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Biomedical subjects

R Jacobs

Publications and source records attributed to R Jacobs.

At least 109 records · Page 6Linked to original sources
PubMed1996

Modulation of the immunologic response to acute stress in humans by beta-blockade or benzodiazepines.

Acute stress evokes immediate responses in the cardiovascular endocrine, and immune systems. In particular, the number and activity of natural killer (NK) lymphocytes increase after stress. Here, we investigate the possibility to pharmacologically interfere with these stress-induced immunologic changes. Twenty-five healthy males were subjected to an acute stressor, a first-time tandem parachute jump. Subjects were randomly assigned to a beta-adrenoceptor antagonist (propranolol), a benzodiazepine (alprazolam), or placebo group. To analyze the role of the spleen in lymphocyte redistribution, splenectomized subjects performed a parachute jump. Propranolol, but no alprazolam, inhibited the heart rate increase during jumping. Increases in epinephrine and cortisol in the propranolol group were comparable to placebo, but were attenuated by alprazolam. The number and activity of NK cells significantly increased in the placebo group but not in the propranolol group immediately after stress. Alprazolam treatment did not alter the increase in NK cell numbers but did inhibit the increase in NK activity. In splenectomized subjects, NK cell numbers, but not NK activity, increased as in placebo subjects. We conclude that stress-induced changes in the immune system are controlled by beta-adrenergic mechanisms and only partly depend on the spleen; central interference with alprazolam differentially affects stress-induced changes in the NK cell compartment.

Adrenergic beta-Antagonists↗
PubMed1996

Administration of oral acyclovir suppressive therapy after neonatal herpes simplex virus disease limited to the skin, eyes and mouth: results of a phase I/II trial.

BACKGROUND: Neonatal herpes simplex virus (HSV) infections limited to the skin, eyes and mouth (SEM) can result in neurologic impairment. A direct correlation exists between the development of neurologic deficits and the frequency of cutaneous HSV recurrences. Thus, the National Institutes of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted a Phase I/II trial of oral acyclovir therapy for the suppression of cutaneous recurrences after SEM disease in 26 neonates. METHODS: Infants < or = 1 month of age with virologically confirmed HSV-2 SEM disease were eligible for enrollment. Suppressive oral acyclovir therapy (300 mg/m2/dose given either twice daily or three times per day) was administered for 6 months. RESULTS: Twelve (46%) of the 26 infants developed neutropenia (< 1000 cells/mm3) while receiving acyclovir. Thirteen (81%) of the 16 infants who received drug 3 times per day experienced no recurrences of skin lesions while receiving therapy. In comparison, a previous Collaborative Antiviral Study Group study found that only 54% of infants have no cutaneous recurrences in the 6 months after resolution of neonatal HSV disease if oral acyclovir suppressive therapy is not initiated. In one infant, HSV DNA was detected in the cerebrospinal fluid during a cutaneous recurrence, and an acyclovir-resistant HSV mutant was isolated from another patient during the course of the study. CONCLUSIONS: Administration of oral acyclovir can prevent cutaneous recurrences of HSV after neonatal SEM disease. The effect of such therapy on neurologic outcome must be assessed in a larger, Phase III study. As such, additional investigation is necessary before routine use of suppressive therapy in this population can be recommended.

Acyclovir↗
PubMed1996

Long-term bone mass evaluation of mandible and lumbar spine in a group of women receiving hormone replacement therapy.

The overall aim of this study was to examine the relationship between bone mass of the jaw and the axial skeleton. Sixty-nine subjects (age at entry: 32-64), who underwent hormone replacement therapy during the study period, participated. Bone mass of the lumbar spine was determined using dual photon absorptiometry. The jaw-bone of the posterior region of the mandible was evaluated by means of standardized long-cone radiography using individual bite-blocks. A densitometric wedge in the film holder provided a reference to quantify bone mass. From both measurements, it appeared that the bone mass of the mandible and the lumbar spine showed a moderate relationship. The present results also confirmed that estrogen replacement therapy had a positive effect on the bone mass of the mandible and the lumbar spine. Different estrogen regimens resulted in different increases in bone mass during the observation period, which was on average 5 yr.

