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Biomedical subjects

G Cohen

Publications and source records attributed to G Cohen.

At least 19 recordsLinked to original sources
PubMed2006

Radiological damage in patients with rheumatoid arthritis on sustained remission.

OBJECTIVE: To assess the radiological damage progression in patients with recent rheumatoid arthritis in sustained remission. METHODS: A cohort of 191 patients with active early (<1 year) rheumatoid arthritis was prospectively assessed at baseline, 3 and 5 years by the Disease Activity Score (DAS) and the Sharp-van der Heijde Score (SHS) for radiographic damage. Patients in remission (DAS<1.6) at the 3-year and 5-year time points were compared with patients with a persistently active rheumatoid arthritis by Wilcoxon's signed rank test. RESULTS: 57 patients died, were lost to follow-up or had incomplete data; 30 (15.7% of those who completed) patients were in remission at 3 and 5 years. The SHS in these two groups was not significantly different at baseline (p = 0.15), but was lower in the remission group at 5 years (p = 0.0047). The median (IQR) radiographic score increased from 0.5 (0-7) at baseline to 2.5 (0-14) after 5 years for the remission group (p = 0.18) and from 2 (0-7) to 13 (3-29) in the group with active rheumatoid arthritis (p<0.001). 5 (16.7%) patients in remission had relevant progression of radiographic damage (ie, progression >4.1 points) and 6 (20%) presented new erosions in a previously unaffected joint between the third and the fifth years. CONCLUSION: Patients with early rheumatoid arthritis in sustained remission did not present statistically significant radiographic degradation at the group level; nevertheless, 16.7% of these patients did present degradation. Absence of progression should be part of the remission definition in rheumatoid arthritis.

Adult↗
PubMed2006

Contact area measurements reveal loading-history dependence of static friction.

We perform quantitative measurements of the actual area of contact, A, formed by two rough solids that are subjected to different normal loading protocols. We show that microscopic motion, induced by Poisson contraction or expansion, produces a strong memory dependence of on the loading history with a large corresponding influence on the system's frictional strength. These effects, together with accompanying transient dynamics, are independent of humidity, loading rates, and material contrast across the interface.

Journal Article↗
PubMed2006

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators.

PKC-delta is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-delta slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-delta dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-delta using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-delta caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P<0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21(Waf1), a cyclin-dependent kinase (cdk) inhibitor in PKC-delta transfectants compared with empty vector (EV) transfected cells, whereas the PKC-delta specific inhibitor rottlerin (3 microM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21(Waf1) expression. Concomitantly, compared to EV control cells, PKC-delta upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-delta increased binding of cdk inhibitor p27(Kip1) to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-delta plays in cell growth and cell cycle regulation, we knocked down PKC-delta using specific siRNA oligonucleotides. PKC-delta specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-delta protein by more than 80% in Caco-2 cells. Moreover, PKC-delta knockdown enhanced cell proliferation ( approximately 1.4-2-fold, P<0.05) and concomitantly increased cyclin D1 and cyclin E expression ( approximately 1.7-fold, P<0.05). This was a specific effect, as nontargeted PKC-zeta was not changed by PKC-delta siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-delta transfectants, compared to EV cells, PKC-delta upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-delta specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-delta regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-delta that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-delta in colonic carcinogenesis.

Apoptosis↗
PubMed2006

Cyclooxygenase-2 (PTGS2) inhibitors augment the rate of hexose transport in L6 myotubes in an insulin- and AMPKalpha-independent manner.

