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J Tobias

Publications and source records attributed to J Tobias.

At least 19 recordsLinked to original sources
PubMed2007

Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse.

Ras-associated binding (Rab) protein 3A is a neuronal guanosine triphosphate (GTP)-binding protein that binds synaptic vesicles and regulates synaptic transmission. A mouse mutant, earlybird (Ebd), with a point mutation in the GTP-binding domain of Rab3A (D77G), exhibits anomalies in circadian behavior and homeostatic response to sleep loss. Here, we show that the D77G substitution in the Ebd allele causes reduced GTP and GDP binding, whereas GTPase activity remains intact, leading to reduced protein levels of both Rab3A and rabphilin3A. Expression profiling of the cortex and hippocampus of Ebd and Rab3a-deficient mice revealed subtle differences between wild-type and mutant mice. Although mice were backcrossed for three generations to a C57BL/6J background, the most robust changes at the transcriptional level between Rab3a(-/-) and Rab3a(+/+) mice were represented by genes from the 129/Sv-derived chromosomal region surrounding the Rab3a gene. These results showed that differences in genetic background have a stronger effect on gene expression than the mutations in the Rab3a gene. In behavioral tests, the Ebd/Ebd mice showed a more pronounced mutant phenotype than the null mice; Ebd/Ebd have reduced anxiety-like behavior in the elevated zero-maze test, reduced response to stress in the forced swim test and a deficit in cued fear conditioning (FC), whereas Rab3a(-/-) showed only a deficit in cued FC. Our data implicate Rab3A in learning and memory as well as in the regulation of emotion. A combination of forward and reverse genetics has provided multiple alleles of the Rab3a gene; our studies illustrate the power and complexities of the parallel analysis of these alleles at the biochemical, molecular and behavioral levels.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Postoperative pain control using epidural catheters after anterior spinal fusion for adolescent scoliosis.

STUDY DESIGN: A prospective review of patients undergoing epidural catheter placement after anterior spinal fusion and instrumentation for adolescent scoliosis was performed. Data were collected using visual analog pain scores reflecting the patients' perception of their pain control. OBJECTIVES: To present the authors' technique for epidural catheter placement and dosing protocol, and to demonstrate the results from postoperative pain control after anterior spinal instrumented fusion for 10 consecutive patients. SUMMARY OF BACKGROUND DATA: The literature regarding the benefits of epidural catheters after spinal surgery is contradictory, even with controlled studies comparing epidural catheters with intravenous morphine patient-controlled anesthesia. The authors believe that this lack of consensus stems from varied epidural dosing protocols and techniques in catheter placement, which they have witnessed anecdotally at their own institution. This prompted the authors to develop and refine a standardized dosing and catheter placement protocol for pain control after spinal surgery. METHODS: Epidural catheters were placed intraoperatively before wound closure, then removed on postoperative Day 5. Dosing consisted of fentanyl (1 microg/kg) and hydromorphone (5 microg/kg) diluted in preservative-free saline (0.2 mL/kg). After surgery, dosing consisted of 0.1% ropivacaine and hydromorphone (10 microg/ml) continuously infused at 0.2 mL/kg/hour. Postoperative pain control was assessed on each postoperative day using a visual analog pain scale with choices ranging from 0 to 10. RESULTS: The arithmetic mean of the median pain scores after surgery was 2.1. The mean of the maximum pain scores for the 5 days was 4.1. Three patients required an epidural bolus and a 20% increase in the epidural infusion rate. One patient was judged to be excessively sleepy, so the epidural infusion rate was decreased by 20%. Pruritus requiring diphenhydramine developed in three patients. No other adverse effects related to epidural analgesia were noted. No catheters were accidentally pulled out or disconnected. CONCLUSION: By following the dosing protocol described, epidural catheters can be used safely and effectively to control postoperative pain after anterior instrumentation and spinal fusion for adolescent scoliosis.

Adolescent↗
PubMed2000

Territoriality as a paternity guard in the European robin, Erithacus rubecula.

