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PubMed1992

Postoperative pulmonary function abnormalities after coronary artery bypass surgery.

In 18 patients, postoperative effects of coronary bypass surgery were evaluated. Pulmonary function studies were conducted preoperatively, and 1 and 6 weeks postoperatively, by means of spirometry, respiratory pressures, body plethysmography and impedance measurement of the respiratory system using the forced oscillation technique. One week postoperatively, total lung capacity (P less than 0.0001), inspiratory vital capacity (P less than 0.0001) forced expiratory volume (P less than 0.0001) and functional residual capacity (P less than 0.01) decreased significantly, while residual volume remained unchanged. This restrictive respiratory impairment was accompanied by significant decreases in inspiratory (P less than 0.0001) and expiratory (P less than 0.01) mouth pressures and significant decreases in respiratory resistance values (P less than 0.01). Six weeks postoperatively, significant differences in total lung capacity (P less than 0.0001), inspiratory vital capacity (P less than 0.0001) and forced expiratory volume (P less than 0.0001) persisted, while respiratory pressures returned to the preoperative values. It is concluded that respiratory muscle weakness contributes to the immediate postoperative restrictive lung function loss. Furthermore, structural alterations of chest wall mechanics have to be supposed for the persisting late restrictive pulmonary impairment.

Adult↗

PubMed2006

Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma.

BACKGROUND: Sex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men. OBJECTIVE: Sequence variants in the estrogen receptor alpha gene (ESR1) may alter estrogen action in asthma. METHODS: Two hundred asthma probands and their families (n=1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESR1 gene (intervening sequence 1 [IVS1]-1505A/G, IVS1-1415T/C, IVS1-397C/T, IVS1-351G/A and exon1+30T/C). Association with asthma and bronchial hyperresponsiveness (BHR) were tested. In the asthma probands, association of SNPs with BHR severity and annual FEV1 decline were determined. RESULTS: No SNP was associated with asthma. IVS1-397 was significantly associated with the presence of BHR (P=.02) and interacted with sex; female subjects with the CT or TT genotype were at risk (P=.01). In asthma probands, all SNPs were associated with FEV1 decline. Exon1+30 CT and TT group had an excess decline of 11.6 mL/y (P=.03) and 15.7 mL/y (P=.01), respectively, compared with the CC group. Of the IVS1 polymorphisms, IVS1-351G/A showed the strongest association, with the AA group having excess decline of 16.1 mL/y (P=.01) compared with the GG group. In subanalyses by sex, these associations were significant only in female subjects. CONCLUSION: ESR1 gene variants may affect development of BHR, particularly in female subjects. They may also lead to a more rapid lung function loss in patients with asthma, and in female subjects specifically. This may result from altered estrogen action, which affects lung development and/or airway remodeling. Further studies on ESR1 gene variations are important to understand better the origin of sex differences in asthma. CLINICAL IMPLICATIONS: Variations in the gene encoding estrogen receptor alpha are associated with BHR and a more rapid annual lung function decline, especially in female subjects. Even though this has no diagnostic or clinical implication, it may open avenues for future sex-specific treatment in asthma.

Adult↗

PubMed2006

[GRKs and arrestins: the therapeutic pathway?].

Phosphorylation of the agonist-activated form of G-protein-coupled receptors (GPCRs) by a protein kinase from the G-protein-coupled receptor kinase (GRK) family initiates, with arrestin proteins, a negative feedback process known as desensitization. Because these receptors are involved in so many vital functions, it seems likely that disorders affecting GRK- or arrestin-mediated regulation of GPCRs would contribute to, if not engender, disease. Traditionally, it is believed that the desensitization process protects the cell against an overstimulation; however, in certain situations, this process is maladjusted and participes in disease progression. For example, in Oguchi disease, excessive rhodopsin stimulation due to a functional loss of GRK1 or arrestin 1 leads to light sensitization and stationary night blindness. Also, transgenic mice with vascular smooth muscle-targeted overexpression of GRK2 showed an elevated resting blood pressure, suggesting that increase in GRK2 level in humans is involved in hypertension associated with a decreased effect of beta-adrenergic receptor-mediated vasorelaxation. The restoration of normal GPCR function in modulating the desensitization process has been successfully demonstrated in animal models of heart failure, which indicates that targeting GRKs or arrestins may open a novel therapeutic strategy in human diseases with GPCR dysregulation. However, the few effective pharmacological compounds in this domain currently preclude human clinical tests.