Absorptiometry, Photon↗
PubMed1996

Population pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group.

The population pharmacokinetics of ganciclovir was investigated in a group of 27 newborns with symptomatic congenital cytomegalovirus infection by nonlinear mixed-effects modeling analysis. Individual characteristics including approximated creatinine clearance from serum (ASCC) and body weight (WGE) were identified to significantly influence total clearance from plasma (CL) and the apparent total volume of distribution (V) of ganciclovir, respectively. The regression equations used to model these relationships were expressed as CL (in liters per hour) = 0.262 + (0.00271 x ASCC) and V (in liters) = 0.627 + (0.437 x WGE). By using this model, typical values of the pharmacokinetic parameter CL and V were 0.428 +/- 0.079 liters/h and 1.773 +/- 0.320 liters, respectively. Upon validation with a larger number of newborns, this model should allow for the definition of possible relationships between the pharmacokinetic disposition of ganciclovir and pharmacodynamic events in neonates.

Antiviral Agents↗
PubMed1996

Two functional muscle groupings during postural equilibrium tasks in standing cats.

1. This study examined the relation between electromyographic (EMG) activation and the contact force and joint torques of the left hindlimb during postural equilibrium tasks in the standing cat. It is the appropriate application of force by the limbs against the support surface that allows the animal to control its center of mass and maintain equilibrium. 2. Cats were trained to stand quietly on a moveable force platform. During quiet stance, the cat was perturbed by a platform translation in each of 12 directions evenly spaced in the horizontal plane. EMG activity of mono- and biarticular thigh muscles, three-dimensional ground reaction force under the paw (contact force), and kinematics of the hindlimb segments were recorded Net joint torques were computed using inverse dynamics. The analysis focused on the functional organization of the rapid, automatic postural response in relation to the sagittal plane contact force and joint torques. 3. The muscles of the thigh were subdivided into two functional groups, based on the relationship of the evoked response to the various components of the sagittal plane contact force or joint torques. The first group, consisting of the monoarticular and some biarticular muscles, was correlated with the vertical force component, Fz. The second group, consisting of a separate group of biarticular muscles, was correlated with the difference between knee and hip torque. This torque difference is a function of both sagittal plane force components, Fz and Fy, and is related to contact force direction. 4. It is suggested that this subdivision of muscle activations reflects a neural strategy of parallel control of the two muscle groups in relation to their influence on Fz and Fy. Such a control mechanism could be a strategy for simplifying the control of the multisegmented limb in contact force tasks such as maintaining postural equilibrium.

Animals↗
PubMed1996

Technical and safety aspects of blood and marrow transplantation using G-CSF mobilized family donors.

An allogeneic transplantation programme using immunoselected blood progenitor and bone marrow CD34+ cells has been established. Thirteen healthy HLA-matched, MLC negative sibling donors received two doses of 5 micrograms kg-1 G-CSF (s.c. daily) for 5 days. On days 4 and 5, large-volume mononuclear cell aphereses were performed (COBE Spectra) and on day 5 one unit of autologous blood was obtained. Mononuclear cells were pooled and cryopreserved after CD34+ cell-immunoselection on day 5. Bone marrow (BM) of the same donors was procured under routine conditions 10-45 days later (median: 27 days). The final graft consisted of blood CD34+ cells with either complete BM (n = 5) or immunoselected BM CD34+ cells (n = 8). The present paper describes the progenitor cell mobilization and apheresis protocol and analyzes the cell loss by BM and peripheral blood progenitor cell (PBPC) donation. Considerably larger amounts of mononuclear cells (CD45+), T-lymphocytes (CD3+) and platelets were lost by the apheresis as compared to bone marrow without apparent immediate clinical consequences for the donors. Owing to cross-cellular contamination of the apheresis concentrate, blood platelet count (PC) significantly decreased (mean PC after the second apheresis 116 x 10 microL-1); furthermore on average 3.04 x 10(10) CD3+ cells were removed by two apheresis sessions. This loss did not lead to long-term total lymphocyte count changes (2370 microL-1 versus 1889 microL-1) as observed during the long-term follow-up of 7/13 donors (mean 290 days). Subjectively, the PBPC collections were better accepted than BM donations in all but one family donor.