AIMS/HYPOTHESIS: Some cyclooxygenase-2 (COX2, also known as prostaglandin-endoperoxide synthase 2 [PTGS2]) inhibitors have been shown to increase insulin sensitivity in man or induce hypoglycaemic episodes when overconsumed or taken in combination with oral hypoglycaemic drugs. These side-effects and their impact on patients are not always recognised in routine clinical practice. We investigated whether these side-effects of COX2 (PTGS2) inhibitors result from stimulation of the glucose transport system in skeletal muscle cells. MATERIALS AND METHODS: L6 myotube cultures were used to study effects of COX2 (PTGS2) inhibitors on the glucose transport system and their relationship to PTGS2 expression, insulin action and AMP-activated protein kinase alpha (AMPKalpha) activity. RESULTS: The inhibitors niflumic acid, nimesulide and rofecoxib increased the rate of hexose uptake in L6 myotubes in the absence of insulin and in a dose- and time-dependent manner. They did this by increasing the total cell content of member 4 of the solute carrier family 2 (SCLC2A4, previously known as glucose transporter 4 [GLUT4]) (but not SCLC2A1 [previously known as GLUT1]) mRNA and protein and the amount of it in the plasma membrane. AMPKalpha was not involved in the latter effect since the inhibitors did not activate it. In addition, none of the inhibitors modulated the rate of hexose transport in vascular endothelial and smooth muscle cells expressing PTGS2 and SCLC2A1. Prostaglandin-endoperoxide synthase 1 (also known as cyclooxygenase 1) inhibitors (acetylsalicylic acid and indomethacin) did not alter the rate of hexose uptake and SCLC2A4 subcellular distribution in L6 myotubes. CONCLUSIONS/INTERPRETATION: This study suggests that certain COX2 (PTGS2) inhibitors can alter glucose homeostasis in vivo by stimulating glucose uptake in skeletal muscles that express PTGS2.

AMP-Activated Protein Kinases↗
PubMed2006

[Total hip arthroplasty after failure of per- and subtrochanteric fracture fixation in elderly subjects].

PURPOSE OF THE STUDY: Most pertrochanteric fractures can be successfully fixed with osteosynthesis. Osteosynthesis fails however is a small number of patients who require re-operation for implantation of a total hip prosthesis. This situation occurs in particular when the material has penetrated the acetabulum and in elderly subjects. Although this type of arthroplasty is routine practice, few series have been reported. We present here outcome and complications of total hip arthroplasty after failure of per- and sub-trochanteric fracture fixation. MATERIAL AND METHODS: Between 1990 and 2000, twenty patients aged 79 years on average (range 62-78 years) underwent revision for total hip arthroplasty after failure of osteosynthesis for fracture of the upper femur. A gliding THS had been used for fixation in 18 patients, a plate in one and a Gamma nail in one. Osteosynthesis failure was related to early disassembly in ten patients, pseudarthrosis in eight and malunion in two. Revision was performed via a posterolateral approach in all cases. A standard total hip prosthesis was used in 16 patients, a longer femoral stem was required in four. Femoral components were cemented in 18 patients and non-cemented in two. The cup was a standard cemented cup in 12, retaining and cemented in eight. RESULTS: Mean operative time and blood loss were greater than in first-intention arthroplasties. All patients had lost their independence prior to the revision procedure. Despite their age, all recovered independence after a stay in rehabilitation. Most still required crutches. Use of a retaining cup enabled avoiding dislocation in all cases. For those who did not have a retaining cup, dislocation was the most frequent complication (3/12). The difficulties observed were: 1) elimination of associated infection before surgery; many of these elderly subjects had altered ESR and CRP values for various reasons; 2) abnormal position of the trochanteric mass because of a rotation defect; 3) malunion of the upper femur in the frontal or sagittal planes; 4) more or less easily achieved positioning of the femoral piece on the calcar; 5) difficult intraoperative identification of limb length due to loss of usual landmarks on the lesser and greater trochanter; 6) removal of fracture screws which sometimes required use of a trephine and bridging the last screw hole with a longer centromedullary stem. The most frequent postoperative orthopedic problems were leg length discrepancy (1-2 cm for eight patients), gluteus medius insufficiency, limping and pain at palpation of the trochanteric area. DISCUSSION: Despite the difficult technique and the potential complications which are more important than for first-intention arthroplasties, this series demonstrates that total hip prosthesis is a reliable solution for treating fixation failures of the upper femur.

Age Factors↗
PubMed2006

The prevalence of congenital and early-onset hearing loss in Jordanian and Israeli infants.