Arrestins↗

PubMed2006

Phenotypic analysis of mice lacking the Tmprss2-encoded protease.

Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2-/- mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2-/- mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2-/- mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2-/- mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.

Animals↗

PubMed1998

Combined characterization of composite tabular silver halide microcrystals by cryo-EFTEM/EELS and cryo-STEM/EDX techniques.

The combination of cryo-energy filtering transmission electron microscopy (EFTEM)/electron spectroscopic diffraction (ESD)/electron energy-loss spectroscopy (EELS) and cryo-energy-dispersive X-ray (EDX) analysis in the scanning transmission (STEM) and scanning (SEM) modes was applied for the characterization of composite tabular Ag(Br,I) microcrystals. A low-loss fine structure in EEL spectra between 4 and 26 eV was attributed to excitons and plasmons possibly superimposed with interband transitions and many-electron effects. The contrast tuning under the energy-filtering in the low-loss region was used to image the crystal morphology, defect structure (random dislocations and ¿111¿ stacking faults) and bend and edge contours as well as electron excitations in the microcrystals. Sharp extra reflections at commensurate positions in between the main Bragg reflections and diffuse honeycomb contours in ESD patterns of the microcrystals taken near the [111] zone were assigned to the number of defects in the shell region parallel to the grain edges and polyhedral clusters of interstitial silver cations, respectively. The imaginary part of the energy-loss function, Im (-1/epsilon), and the real and imaginary parts, epsilon1 and epsilon2, of the dielectric permittivity were determined by means of a Kramers-Kronig analysis. An assignment of exciton peaks based on calculations of electronic band structure of silver bromide is proposed. Inner-shell excitation bands of silver halide were detected in line with EDX-analyses. The energy-loss near-edge structure (ELNES) of the AgM4,5-edge governed by spin-orbital splitting between the 3d3/2- and 3d5/2-states has been evaluated. Combined silver and halide distributions were obtained by a three-window method (EFTEM) and by EDX/STEM including area mapping and line profiling of iodide.

Bromides↗

PubMed1994

Presence and further development of retinal dysfunction after 3-year follow up in IDDM patients without angiographically documented vasculopathy.

Abnormalities in neuroretinal function may play a role in the development of diabetic retinopathy. The natural course of diabetic retinal dysfunction in a group of subjects with insulin-dependent diabetes mellitus and with no apparent microvascular alterations in the retina was followed-up with fluorescein angiography and a sensitive electrophysiological technique, i.e., steady-state focal electroretinogram at the macula, for 3 years. Before the beginning and throughout our study, strict glycaemic control was maintained by three or four daily insulin injections under careful monitoring. Analysis of macular electroretinogram provided information from different neural layers. At the first examination, functional activities of postreceptoral neurons were significantly decreased with respect to those of age-matched control subjects. Diabetic patients showed a functional loss of both ganglion cell (0.53 +/- 0.09 vs 0.42 +/- 0.11 microV; t = 5; p = 0.0001) and preganglion cell (0.51 +/- 0.13 vs 0.42 +/- 0.14 microV; t = 2.8; p = 0.007) layers. Diabetes did not alter photoreceptor activity. After 3 years, dysfunction was significantly greater in the preganglion cell layer (0.28 +/- 0.11 microV; t = 6.3; p = 0.0001). Although in some patients further impairment of ganglion cell function was shown, no significant difference was found in 3 years. Photoreceptor function remained unaltered. No vascular abnormalities in the retina were noted after 3 years in this group of patients. Metabolic control was not correlated to functional changes. Our findings suggest that the middle retinal layer is the most sensitive physiological locus of progressive diabetes-induced dysfunction in the absence of angiographically documented abnormalities.