Adult↗
PubMed1995

The treatment of stage III nonsmall cell lung cancer using high dose conformal radiotherapy.

PURPOSE: To review our experience using conformal treatment planning and high-dose radiotherapy for Stage IIIa and IIIb nonsmall cell lung cancer (NSCLC), and to identify a subset of patients best suited for this approach by analyzing multiple pretreatment patient and tumor characteristics. METHODS AND MATERIALS: Between December 1987 and June 1992, 37 patients with Stage III NSCLC treated with high-dose radiotherapy using conformal radiotherapy were reviewed. The patient characteristics were as follows: Stage IIIa (18 patients), IIIb [19]; T1-2 [13], T3-4 [24]; N0-1 [8], N2-3 [29]; and median age 63. All patients were treated with 1.8-2.0 Gy fractions to a median dose of 66 Gy (range 60-70 Gy). Outcome was analyzed by multiple pretreatment variables including age, sex, Karnofsky performance score, pretreatment symptoms, stage group, T and N stage, tumor volume (calculated from computed tomography (CT) contours), presence of atelectasis, and tumor histology. Outcome was also analyzed by total radiotherapy dose. RESULTS: The median, 1-year and 2-year survival rates for the entire group were 19.5 months, 75 and 37%, respectively. The median, 1-year, and 2-year local progression-free survival rates are 15.6 months, 62 and 23%. There was no difference in survival by stage group (IIIa vs. IIIb) or by T or N stage. Tumor volumes ranged from 47-511 cc in the patients without atelectasis and were not a significant prognostic factor. Histology was found to be a significant prognostic factor, with squamous cell carcinoma having a better overall survival and local progression-free survival than other histologies. No other patient characteristic was found to be significant by either univariate or multivariate analysis. When outcome was analyzed by radiotherapy dose, no dose response was evident in the narrow dose range studied (60-70 Gy). Toxicity included two cases of pneumonitis, which resolved with conservative therapy. CONCLUSION: High-dose conformal radiotherapy, in our experience, results in overall survival rates that compare favorably with trials of chemoradiotherapy or conventional radiotherapy with a low treatment-associated morbidity. However, local progression remains a significant problem despite median radiotherapy doses of 66 Gy. Future trials using escalating radiotherapy doses with conformal radiotherapy are therefore, indicated.

Adult↗
PubMed1995

Combined transplantation of allogeneic bone marrow and CD34+ blood cells.

Allogeneic peripheral blood progenitor cells (PBPCs) were transplanted after immunoselection of CD34+ cells. Two patient groups were studied: group I patients received immunoselected blood CD34+ cells and unmanipulated marrow cells from the same donor. Group II patients were given immunoselected blood and bone marrow (BM) CD34+ cells. One to 6 weeks before bone marrow transplantation (BMT), PBPCs from HLA-identical and MLC- sibling donors were mobilized with granulocyte colony-stimulating factor (G-CSF) (5 micrograms/kg twice daily subcutaneously) for 5 days. Aphereses were performed at days 4 and 5 of G-CSF application. CD34+ cells were separated from the pooled PBPC concentrates by immunoadsorption onto avidin with the biotinylated anti-CD34 monoclonal antibody 12.8 and then stored in liquid nitrogen. BM was procured on the day of transplantation. Patients were conditioned with either busulfan (16 mg/kg) or total body irradiation (12 Gy) followed by cyclophosphamide (120 mg/kg). Cyclosporin A and short methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. After transplantation, all patients received 5 micrograms G-CSF/kg/d from day 1 until greater than 500 neutrophils/microL were reached and 150 U erythropoietin/kg/d from day 7 until erythrocyte transfusion independence for 7 days. Group I consisted of patients with acute myeloid leukemia (AML) (n = 2), chronic myeloid leukemia (CML) (n = 2), and T-gamma-lymphoproliferative syndrome and BM aplasia (n = 1). The patients received a mean of 3.3 x 10(6) CD34+ and 3.7 x 10(5) CD3+ cells/kg body weight of PBPC origin and 4.5 x 10(6) CD34+ and 172 x 10(5) cells/kg body weight of BM origin. Group II consisted of five patients (two AML, two CML, one non-Hodgkin's lymphoma). They received a mean of 3.3 x 10(6) CD34+ and 3.2 x 10(5) CD3+ cells/kg from PBPC and 1.4 x 10(6) CD34+ and 0.6 x 10(5) CD3+ cells from BM. A matched historical control group (n = 12) transplanted with a mean of 5.2 x 10(6) CD34+ and 156 x 10(5) CD3+ cells/kg from BM alone was assembled for comparison. In group I, the median time to neutrophil recovery to > 100, > 500, and > 1,000/microL was 12, 15, and 17 days, respectively. Patients from group II reached these neutrophil levels at days 13, 15 and 17 post BMT. Neutrophil recovery in the control patient group occurred at days 17, 18, and 20 respectively. Group I patients were given platelet transfusions within 18 days and red blood cells within 10 days, whereas for group II patients, these time points were 26 and 17 days, respectively. These same transfusions could be ceased within 38 and 24 days, respectively, in control patients. The addition of about 2% more peripheral blood CD3+ cells (group I patients) did not result in higher grades of acute GVHD (median grade II) as compared with the controls (median grade II). Four of five group II patients showed no signs of acute GVHD. These data suggest that the addition of immunoselected allogeneic CD34+ progenitor cells to BM cells may accelerate hematopoietic recovery.

