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A Kessel

Publications and source records attributed to A Kessel.

At least 37 records · Page 2Linked to original sources
PubMed2000

Calculations suggest a pathway for the transverse diffusion of a hydrophobic peptide across a lipid bilayer.

Alamethicin is a hydrophobic antibiotic peptide 20 amino acids in length. It is predominantly helical and partitions into lipid bilayers mostly in transmembrane orientations. The rate of the peptide transverse diffusion (flip-flop) in palmitoyl-oleyl-phosphatidylcholine vesicles has been measured recently and the results suggest that it involves an energy barrier, presumably due to the free energy of transfer of the peptide termini across the bilayer. We used continuum-solvent model calculations, the known x-ray crystal structure of alamethicin and a simplified representation of the lipid bilayer as a slab of low dielectric constant to calculate the flip-flop rate. We assumed that the lipids adjust rapidly to each configuration of alamethicin in the bilayer because their motions are significantly faster than the average peptide flip-flop time. Thus, we considered the process as a sequence of discrete peptide-membrane configurations, representing critical steps in the diffusion, and estimated the transmembrane flip-flop rate from the calculated free energy of the system in each configuration. Our calculations indicate that the simplest possible pathway, i.e., the rotation of the helix around the bilayer midplane, involving the simultaneous burial of the two termini in the membrane, is energetically unfavorable. The most plausible alternative is a two-step process, comprised of a rotation of alamethicin around its C-terminus residue from the initial transmembrane orientation to a surface orientation, followed by a rotation around the N-terminus residue from the surface to the final reversed transmembrane orientation. This process involves the burial of one terminus at a time and is much more likely than the rotation of the helix around the bilayer midplane. Our calculations give flip-flop rates of approximately 10(-7)/s for this pathway, in accord with the measured value of 1.7 x 10(-6)/s.

Alamethicin↗
PubMed2000

Continuum solvent model calculations of alamethicin-membrane interactions: thermodynamic aspects.

Alamethicin is a 20-amino acid antibiotic peptide that forms voltage-gated ion channels in lipid bilayers. Here we report calculations of its association free energy with membranes. The calculations take into account the various free-energy terms that contribute to the transfer of the peptide from the aqueous phase into bilayers of different widths. The electrostatic and nonpolar contributions to the solvation free energy are calculated using continuum solvent models. The contributions from the lipid perturbation and membrane deformation effects and the entropy loss associated with peptide immobilization in the bilayer are estimated from a statistical thermodynamic model. The calculations were carried out using two classes of experimentally observed conformations, both of which are helical: the NMR and the x-ray crystal structures. Our calculations show that alamethicin is unlikely to partition into bilayers in any of the NMR conformations because they have uncompensated backbone hydrogen bonds and their association with the membrane involves a large electrostatic solvation free energy penalty. In contrast, the x-ray conformations provide enough backbone hydrogen bonds for the peptide to associate with bilayers. We tested numerous transmembrane and surface orientations of the peptide in bilayers, and our calculations indicate that the most favorable orientation is transmembrane, where the peptide protrudes approximately 4 A into the water-membrane interface, in very good agreement with electron paramagnetic resonance and oriented circular dichroism measurements. The calculations were carried out using two alamethicin isoforms: one with glutamine and the other with glutamate in the 18th position. The calculations indicate that the two isoforms have similar membrane orientations and that their insertion into the membrane is likely to involve a 2-A deformation of the bilayer, again, in good agreement with experimental data. The implications of the results for the biological function of alamethicin and its capacity to oligomerize and form ion channels are discussed.

Alamethicin↗
PubMed2000

Immune aberrations in B and T lymphocytes derived from chronic urticaria patients.

To investigate the pathophysiology of chronic urticaria (CU) in light of the abundant evidences that it is an autoimmune disease and to define some cellular markers in B/T lymphocytes that could be of pathogenic significance, we investigated 14 patients suffering from CU, compared to 7 contact dermatitis patients and 10 normal control individuals. We tested the expression of CD5, B7.1 (CD80), CD23, and CD25 on B cells and of CD(40L)) and CD25 on T cells from all studied individuals. We also tested B cell proliferation upon their activation followed by dexamethazone induced inhibition of proliferation. The expression of bcl-2 protein in activated lymphocytes from normal individuals was compared to that of contact dermatitis and CU patients. CD(40L) expression was found significantly higher on in (vitro activated CD3 [with phorbol myristate acetate (PMA) and ionomycine Ca2+ at 12 hr of culture] from CU patients compared to that of contact dermatitis and normal individuals. Whereas the proliferation of activated B cells from CU patients was higher, dexamethazone-induced inhibition of B cell proliferation was found statistically similar in both groups yet lower in B cells from most severe CU patients. We demonstrate a higher bcl-2 expression in activated B and T lymphocytes of severe CU patients compared to that of moderate CU and both contact dermatitis and normal individuals. The increased expression of CD(40L) on activated T cells might play a role in the polyclonal increased B cell proliferation of CU patients. This increased proliferation accompanies the finding that activated B and T lymphocytes from these patients demonstrate increased bcl-2 expression. The resistance of some B cells to dexamethazone-induced inhibition of proliferation encourages us to investigate the possibility that B cells from some CU patients might develop rescue mechanisms from activated cell death. These findings provide further evidence that CU is indeed an autoimmune disease, although its precise nature has yet to be fully elucidated.