Adolescent↗

PubMed2005

[Differential therapy for the rheumatoid thumb].

The thumb frequently is involved in rheumatoid arthritis and often is a source of significant functional loss, pain, and deformity. Surgical intervention in patients with rheumatoid arthritis of the thumb should be based on the degree of radiological destruction according to Larsen, the natural course of the rheumatoid hand, the nature and stage of deformity as well as the status of tendons, ligaments, and adjacent joints. The goals of surgery are to relieve pain, increase motion, and restore thumb function. The timing for shoulder surgery should be early in the course of the disease, since it determines the long-term prognosis and the remaining surgical options. Treatment options, alone or in combination, include synovectomy, arthrodesis, arthroplasty, and tendon repair or transfer. Joint-preserving surgery is indicated in the early stages of radiological destruction according to Larsen classification O-III, whereas the late stages of destruction (Larsen IV-V) require reconstructive surgery. Especially in hand and finger arthritis, the "wait and see" strategy should no longer be followed. Close interdisciplinary cooperation between surgeon and rheumatologist is necessary for early therapeutic strategy, taking into account the functional unit of the whole upper extremity. The ultimate aim is to provide pain relief, improve function, enhance appearance, and slow the progression of disease. When the pathogenesis and pathoanatomy of the impaired rheumatoid thumb are appreciated, and appropriate treatment is selected, surgical intervention is likely to provide a favorable outcome for the patient.

Arthralgia↗

PubMed2026

The dynamic pool of Rec8-cohesin is crucial for meiotic recombination and transcription regulation in the yeast Saccharomyces cerevisiae.

Cohesin is a ring-shaped protein complex that mediates sister-chromatid cohesion (SCC) to ensure accurate chromosome segregation during mitosis and meiosis. In Saccharomyces cerevisiae, cohesin consists of four core subunits-Smc1, Smc3, Scc1/Mcd1, and Scc3. During meiosis, the mitotic α-kleisin Scc1/Mcd1 is replaced by the meiosis-specific α-kleisin Rec8. Rec8-containing cohesin is essential for multiple meiotic processes, including chromosome morphogenesis, homologous recombination, axis and synaptonemal complex formation, SCC, and transcriptional regulation. While stable association of Rec8-cohesin with chromatin is required to maintain SCC from premeiotic S phase through anaphase II, dynamic chromatin association is thought to underlie its roles in recombination, chromosome architecture, and transcription via loop extrusion. Whether distinct stable and dynamic pools of Rec8-cohesin coexist during meiosis and how their functions are partitioned remained unclear. Here, we employed an anchor-away strategy to conditionally deplete only the dynamic pool of Rec8-cohesin from the nucleus while preserving the stable pool. Selective depletion reduced sporulation efficiency and spore viability without compromising SCC. Calibrated ChIP-seq revealed a genome-wide reduction in Rec8-cohesin levels rather than locus-specific loss. Functional analyses demonstrated that the dynamic pool of Rec8-cohesin is required for efficient meiotic recombination, establishment of meiosis-specific chromosome architecture and synaptonemal complex formation, and proper transcriptional regulation of key meiotic regulators. In contrast, the stable pool alone was sufficient to maintain spindle pole body cohesion. Together, our findings demonstrate the existence of two functionally distinct pools of Rec8-cohesin during yeast meiosis.

Saccharomyces cerevisiae↗

PubMed2006

Regional correlation of structure and function in glaucoma, using the Disc Damage Likelihood Scale, Heidelberg Retina Tomograph, and visual fields.