Adult↗
PubMed1995

The formation of Golgi stacks from vesiculated Golgi membranes requires two distinct fusion events.

We have reconstituted the fusion and assembly of vesiculated Golgi membranes (VGMs) into functionally active stacks of cisternae. A kinetic analysis of this assembly process revealed that highly dispersed VGMs of 60-90 nm diameter first fuse to form larger vesicles of 200-300 nm diameter that are clustered together. These vesicles then fuse to form tubular elements and short cisternae, which finally assemble into stacks of cisternae. We now provide evidence that the sequential stack formation from VGMs reflects two distinct fusion processes: the first event is N-ethyl-maleimide (NEM)-sensitive factor (NSF) dependent, and the second fusion event requires an NSF-like NEM-sensitive ATPase called p97. Interestingly, while the earliest steps in stack formation share some similarities with events catalyzing fusion of transport vesicles to its target membrane, neither GTP gamma S nor Rab-GDI, inhibitors of vesicular protein traffic, inhibit stack formation.

Carrier Proteins↗
PubMed1995

The control of mono-articular muscles in multijoint leg extensions in man.

1. Movements often require control of direction and a magnitude of force exerted externally on the environment. Bi-articular upper leg muscles appear to play a unique role in the regulation of the net torques about the hip and knee joints, necessary for the control of this external force. 2. The aim of this study was to test the hypothesis that the mono-articular muscles act as work generators in powerful dynamic leg extensions, which means that they should be activated primarily in the phases during which they can contribute to work, irrespective of the net joint torques required to control the external force. 3. Cycling movements of six trained subjects were analysed by means of inverse dynamics, yielding net joint torques as well as activity patterns and shortening velocities of four mono- and four bi-articular leg muscles. 4. The results show that the mono-articular muscles exert force only in the phase in which these muscles shorten, whereas this appears not to be the case for the bi-articular muscles. 5. Reciprocal patterns of activation of the rectus femoris and hamstring muscles appear to tune the distribution of net joint torques about the hip and knee joints, necessary to control the (changing) direction of the force on the pedal. 6. An analysis of running in man and additional related literature based on animal studies appears to provide further support for the hypothesis that mono- and bi-articular muscles have essentially different roles in these powerful multijoint leg extension tasks.

Bicycling↗
PubMed1995

Masseter muscle fatigue before and after rehabilitation with implant-supported prostheses.