To investigate the relative importance of paternity defences in the European robin we used behavioural observations, simulated intrusions and temporary male removal experiments. Given that paired males did not increase their mate attendance, copulation rate or territory size during the female's fertile period, the most frequently quoted paternity assurance strategies in birds were absent. However, males with fertile females sang and patrolled their territories more regularly, suggesting that territorial motivation and vigilance were elevated when the risk of cuckoldry was greatest. In addition, there was a significant effect of breeding period on response to simulated intrusions: residents approached and attacked freeze-dried mounts more readily in the fertile period. During 90-min removals of the pair male in the fertile period, neighbours trespassed more frequently relative to prefertile and fertile period controls and appeared to seek copulations with unattended females. When replaced on their territories, males immediately increased both song rate and patrolling rate in comparison with controls. We propose that male robins sing to signal their presence, and increase their territorial vigilance and aggression in the fertile period to protect paternity. Copyright 2000 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMed2000

A randomised, prospective, phase III clinical trial of primary bleomycin, ifosfamide and cisplatin (BIP) chemotherapy followed by radiotherapy versus radiotherapy alone in inoperable cancer of the cervix.

BACKGROUND: Phase II studies have shown primary (neo-adjuvant) chemotherapy with bleomycin, ifosfamide and cisplatin (BIP) is active against inoperable cervical cancer. We present here results of a randomised phase III multicentre trial comparing radical radiotherapy with neo-adjuvant BIP chemotherapy followed by radical radiotherapy in patients with inoperable cervical cancer, designed to discover whether this combination might improve survival. PATIENTS AND METHODS: Patients with inoperable cervical carcinoma were randomised to pelvic radiotherapy alone [RT] or two to three cycles of bleomycin 30 units/24-hour infusion, ifosfamide 5 g/m2/24 hours, and cisplatin 50 mg/m2) chemotherapy followed by pelvic radiotherapy (BIP + RT). Randomisation was stratified by stage and radiotherapy centre. RESULTS: One hundred seventy-two eligible women were randomised into this trial; eighty-six to RT and eighty-six to BIP + RT. A total of 190 cycles of chemotherapy were given. Median follow-up for the 47 patients still alive is 9 years with a minimum follow-up of 3 years. Complete or partial response occurred in 51 of 86 (59%) of those randomised to RT and 60 of 86 (69%) of those randomised to BIP + RT. The difference between response rates does not reach statistical significance (chi2 = 2.06, P = 0.15). Median survival is two years with an actuarial survival at five years of 32% (95% confidence interval (95% CI): 25%-39%). There is no significant difference between the treatment groups (chi2log-rank = 0.11, P = 0.74). CONCLUSIONS: This study does not show any survival benefit from the use of neo-adjuvant BIP chemotherapy in advanced cervical cancer.

Adult↗
PubMed1999

Early effects of hormone replacement therapy on bone.

Estrogen replacement is currently the preferred therapy for postmenopausal osteoporosis, although its mechanism of action remains poorly understood. Its primary action on bone is generally considered to be antiresorptive, but there is evidence in animals to suggest a stimulatory effect on bone formation. We have now attempted to detect a similar effect in humans by administering hormone replacement therapy (estradiol valerate 2 mg/day and dydrogesterone 5 mg/day given in a continuous, combined manner) to ten postmenopausal women. We carried out histomorphometric analyses of transiliac bone biopsies after quadruple tetracycline labeling, which was commenced before and continued during the first 4 weeks of hormone replacement therapy. Biochemical markers of bone turnover suggested that bone resorption decreased, but no significant effects on histomorphometric parameters of bone formation were detected. We conclude that hormone replacement therapy at the dose given does not stimulate bone formation in the iliac crest as assessed by histomorphometry.

Absorptiometry, Photon↗
PubMed1999

Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life.