PURPOSE: To evaluate relationships between the Disc Damage Likelihood Scale (DDLS), global and sectoral structural parameters provided by the Heidelberg Retina Tomograph (HRT), and global and regional functional loss in visual field (VF) testing. DESIGN: Consecutive observational case series. PARTICIPANTS: One hundred ten eyes from 110 patients categorized as glaucoma, glaucoma suspect, or normal. METHODS: Participants were examined clinically to grade the DDLS score and were tested with HRT and Swedish Interactive Threshold Algorithm standard 24-2 VF tests. All tests were performed within 6 months of each other by examiners masked to the other findings. For each patient, the eye with the worse mean deviation (MD) of the VF test was enrolled in the study. Each field was divided into 6 sectors based on a published scheme, and the MD for each sector was calculated. The relationships among clinical DDLS score, HRT parameters, and VF indexes were analyzed by correlation coefficients and linear regression analysis. MAIN OUTCOME MEASURES: The relationship between the DDLS score, global and sectoral optic disc (HRT) parameters, and global and sectoral VF MDs was evaluated. RESULTS: The DDLS showed significant correlation with all global and sectoral VF indexes (r = -0.39 to -0.62, all Ps < 0.0001) and with sectoral rim area HRT measurements (r = -0.27 to -0.51, all Ps < 0.006). The DDLS correlated most strongly with superior and inferior regional data from HRT and VF, and less well with temporal and nasal data. Heidelberg Retina Tomograph rim area and rim volume were the only HRT parameters to correlate moderately with global VF MD (r = 0.30, P = 0.0018, and r = 0.28, P = 0.0030, respectively). Sectoral HRT rim area correlated moderately strongly with the corresponding sectoral VF MDs in the superior and inferior sectors (r = 0.35-0.46, P = <0.0001-0.04). CONCLUSION: Clinical disc assessment and laser tomographic data that determine the state of the neuroretinal rim are associated with sensitivity loss in VF testing in corresponding regions.

Adolescent↗

PubMed2006

Comparative study on the forefoot and hindfoot intrinsic muscles of some cavioidea rodents (Mammalia, Rodentia).

The present study compares the forefoot and hindfoot musculature of five representative species of Cavioidea rodents. In all species, the musculature of both forefeet and hindfeet have the same array regardless of the absence of digit I in the manus of Hydrochaeris hydrochaeris and Cavia porcellus. Our results suggest a tendency in these species towards a three-digit system, with a functional loss of digit V and a predominance of digit III in their forefeet. In the same way, the muscular reduction of digit I in the other rodents analyzed indicates a four-digit system with predominance of digit II in Myoprocta acouchy and Dasyprocta leporina and of digit V in Agouti paca. There seems to be an association between the muscular arrangement and functional axis of the foot, raising the general question why this axis runs between the third and forth digit, or along the third digit.

Animals↗

PubMed1994

Symptoms and pulmonary functions as measures of morbidity.

A contemporary list of non-malignant respiratory conditions associated with exposure to environments contaminated by chrysotile asbestos dust includes pulmonary parenchymal and pleural fibrosis, small airway abnormality and conditions affecting the large airways such as chronic bronchitis and chronic airflow limitation. The first two are attributed to the specific biological effects of asbestos dust, the latter two to nonspecific effects of exposure to mineral dusts and/or other airborne pollutants in workplaces contaminated by asbestos dust. Prevalence rates for all the clinical markers of morbidity (radiographic change, lung function deficit and symptoms) have been shown to increase with increasing exposure to chrysotile but more steeply when exposure is in textile and other manufacturing plants than in mining and milling. The presence of amphiboles such as tremolite in the airborne dust may also result in steeper exposure-response relationships, while exposure in crocidolite mining results in very much steeper exposure-response relationships. Clinical asbestosis, though less frequent and less severe than previously, is still associated with increased moribidity, while localized pleural fibrosis in the form of plaques with minimal or no parenchymal fibrosis, currently the most frequently encountered non-malignant asbestos related condition encountered in clinical practice, may also be associated with morbidity, including lung function deficit. Determinants of progression of chrysotile-related parenchymal and pleural radiographic abnormality include duration and time since first exposure and, possibly, continued exposure after first appearance of radiographic changes. Progression of asbestos-related airway disease, documented as lung function loss over time, may, under the influence of continued exposure, be comparable to the progression observed under the influence of continued smoking.

Adult↗

PubMed2005

Clinicopathologic features, outcome, and therapeutic interventions in four children with isolated C3 mesangial proliferative glomerulonephritis.