To establish whether different implant-supported prosthetic reconstructions influence jaw muscle resistance to clenching efforts, sustained submaximal (50%) clenching was performed in two groups of patients who were edentulous in one or both jaws. One group consisted of patients who were rehabilitated by means of an overdenture on two to four implants connected by a bar; the other group consisted of patients who were rehabilitated with an implant-supported fixed prosthesis on four to seven implants in either the maxilla or the mandible. Results indicated that after rehabilitation with implant-supported fixed reconstructions, the myoelectric output level increased over time, which was parallel to a higher bite force level. For the other group, such a time-dependent change in electromyographic amplitude did not occur. On the other hand, power spectrum analysis revealed a significant downward shift of the mean power frequency during sustained clenching after rehabilitation with implant-supported overdentures but not with implant-supported fixed prostheses. The absence of a spectral shift in the latter group probably expressed a fear of biting too hard and fracturing the prosthesis.

Adult↗
PubMed1995

Reconstitution of vesiculated Golgi membranes into stacks of cisternae: requirement of NSF in stack formation.

We have developed an in vitro system to study the biochemical events in the fusion of ilimaquinone (IQ) induced vesiculated Golgi membranes (VGMs) into stacks of cisternae. The Golgi complex in intact normal rat kidney cells (NRK) is vesiculated by treatment with IQ. The cells are washed to remove the drug and then permeabilized by a rapid freeze-thaw procedure. VGMs of 60 nm average diameter assemble into stacks of Golgi cisternae by a process that is temperature dependent, requires ATP and a high speed supernatant from cell extract (cytosol), as revealed by immunofluorescence and electron microscopy. The newly assembled stacks are functionally active in vesicular protein transport and contain processing enzymes that carry out Golgi specific modifications of glycoproteins. The fusion of VGMs requires NSF, a protein known to promote fusion of transport vesicles with the target membrane in the exocytic and endocytic pathways. Immunoelectron microscopy using Golgi specific anti-mannosidase II antibody reveals that VGMs undergo sequential changes in their morphology, whereby they first fuse to form larger vesicles of 200-300-nm average diameter which subsequently extend into tubular elements and finally assemble into stacks of cisternae.

Adenosine Triphosphate↗
PubMed1995

Biological activity of adrenocorticotropic hormone precursors on ovine adrenal cells.

Adrenocorticotropic hormone (ACTH) is synthesized in the corticotrophs as a precursor, pro-opiomelanocortin (POMC), which is processed via proACTH to ACTH. Both precursors and ACTH are secreted. Although the steroidogenic activity of ACTH is well characterized, that of the precursors is not. This study assessed the capacity of POMC and proACTH to alter cortisol synthesis. POMC and proACTH were prepared by subjecting medium, conditioned by exposure to DMS-79 cells, to Sephadex chromatography, and the bioactivity was assessed in cultured-dissociated ovine adrenal cells. Alone neither POMC (< or = 2.6 nM) nor proACTH (< or = 0.7 nM) showed any consistent acute (6 h) stimulatory or inhibitory action on cortisol in either fetal or adult cells. In contrast, in fetal cells the precursors inhibited steroidogenic response to ACTH-(1-24). POMC at 2.6 nM, but not lower concentrations, decreased the cortisol responses to 0.01, 0.1, and 1 nM ACTH by at least 50%. ProACTH (0.70 and 0.23 nM) decreased the responses to ACTH at 0.01 nM by 89 and 67%, respectively, and at 0.1 nM by 49 and 34%, respectively. At 1 nM ACTH only 0.7 nM proACTH decreased the response to ACTH (by 69%). In contrast, in adult adrenal cells, the precursors did not significantly reduce the response to ACTH (range 0.01-1 nM). Therefore, these data indicate that POMC and proACTH can inhibit the cortisol response to ACTH in fetal adrenal cells, an effect that is concentration dependent. The data suggest that precursors may play a physiological role, possibly regulating fetal plasma cortisol concentrations.

Adrenal Glands↗
PubMed1994

Hepatitis C virus-polymerase chain reaction of routinely processed liver biopsies.

