesthetic, surgical and postoperative challenges and considerations are discussed. In addition, the literature on limb surgeries of FOP patients is systemically reviewed. The 44 year-old female patient was scheduled for a through-knee amputation. Airway and pulmonary evaluation elicited severe abnormalities, rendering standard general anesthesia a rather complication-prone approach in this patient. Thus, regional anesthesia, supplemented with intravenous analgosedation and N2O-inhalation were performed in this case. The surgery itself was securely planned to avoid any unnecessary tissue damage. Postoperatively the patient was closely monitored for FOP activity by ultrasound and [18F]PET/CT-scan. One year after surgery, a non-significant amount of HO had formed at the operated site. The systematic review revealed seventeen articles in which thirty-two limb surgeries in FOP patients were described. HO reoccurrence was described in 90% of the cases. Clinical improvement due to improved mobility of the operated joint was noted in 16% of the cases. It should be noted, though, that follow-up time was limited and no or inadequate imaging modalities were used to follow-up in the majority of these cases. To conclude, if medically urgent, limb surgery in FOP is possible even when general anesthesia is not preferred. The procedure should be well-planned, alternative techniques or procedures should be tested prior to surgery and special attention should be paid to the correct positioning of the patient. According to the literature recurrent HO should be expected after surgery of a limb, even though it was limited in the case described
Distress and quality of life after autologous stem cell transplantation: a randomized clinical trial to evaluate the outcome of a web-based stepped care intervention
Background Psychological distress (i.e. depression and anxiety) is a strong predictor of functional status and other aspects of quality of life in autologous stem cell transplantation following high-dose chemotherapy. Treatment of psychological distress is hypothesized to result in improvement of functional status and other aspects of quality of life. The aim is to evaluate the outcome of stepped care for psychological distress on functional status and other aspects of quality of life in patients with hematological malignancy treated with autologous stem cell transplantation. Methods/Design The study is designed as a randomized clinical trial with 2 treatment arms: a stepped care intervention program versus care as usual. Patients are randomized immediately pre transplant. Stepped care and care as usual are initiated after a 6 weeks buffer period. Outcome is evaluated at 13, 30, and 42 weeks post transplant. In the experimental group, the first step includes an Internet-based self-help program. If psychological distress persists after the self-help intervention, the second step of the program is executed, i.e. a diagnostic evaluation and a standardized interview, yielding a problem analysis. Based on this information, a contract is made with the patient and treatment is provided consisting of individual face-to-face counseling, medication, or referral to other services. Care as usual comprises an interview with the patient, on ad hoc basis; emotional support and advice, on ad hoc basis; if urgent problems emerge, the patient is referred to other services. Primary outcome variables are psychological distress and functional status. Data are analyzed according to the intention to treat-principle. Discussion This study has several innovative characteristics. First, the outcome of the intervention for psychological distress in patients with hematological malignancy treated with autologous stem cell transplantation is evaluated in a randomized controlled study. Second, the impact of the intervention on functional status is evaluated: it is hypothesized that reduction of psychological distress results in improved functional status. Furthermore, the intervention concerns an Internet-based treatment in the first step. Finally, the intervention is characterized by an emphasis on self-management, efficiency, and a multi-disciplinary approach with nurses taking up a central role
Consensus guidelines for lumbar puncture in patients with neurological diseases
Introduction Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. Methods We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Results Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. Discussion When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate
Risk factors for atherosclerotic and medial arterial calcification of the intracranial internal carotid artery
_Background and aims:_ Calcifications of the intracranial internal carotid artery (iICA) are an important risk factor for stroke. The calcifications can occur both in the intimal and medial layer of the vascular wall. The aim of this study is to assess whether medial calcification in the iICA is differently related to risk factors for cardiovascular disease, compared to intimal calcification.
_Methods:_ Unenhanced thin slice computed tomography (CT) scans from 1132 patients from the Dutch acute stroke study cohort were assessed for dominant localization of calcification (medial or intimal) by one of three observers based on established methodology. Associations between known cardiovascular risk factors (age, gender, body mass index, pulse pressure, eGFR, smoking, hypertension, diabetes mellitus, hyperlipidemia, previous vascular disease, and family history) and the dominant localization of calcifications were assessed via logistic regression analysis.
_Results:_ In the 1132 patients (57% males, mean age 67.4 years [SD 13.8]), dominant intimal calcification was present in 30.9% and dominant medial calcification in 46.9%. In 10.5%, no calcification was seen. Age, pulse pressure and family history were risk factors for both types of calcification. Multivariably adjusted risk factors for dominant intimal calcification only were smoking (OR 2.09 [CI 1.27–3.44]) and hypertension (OR 2.09 [CI 1.29–3.40]) and for dominant medial calcification diabetes mellitus (OR 2.39 [CI 1.11–5.14]) and previous vascular disease (OR 2.20 [CI 1.30–3.75]).
_Conclusions:_ Risk factors are differently related to the dominant localizations of calcifications, a finding that supports the hypothesis that the intimal and medial calcification represents a distinct etiology