Since isolated C3 mesangial proliferative glomerulonephritis in the absence of systemic disease (i-C3-GN) is an uncommon chronic glomerular disease, long-term prognosis and optimal therapeutic intervention for it are not yet fully defined, especially in children. We report clinical features, outcome, and interventions in 4 patients, ranging from 6 to 18 years old, with i-C3-GN. Microscopic or macroscopic hematuria with or without proteinuria was first noted between 3 and 8 years. When present, proteinuria ranged from 0.2 to 1.0 g/24 h. Persistent hypocomplementemia and circulating immune complexes were found in 1 patient. None of the patients had nephrotic syndrome or hypertension. Percutaneous renal biopsy specimens showed varying degrees of mesangial proliferative glomerulonephritis; 2 patients showed mild mesangial proliferation, while others exhibited moderate histologic severity. In 1 patient with a mild mesangial increase, tubulointerstitial changes were associated. Both patients exhibiting mild mesangial changes followed a benign clinical course with normal renal function over 10 years of follow-up. Patients with moderately severe mesangial alteration manifested slight renal function loss and moderate proteinuria at the time of biopsy, but these largely resolved after a six-month course of prednisolone combined with cyclophosphamide, warfarin, and an angiotensin-converting enzyme inhibitor. Thus, clinical manifestations and the need for aggressive treatment appear to vary among pediatric patients with i-C3-GN. Therapy combining prednisolone with immunosuppression seemed to reduce proteinuria and improve glomerular function in patients with moderately severe mesangial proliferation.

Adolescent↗

PubMed2002

CP27 affects viability, proliferation, attachment and gene expression in embryonic fibroblasts.

CP27 is a gene that has been cloned from an E11 early embryonic library and has been suggested to mediate early organogenesis (Diekwisch et al., 1999, Gene 235, 19). We have hypothesized that CP27 exhibits its effects on organogenesis by affecting individual cell function. Based on the CP27 expression pattern we have selected the CP27 expressing embryonic fibroblast cell line BALB/c 3T3 to determine the effects of CP27 on cell function. CP27 loss of function strategies were performed by adding 5, 12.5 or 25 micro g/ml anti-CP27 antibody to cultured BALB/c 3T3 cells and comparing the results to controls in which identical concentrations of rabbit serum were added to the culture medium. Other controls included an antibody against another extracellular matrix protein amelogenin (negative control) and anti-CP27 antibodies directed against other areas of the CP27 molecule (positive control). Following cell culture, cell viability, apoptosis, cell proliferation, cell shape, cellular attachment and fibronectin matrix production were assayed using MTT colourimetric assay, BrdU staining, morphometry, immunostaining and western blot analysis. Block of CP27 function using an antibody strategy resulted in the following significant changes: (i) reduced viability, (ii) increased number of apoptotic cells, (iii) reduced proliferation, (iv) alterations in cell shape, (v) loss of attachment, and (vi) reduction in fibronectin matrix production. There was also a redistribution in fibronectin matrix organization demonstrated by immunohistochemistry. We conclude that CP27 plays an important role in the maintance of normal cell function and that CP27 block leads to significant changes in cellular behaviour.

3T3 Cells↗

PubMed2003

Lung function decrease in relation to pneumoconiosis and exposure to quartz-containing dust in construction workers.

BACKGROUND: Prevalence of exposure related respiratory symptoms and decreases in lung function are unknown among quartz dust exposed construction workers. METHODS: In a cross-sectional study (n = 1335), the occurrence of respiratory symptoms, was recorded and spirometric lung function was measured. Results were associated with exposure data and presence of radiographic abnormalities and compared with a reference population. RESULTS: Pneumoconiosis (profusion category 1/1 or greater) was associated with increased risks of FEV(1) and FVC values in the lowest 5% group, and with group-based decreases of 270 ml/s and 180 ml, respectively. Average lung function of construction workers was somewhat lower compared to a Dutch reference population. Lung function was not associated with exposure, except for a reduction in FVC of 5 ml per year for those with higher exposure. CONCLUSIONS: In quartz dust exposed construction workers obstructive and restrictive lung function loss was detected.