Adult↗
PubMed2000

The benefit of combining hydroxychloroquine with quinacrine in the treatment of SLE patients.

BACKGROUND: Although the benefit of antimalarials in the treatment of cutaneous LE is well established, the effect of combined hydroxychloroquine and quinacrine treatment in systemic lupus erythematosus with major organ involvement remains underappreciated. PATIENTS: Six active SLE patients (SLEDAI score > 5 points), with a mean duration of illness 9.1 yr (range 2-17 yr) were started on quinacrine (100 mg/d) following failure to achieve clinical remission on a therapeutic regimen which included a maintenance dose of hydroxychloroquine (400 mg/d) together with prednisone (either 10-20 mg/d or higher daily doses of this agent for short periods) and azathioprine (150 mg/d) or methotrexate (7.5 mg/week). OUTCOME: In 5/6 of the patients the addition of quinacrine to the previous treatment resulted in complete remission (SLEDAI 0-2 points), which persisted over the follow-up period [mean +/- 2.2 yr (range 0.5-3.5)]. During this period hydroxychloroquine and azathioprine were reduced to 200 mg/d and 100 mg/d respectively, whereas prednisone was modified as follows: in 2 patients daily administration was discontinued; in one the dose was reduced to 2.5 mg/d (from that of > or = 20 mg/d); in 2 others the previous need for an intermittent course was avoided. However, in one out of the six patients the addition for 3 months of quinacrine to the therapeutic protocol did not result in clinical improvement and was therefore discontinued. CONCLUSIONS: The promising results of this preliminary investigation encourages the combined use of the two antimalarial drugs in appropriate candidates. This modality may induce remission, seems to be safe and possesses a steroid sparing effect.

Adult↗
PubMed2000

Use of antikeratin antibodies to distinguish between rheumatoid arthritis and polyarthritis associated with hepatitis C infection.

OBJECTIVE: To investigate whether antikeratin antibodies (AKA) could be useful in the differential diagnosis of patients with rheumatoid arthritis (RA) compared to patients with hepatitis C virus (HCV) associated polyarthritis, who are seropositive for rheumatoid factor (RF). METHODS: AKA were assayed in 3 different groups of patients; all were RF seropositive: Group 1: 25 patients with HCV associated polyarthralgia or arthritis. Group 2: 33 patients with RA. Group 3: 13 patients with autoimmune disorders other than RA. Fifteen healthy individuals served as controls. RESULTS: AKA were detected in 20/33 patients with RA (60.6%) compared to only 2/25 patients (8%) with HCV associated arthritis (p < 0.0001). AKA were observed in 2/13 patients of Group 3 (15.3%). These results were also statistically different from those of patients with RA (p = 0.008). AKA were not found in the sera of the healthy controls. CONCLUSION: AKA is a useful marker to differentiate patients with RA from those with hepatitis C arthritis.

Adult↗
PubMed1999

Outcome of idiopathic apparent life-threatening events: infant and mother perspectives.

The objective of this study was to determine the neurodevelopmental and temperamental outcome of infants who suffered an idiopathic apparent life-threatening event (IALTE) and their mothers' perceptions of such an event, and to compare such infants with a matched group of babies hospitalized for nonthreatening events. Infants (N = 19) who were hospitalized at a mean age of 2.8 months for an IALTE with no underlying disease and matched controls hospitalized for an acute nonthreatening illness were sequentially recruited to the study at a mean age of 24 months (SD, 14 months). Physical, neurological, developmental, and temperamental status were assessed. Mothers' stress was assessed by their salivary cortisol response to the physical examination of their infants and completion of appropriate questionnaires assessing their infants' temperament. The investigators were not blinded to the assignment of the infants to each of the study groups. Infants' perceived "difficultness" was positively correlated with the time interval following the event (r = 0.5, P = 0.001), mothers' stress as related to their child (r = 0.4, P = 0.004), and mothers' cortisol response (r = 0.5, P = 0.01) among the study group mothers only. IALTE during early infancy was associated with developmentally and neurologically normal outcome in infancy. We conclude that mothers of infants with IALTE differed in the way they perceived their infants' temperament over time, and in their stress response compared to mothers of a control group of hospitalized children who had not experienced an IALTE.

Adult↗
PubMed1999

Follow-up after systemic adverse reactions of immunotherapy.