The objective of the study was to investigate the prevalence of congenital and early-onset hearing loss, and the influence of the known risk factors for hearing loss on infants in Jordan and Israel. Subjects were a total of nearly 17,000 infants from both countries, including infants with and without risk factors for hearing loss. The hearing screening protocol included distortion product otoacoustic emission, followed in case of repeated OAE referral or high risk (HR) infant by diagnostic auditory brainstem responses. The results indicate that the prevalence and severity of hearing loss amongst Jordanian infants (1.37%) is remarkably higher as compared to the Israeli infants (0.48%). The overall prevalence of bilateral SNHL was seven times more in the Jordanian infants, 18 times in non-risk, and three times in the HR infants relative to the Israeli infants. Risk factors including family history, hyperbilirubinemia, bacterial meningitis, and associated syndromes were more prevalent amongst Jordanian infants. This unique study underscores the importance of sharing and exchanging information to create empirical data to guide health-care providers in adapting protocols to the local constraints in developing countries.

Developing Countries↗
PubMed2005

Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: an electrographic, behavioral, and histological study in freely moving rats.

Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 +/- 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 +/- 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.

Administration, Intranasal↗
PubMed2005

Universality and hysteretic dynamics in rapid fracture.

Experiments in the dynamic fracture of brittle polyacrylamide gels show that a single-crack state undergoes a hysteretic transition to the microbranching instability with a characteristic activation time. Quantitative measurements also indicate that features such as crack front inertia, self-focusing of microbranches, and the appearance of front waves are universal attributes of dynamic fracture.

Journal Article↗
PubMed2005

Primary spontaneous pneumothorax in children: the role of CT in guiding management.

AIM: Primary spontaneous pneumothorax (PSP) is rare in older children and most likely to be associated with apical subpleural blebs; there is a significant risk of recurrence. Our aim was to assess the radiological findings and final treatment of PSP in children presenting at our institution. METHODS: The study included 3 children presenting over a 15-month period at our institution with PSP; the clinical features at presentation and examination findings were recorded. The chest radiographic and CT appearances and findings at surgery were reviewed. RESULTS: In all cases, chest pain and breathlessness were presenting features and initial treatment included intercostal chest drainage. Chest radiographs on admission raised the suspicion of unilateral apical blebs in 2 children and bilateral apical blebs in the 3rd. Chest CT demonstrated apical blebs/cysts in all 3 children. The cysts ranged in size from 0.5 to 3.0 cm and were bilateral in 2 children. Surgery confirmed the radiological findings in all cases. CONCLUSION: CT is of value in the detection of apical pleural blebs in children with PSP. On CT, particular attention should be paid to the lung apices, where majority of blebs in otherwise healthy young patients are located. Prompt diagnosis of a morphological abnormality in these children is likely to expedite definitive surgical treatment.

Adolescent↗
PubMed2005

[Not Available].

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Journal Article↗
PubMed2004

Crosstalk between protein kinase A and C regulates phospholipase D and F-actin formation during sperm capacitation.

Mammalian spermatozoa should reside in the female reproductive tract for a certain time before gaining the ability to fertilize. During this time, the spermatozoa undergo a series of biochemical processes collectively called capacitation. We recently demonstrated that actin polymerization is a necessary step in the cascade leading to capacitation. We demonstrate here for the first time a role for phospholipase D (PLD) in the induction of actin polymerization and capacitation in spermatozoa. The involvement of PLD is supported by specific inhibition of F-actin formation during sperm capacitation by PLD inhibitors and the stimulation of fast F-actin formation by exogenous PLD or phosphatidic acid (PA). Moreover, PLD activity is enhanced during capacitation before actin polymerization. Protein kinase A (PKA), known to be active in sperm capacitation, and protein kinase C (PKC), involved in the acrosome reaction, can both activate PLD and actin polymerization. We suggest that PKA- and PKC-dependent signal transduction pathways can potentially lead to PLD activation; however, under physiological conditions, actin polymerization depends primarily on PKA activity. Activation of PKA during capacitation causes inactivation of phospholipase C, and as a result, PKC activation is prevented. It appears that PKA activation promotes sperm capacitation whereas early activation of PKC during capacitation would jeopardize this process.