The aim of the study was to evaluate the specificity and sensitivity of detection of hepatitis C virus (HCV)-RNA in formalin-fixed paraffin-embedded (FFPE) liver biopsies by polymerase chain reaction (PCR). Routinely processed FFPE diagnostic needle liver biopsies as well as stored serum samples from 43 patients with liver disease were tested for HCV-RNA by reverse transcription-nested PCR using the same sets of primers and following strict anticontamination measures. Twenty-nine cases were positive and 14 were negative for serum HCV-RNA. Tissue HCV-RNA was detected in 17 out of the 29 serum HCV-RNA-positive cases but not in any of the 14 serum HCV-RNA-negative cases. Compared to serum-PCR, tissue-PCR was 100% specific, 58.6% sensitive, and 72% efficient. HCV-RNA was detected more frequently in biopsies stored for less than 1 year, than in those stored for more than 1 year (P = 0.046). In biopsies stored for up to 1 year detection of HCV-RNA by PCR was 81.8% sensitive and 90.9% efficient. Short (< 0.5 cm) liver biopsies were as sufficient for nucleic acid extraction and amplification as long (> 0.5 cm) ones. It is concluded that following strict anticontamination measures, HCV-RNA detection by PCR in routinely fixed, processed, and stored diagnostic liver biopsies provides a valuable adjunct to diagnosis of HCV infection. In this study, this option was free from contamination problems, even though routine batch histological processing schedules were used.

Base Sequence↗
PubMed1994

TCR1+ large granular lymphocyte proliferation in rheumatoid arthritis.

The T gamma-lymphoproliferative syndrome is characterized by a proliferation of large granular lymphocytes (LGL). It is often associated with neutropenia, and in 30% of cases with rheumatoid arthritis (RA). Phenotypic analysis has demonstrated that in most cases of RA with T gamma-proliferative disease, the LGL represent T cells with a clonal rearrangement of the alpha/beta T cell receptor (TCR2). Here, three patients with gamma/delta TCR1+ LGL proliferation suffering from long-standing arthritis and neutropenia are described. The first patient with RA showed an expansion of a heterogeneous CD2+ CD16+ CD56- LGL population, of which 30% coexpressed TCR1 with V delta 1 rearrangement. The second patient with ankylosing spondylitis and RA was suffering from proliferation of TCR1+ (V gamma 9-, V delta 1-), CD2+ CD16- CD56- LGL with low coexpression of CD8. The third patient with RA was suffering from a proliferation of TCR1+ (V delta 1+, V gamma 9-) CD4- CD8- CD16- CD56- lymphocytes. On the basis of these unusual findings, the pathogenetic role of TCR1+ T cells in RA is discussed.

Aged↗
PubMed1994

Idiopathic focal segmental glomerulosclerosis in a patient with systemic lupus erythematosus: an unusual combination.

Renal involvement is a major cause of morbidity in patients with systemic lupus erythematosus (SLE). Histologic examination of renal tissue using light microscopy, immunofluorescent staining, and electron microscopy permit identification of glomerular immune complex deposits in virtually all patients with SLE. We report a patient who fulfilled four American College of Rheumatology criteria for the classification of SLE whose clinical course was consistent with SLE, yet whose renal failure resulted from focal glomerulosclerosis that was not mediated by immune complexes. The characteristics of this case of focal glomerulosclerosis that differentiate it from healed focal proliferative glomerulonephritis are discussed.

Biopsy↗
PubMed1994

The effect of electronic dental analgesia during sonic scaling.

The aim of the present study was to investigate the effects of electronic dental analgesia (EDA) during sonic scaling. The clinical trial included 30 healthy adult subjects and was conducted as a randomised single-blind split-mouth design. The applied procedure consisted of periodontal scaling by means of a sonic scaler, while using the EDA device either in an active or placebo state. Rather similar results were obtained for the subjective pain rating in both the active and the placebo trials. When patients rated their discomfort on a scale 0-4 from no pain to very severe pain, the mean (s.d.) score for both the EDA and the placebo was 1.2 (0.6). The subjective pain estimate was positively correlated to the electrical current intensity provided. This implied that with a stronger pain experience, patients tried to administer more anaesthesia by turning the dial of the control box to an increased intensity of the electrical current. This remained insufficient to eliminate pain sensation. It was concluded that application of electronic dental anaesthesia in periodontal treatment remains questionable.

Adult↗