PURPOSE: Chemotherapy for non-small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease. PATIENTS AND METHODS: Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses. RESULTS: Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P =.14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4. 8 months (PC alone) (P =.03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P =.01) and after adjusting for prognostic factors (P =.01). CONCLUSION: MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.

Adult↗
PubMed1997

Asymmetric territorial contests in the European robin: the role of settlement costs

A widespread feature of territorial systems is that residents almost invariably defeat challengers. This phenomenon has been explained by the existence of value asymmetries, variations in resource-holding potential or an 'owners always win' convention. Removal-replacement experiments were performed on 75 robins, Erithacus rubeculato test these hypotheses. The settling behaviour of newcomers was also examined in order to identify energetic costs incurred during territory establishment. In winter, dominance shifted gradually from removed owners to newcomers with increasing time of newcomer residence, and there was a peak in contest duration at 4-7 days. Removals of newcomers, followed by replacement with another newcomer, confirmed that dominance was determined by the time newcomers were in residence rather than the time original owners were absent. These results support the hypothesis that asymmetries in territory value govern the outcome of contests. It is proposed that high singing rates and low foraging rates of newcomers settling boundaries with neighbours contribute to this asymmetry, skewing outcomes in favour of original owners until replacements are fully established. The key result in this study is that the time at which dominance tends to reverse (5-6 days in winter) is predicted by the time taken for newcomers to settle territory boundaries and achieve base-line foraging effort. In spring, original owners become subordinate almost immediately after removal. Reductions in settlement cost for newcomers, and increases in territory value, are proposed to accelerate dominance reversal. Age and sex effects on dominance suggest that the value asymmetry rule is modified by variations in resource-holding potential.

Journal Article↗
PubMed1997

Standardized exercise oximetry predicts postpneumonectomy outcome.

BACKGROUND: We have developed a safe, simple, and easily performed standardized exercise oximetry outpatient test to assess patients undergoing lung resections. We studied its ability to predict outcome after pneumonectomy in 46 consecutive patients over a 5-year period. METHODS: Room air oximetry is initially performed at rest. The patient then begins to exercise on a stair-stepper apparatus (Stamina Stepper), which provides uniform resistance to stepping. Oxygen saturation values are noted at 10, 20, and 30 steps, equivalent to climbing three flights of stairs. Group 1 consisted of the patients who either had a resting saturation less than 90%, or desaturation greater than or equal to 4% during exercise. Group 2 consisted of all patients who had a preoperative forced expiratory volume in 1 second of 60% or less. Group 3 consisted of all patients who had a predicted postoperative forced expiratory volume in 1 second of 40% or less. Group 4 consisted of patients who had a predicted postoperative diffusing capacity of 40% or less. RESULTS: There were four deaths (8.6%), 12 patients (26%) remained in the intensive care unit 4 or more days, and 11 patients (23%) suffered major morbidity. Desaturation during exercise (group 1) significantly predicted longer intensive care unit stay (p = 0.0002) and incidence of major morbidity (p < 0.0001). Groups 2, 3, and 4 were not significantly predictive of either longer intensive care unit stay or major morbidity. CONCLUSIONS: Standardized exercise oximetry performed in the outpatient facility is highly predictive of major morbidity and prolonged intensive care unit stay after pneumonectomy.

Adult↗
PubMed1997

Nonsurgical management of acute jejunal diverticulitis: a review.

BACKGROUND: Diverticular disease of the colon and its complications are well known and readily considered when patients present with the proper clinical scenario. Conversely, complications of small bowel diverticula are very uncommon entities and are not often thought of as a cause of bleeding, obstruction, or an acute abdomen. OBJECTIVE: To report two patients presenting with an acute abdomen caused by acute jejunal diverticulitis who were treated nonsurgically as opposed to surgically as the literature dictates. METHODS: Two patients presented with sudden onset of acute periumbilical pain that had increased progressively over 1-2 days before admission. An emergent CT scan performed in each patient with localized peritonitis revealed "collections" consistent with abscess cavities. One patient was treated with antibiotics alone and the other with a combination of antibiotics and percutaneous CT-guided aspiration. CT-guided needle aspiration was performed and the injection of contrast clearly revealed communication with a jejunal diverticulum. Both patients did well and were subsequently discharged without incident or surgical intervention. CONCLUSIONS: Acute jejunal diverticulitis must be considered in the differential diagnosis of an acute abdominal process and may be successfully treated nonsurgically despite the recommendations of previous reports.