Out of 280 immunotherapy (IT)-treated patients in our allergy clinic, 37 (13%) developed systemic adverse reactions. Parietaria judaica (Pj) extract, a highly allergenic pollen in northern Israel, was part of the IT regimen in 46% of treated patients who developed systemic adverse reactions. Twenty-six (70%) of systemic adverse reactions occurred during the buildup phase, whereas 11 (30%) occurred in the maintenance phase of treatment. Mild systemic reactions developed in 15/37 (40%), moderate in 20/37 (54%), and severe in 2/37 (5%) of patients. In 22/37 (59% of our IT-treated patients, adverse reactions developed within 30 min after injection. Among these were the two patients with severe systemic reactions. In 19%, moderate adverse reactions appeared at 30-60 min; in 22%, mild to moderate reactions appeared after 1-2 h. Our study concludes that severe systemic reactions to IT usually appear within 30 min after injection. In Israel, IT with highly allergenic pollens such as Pj frequently causes systemic reactions, even during the maintenance phase of treatment. In such cases, the reduction of IT dosage should be more than 50% during the pollen season, and a waiting period of 1 h should also be considered.

Allergens↗
PubMed1997

Low-dose cyclosporin A in the treatment of severe chronic idiopathic urticaria.

In a limited number of severe chronic idiopathic urticaria (CIU) patients, low-dose cyclosporin A (CsA) treatment was found to be effective. This open study aimed to extend this clinical observation and determine the safety of treatment with CsA. In addition, it aimed to determine the prevalence and characteristics of the autologous serum skin test (AST) in such patients, and whether this test is affected by CsA treatment. Thirty-five patients who suffered from severe CIU (score 3), and who were followed for 6 months (using a clinical urticaria-severity score [range 0-3]) were divided into three groups: 19/35 were treated for 3 months with low-dose CsA, and thereafter followed for an additional 3 months; 6/35 dropped out of protocol treatment; and 10/35 untreated patients (followed for the same period) served as a disease controls. In the treated group, no side-effects were observed, and by the end of treatment, 13/19 (68%) patients were in full remission (score 0) and the remainder scored 1. In contrast, the 10 CsA-untreated patients scored 3 for the whole follow-up period of 6 months. Positive AST was found in 14/35 (40%) of patients, whereas none were detected in 20 healty control subjects. AST neither correlated with disease activity nor predicted response to treatment. This uncontrolled study shows that low-dose CsA is effective in treating CIU patients, and can be given safely for 3 months. However, CIU patients requiring initially high doses of glucocorticosteroids and with a long clinical history are less amenable to CsA treatment.

Adult↗
PubMed1997

Autoimmune aberration in sudden sensorineural hearing loss: association with anti-cardiolipin antibodies.

In view of the presence of autoantibodies against inner ear antigens, the pathogenesis of sudden deafness (SD) and progressive sensorineural hearing loss (PSNHL) is suggested to be of an autoimmune nature. However, microthrombosis of the inner ear may result from pathogenic anti-cardiolipin antibody (aCL) activity. We studied 30 patients (17 females and 13 males, age range 20-52 y), of whom 11 suffered from SD and 19 from PSNHL. All were clinically and serologically evaluated for association with autoimmune disorders (serological examination included: aCL, ANA, ENA, ANCA, proteinelectrophoresis, and complement levels). Twenty healthy matched subjects served as controls. None of the control group were aCL positive, whereas 8 out of 30 (27%) patients demonstrated low-moderate titers (P < 0.02), of whom 5 out of 8 suffered from SD. In addition, 2 aCL negative patients with PSNHL demonstrated hypergammaglubolinemia accompanied by hypocomplementemia, whereas none with SD had such abnormalities. Our data suggests that aCL is detected in patients with sudden sensorineural hearing loss and therefore may play an important role in the pathogenesis of this disability. If sustained by additional studies, these findings would warrant the consideration of anticoagulant therapy.

Adult↗
PubMed1996

The parachute reactions in normal and late walkers.

To study the relationship of the parachute responses to the age of independent walking, three groups of infants were prospectively examined: a normal sitting, normal walking group; a late sitting, normal walking group; and a late sitting, late walking group. All other spheres of the neurodevelopmental examination were normal. It was found that when the parachute responses appeared by age 10 months in the late sitting infants, most of them would achieve independent walking by 15 months. A delay in the parachute reaction in these infants predicted a delay in walking.

Child Development↗
PubMed1996

Reversible brain atrophy and reversible developmental retardation in a malnourished infant.

An 11-month-old infant suffering from microcephalus, developmental delay, severe failure to thrive and marked cortical atrophy on brain CT is presented. The cause of this condition was total calorie malnutrition induced by the emotional dysfunction of the mother. Improvement of the maternal-infant relationship, combined with appropriate nutrition, transformed the infant within 2 months into a normally developing baby with body weight and head circumference within the normal percentile range. A corresponding improvement was found in the brain CT.

Cerebral Cortex↗