Actins↗
PubMed2004

Control of breathing in newborn mice lacking the beta-2 nAChR subunit.

AIM: To study the ventilatory and arousal/defence responses to hypoxia in newborn mutant mice lacking the beta2 subunit of the nicotinic acetylcholine receptors. METHODS: Breathing variables were measured non-invasively in mutant (n = 31) and wild-type age-matched mice (n = 57) at 2 and 8 days of age using flow barometric whole-body plethysmography. The arousal/defence response to hypoxia was determined using behavioural criteria. RESULTS: On day 2, mutant pups had significantly greater baseline ventilation (16%) than wild-type pups (P < 0.02). Mutant pups had a decreased hypoxic ventilatory declines. Arousal latency was significantly shorter in mutant than in wild-type pups (133 +/- 40 vs. 146 +/- 20 s, respectively, P < 0.026). However, the duration of movement elicited by hypoxia was shorter in mutant than in wild-type pups (14.7 +/- 5.9 vs. 23.0 +/- 10.7 s, respectively, P < 0.0005). Most differences disappeared on P8, suggesting a high degree of functional plasticity. CONCLUSION: The blunted hypoxic ventilatory decline and the shorter arousal latency on day 2 suggested that disruption of the beta2 nicotinic acetylcholine receptors impaired inhibitory processes affecting both the ventilatory and the arousal response to hypoxia during postnatal development.

Animals↗
PubMed2004

Granulocyte function in patients with L-ferritin iron-responsive element (IRE) 39C-->T-positive hereditary hyperferritinaemia-cataract syndrome.

BACKGROUND: Hereditary hyperferritinaemia-cataract syndrome (HHCS) is an autosomal dominant trait associated with mutations in the iron responsive element (IRE) of the ferritin light-chain (L-ferritin) gene. Patients typically show elevated serum ferritin concentrations without iron overload and a bilateral cataract. Hyperferritinaemia can be associated with granulocyte dysfunction in patients with thalassemia beta and in haemodialysis patients. The effect of increased L-ferritin levels on granulocyte function in patients with HHCS is unknown. MATERIAL AND METHODS: We examined glucose uptake, oxidative burst, chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations in polymorphonuclear leucocytes (PMNLs) of five affected members of a family with HHCS and in five healthy individuals matched for age and gender. RESULTS: Mutation testing revealed a 39C-->T transition in IRE in all five patients with HHCS. Serum ferritin levels of patients ranged between 907 and 2030 microg L(-1), respectively. In comparison with healthy individuals, PMNLs of patients with HHCS showed a significant increase in PMA-mediated stimulation of the oxidative burst, as well as a significantly higher stimulation of glucose uptake but no difference with respect to chemotaxis, phagocytosis, apoptosis and intracellular calcium concentrations. CONCLUSION: In summary, our study suggests that hyperferritinaemia in patients with IRE 39C-->T-positive HHCS is associated with activation of PMNLs but not with disturbance of fundamental PMNL function.

Adolescent↗
PubMed2004

Retinol binding protein isolated from acute renal failure patients inhibits polymorphonuclear leucocyte functions.