Adult↗

PubMed2005

Treatment of neurodegenerative diseases using adult bone marrow stromal cell-derived neurons.

Many neurodegenerative diseases are attributed to the degeneration of neurons with subsequent functional loss. Cell transplantation is a strategy with potential for treating such diseases, and many kinds of cells are considered candidates for transplantation therapy. Bone marrow stromal cells (MSCs) have great potential as therapeutic agents, as they are easy to isolate and expand from patients without serious ethical and technical problems. The authors have found a method for the highly efficient, exclusive and specific induction of functional postmitotic neuronal cells from both rat and human MSCs. Gene transfer of Notch intracellular domain (NICD) followed by the administration of certain trophic factors induced mature neurons expressing neuronal markers, some of which showed action potentials. Induced neurons were transplanted to animal models of neurodegenerative disorders, including Parkinson's disease and ischaemic brain injury, resulting in the successful integration of transplanted cells and improvement in function of the transplanted animals. This review summarises the respective potentials, benefits and drawbacks of MSC-derived neurons, and discusses the possibility of their clinical application in neurodegenerative diseases.

Adult↗

PubMed1985

Influence of hypoosmotic and ammonium chloride-mediated haemolysis on the integrity of human mononuclear blood cells.

Side effects of both hypoosmotic and ammonium chloride-mediated hemolysis were compared looking for cellular integrity of human peripheral blood mononuclear cells. Recovery and viability of mononuclear cells significantly declined only following water treatment. Cell loss by lysis of non-erythrocyte cells (monitored by 51Cr release) preferentially occurred in the lymphocyte population resulting in a relative enrichment of monocytes (identified by peroxidase and esterase staining as well as phagocytosis of fluorescent latex particles). Consequences of this shifted monocyte/lymphocyte ratio for immunological tests are obvious. Necessity of red cell lysis and disadvantages referred especially to NH4Cl-induced white cell functional losses are outlined.

Adolescent↗

PubMed2006

Olfactory ensheathing cells: ripples of an incoming tide?

Until now, brain and spinal cord injuries that sever nerve fibres have resulted in a degree of incurable functional loss. An incoming tide of research is now beginning to challenge this as yet unbreached sea wall. One of the most promising approaches involves a recently discovered type of cell, the olfactory ensheathing cell, which can be obtained from the adult nasal lining. In animal models transplantation of cultured olfactory ensheathing cells into an injured spinal cord induces regeneration, remyelination of severed spinal nerve fibres, and functional recovery. Although several clinical centres worldwide have shown an interest in applying this approach to patients with spinal cord injury, there is no agreement on cell technology, and claims of beneficial results lack independent confirmation. Important aspects still need to be worked out at the laboratory level. Overall, the outlook is optimistic, but there is still some way to go.

Animals↗

PubMed1992

Functional studies on long-term cryopreserved peripheral blood mononuclear cells from patients with lung cancer and from healthy subjects.

To determine the functional abilities of long-term cryopreserved peripheral blood mononuclear cells (PBMCs) from patients with lung cancer and from healthy subjects, we assayed the proliferative and plaque-forming cell (PFC) responses of cells from these individuals after the cells had been cryopreserved for up to 31 months. The stability of these cells for B and T cell quantitative assays was also determined by using their respective monoclonal antibodies. The patients' results were compared with those in healthy subjects to ascertain whether the conclusions derived from the assay of cryopreserved cells are consistent with our earlier studies on fresh cells from similar patients. The results show that proliferative and PFC responses of the frozen cells were not significantly affected by further storage, despite an initial, irreversible functional loss in some subsets of T lymphocytes and monocytes during the process of freezing. They also demonstrate that cryopreserved PBMCs from both patients and controls can be successfully utilized for B and T cell quantitative assays. The conclusions derived from the assay of cryopreserved cells are also consistent with our earlier observations on fresh cells from patients with lung cancer; those studies indicated a B cell functional abnormality caused in part by increased suppressor T cell and monocyte activity.

Aged↗