BACKGROUND: Protein factors accumulating in sera of patients with end-stage renal disease (ESRD) that interfere with the nonspecific immune response by inhibiting essential functions of polymorphonuclear leucocytes (PMNLs) have previously been described. No such factor has been isolated from acute renal failure (ARF) patients to date. MATERIALS AND METHODS: Using a three-step chromatographic procedure involving ion exchange, size exclusion and hydrophobic interaction chromatography we purified the apo- and holo-form of retinol binding protein (RBP) from high-flux dialyser (polyacrylonitrile; AN69) ultrafiltrates of patients with ARF. Their effect on the chemotaxis of PMNLs isolated from healthy donors was determined by the under-agarose method. Whole-blood assays applying flow cytometry were used to assess phagocytosis and the oxidative metabolism of PMNLs. Apoptosis was assessed by determining the DNA content using propidium iodide. RESULTS: Isolated apo- and holo-forms of RBP were truncated on their C-terminus as determined by mass spectrometry. All isolates significantly inhibited the chemotactic movement of PMNLs obtained from healthy donors and the PMNL oxidative metabolism stimulated by E. coli. These effects were concentration dependent. Retinol binding protein had no influence on the PMNL oxidative metabolism stimulated by PMA and on PMNL phagocytosis. Commercially available RBP isolated from urine influenced PMNL functions in the same way. Inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580 significantly attenuated the phagocytosis-induced respiratory burst and RBP did not lead to a further decrease. Polymorphonuclear leucocyte apoptosis was significantly inhibited by RBP. CONCLUSIONS: The apo- and holo-forms of RBP isolated from the ultrafiltrate of ARF patients inhibit PMNL chemotaxis, oxidative metabolism and apoptosis. Therefore, RBP may be considered a uraemic toxin contributing to a disturbed immune defence.

Acute Kidney Injury↗
PubMed2004

Cardiac ECMO for biventricular hearts after paediatric open heart surgery.

OBJECTIVE: To delineate predictors of hospital survival in a large series of children with biventricular physiology supported with extracorporeal membrane oxygenation (ECMO) after open heart surgery. RESULTS: 81 children were placed on ECMO after open heart surgery. 58% (47 of 81) were transferred directly from cardiopulmonary bypass to ECMO. Hospital survival was 49% (40 of 81) but there were seven late deaths among these survivors (18%). Factors that improved the odds of survival were initiation of ECMO in theatre (64% survival (30 of 47)) rather than the cardiac intensive care unit (29% survival (10 of 34)) and initiation of ECMO for reactive pulmonary hypertension. Important adverse factors for hospital survival were serious mechanical ECMO circuit problems, renal support, residual lesions, and duration of ECMO. CONCLUSIONS: Hospital survival of children with biventricular physiology who require cardiac ECMO is similar to that found in series that include univentricular hearts, suggesting that successful cardiac ECMO is critically dependent on the identification of hearts with reversible ventricular dysfunction. In our experience of postoperative cardiac ECMO, the higher survival of patients cannulated in the operating room than in the cardiac intensive care unit is due to early effective support preventing prolonged hypoperfusion and the avoidance of a catastrophic cardiac arrest.

Cardiopulmonary Bypass↗
PubMed2003

Immunoglobulin light chains modulate polymorphonuclear leucocyte apoptosis.

BACKGROUND: Apoptosis of polymorphonuclear leucocytes (PMNLs) is important for the resolution of inflammation. Recently, we demonstrated that glucose-modified proteins increase PMNL apoptosis. No protein factors in sera of uraemic patients attenuating PMNL apoptosis have been identified to date. MATERIALS AND METHODS: We tested the influence of commercially available monoclonal immunoglobulin light chains (IgLCs) from multiple myeloma patients and polyclonal IgLCs isolated from haemodialysis patients, previously shown to modulate PMNL functions and to contribute to their prestimulation, on PMNL apoptosis. We detected morphological changes, DNA strand breaks and the loss of DNA content. RESULTS: All three apoptosis assays showed that kappa and lambda type IgLCs increase the percentage of viable PMNLs by inhibiting apoptosis in a concentration-dependent manner. The effect of IgLCs was abolished by specific antibodies. Addition of genistein abolished the reduction of PMNL apoptosis by IgLCs, suggesting that IgLCs exert their effect via tyrosine phosphorylation. Furthermore, we showed that the inhibition of caspase-3 activity is involved in the decrease of PMNL apoptosis. CONCLUSION: In concentrations present in sera of uraemic patients IgLCs could interfere with the normal resolution of inflammation and thereby contribute to the chronic inflammatory state found in end-stage renal disease patients.

Apoptosis↗