Acute Disease↗
PubMed1996

Breast surgery after neoadjuvant treatment. Is it necessary?

The optimum management of women with advanced loco-regional breast cancer (T3-4, N1-2) is controversial. Neoadjuvant therapy in the form of chemotherapy and or radiotherapy is popular and results in an encouraging local response in over 70% of patients. However, should subsequent surgery (either mastectomy or breast conservation treatment) be undertaken in women who respond? We present a prospective evaluation of 15 patients with T3-4, N1-2 tumours (including 1 bilateral cancer) who underwent mastectomy after achieving a complete clinical response to neoadjuvant treatment. All patients had 6 cycles of chemotherapy and 10 also received 50 Gy radiotherapy. In addition to clinical examination, the response to neoadjuvant treatment was assessed by mammography (in all cases) and by magnetic resonance imaging (MR) (in eight patients). Careful histopathological assessment of the breast was undertaken to determine the extent of residual disease. In all patients histological malignancy was recognized within the breast. The size varied from 0.6 to 6.5 cm in maximum diameter with three grade I, eight grade II and five grade III tumours. Axillary lymph nodes were positive in seven patients. In conclusion, surgery is indicated for control of residual disease in locally advanced breast cancer regardless of the response to neoadjuvant treatment. Our preliminary observations suggest a potential role for breast MR in defining the extent of residual disease which may aid in the planning of surgery.

Adult↗
PubMed1993

Intratumoral interleukin-2 immunotherapy: activation of tumor-infiltrating and splenic lymphocytes in vivo.

Direct intratumoral injection of interleukin-2 (IL-2) was evaluated in a murine model. Balb/c mice received 5 x 10(4) Line 1 alveolar carcinoma cells (L1C2) by subcutaneous injection. On the third day following tumor implantation, mice received injections of IL-2 (5 x 10(3)-5 x 10(4) units) or diluent twice daily, either by i.p. or intratumoral injection, 5 days/week for 3 weeks. Intratumoral injection of 5 x 10(4) units IL-2 significantly reduced tumor volume (P < 0.05 versus control), increased median survival time (P = 0.0001), and resulted in a 23.5% cure rate (P = 0.008). There were no long-term survivors in the other treatment groups. Both tumor-infiltrating lymphocytes (TIL) and splenic lymphocytes isolated directly from IL-2-treated mice demonstrated enhanced cytolytic activity compared to diluent-treated controls. To determine whether non-T-cell-mediated antitumor responses were active in our model, intratumoral immunotherapy was evaluated in athymic Balb/c nu/nu mice. In order to decrease the recruitment of lymphocyte precursors, nude mice were splenectomized and received cyclophosphamide prior to tumor injection and IL-2 therapy. Intratumoral IL-2 immunotherapy also significantly decreased tumor volume in these immunodeficient mice (P < 0.02), but did not lead to long-term survival. We conclude that both TIL and splenic lymphocytes are activated in vivo in response to intratumoral IL-2 immunotherapy, suggesting that intratumoral therapy with IL-2 activates both local and systemic antitumor responses.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1993

Interleukin-2-responsive wound-infiltrating lymphocytes in surgical adjuvant cancer immunotherapy.

Wound-infiltrating lymphocytes (WIL) were assessed in murine models of localized sarcoma and carcinoma to evaluate the role of interleukin-2 (IL-2)-responsive lymphocytes in adjuvant immunotherapy. Following tumor resection, IL-2 or diluent was injected at the surgical site for 6 days. Surgical site tissues were harvested and digested in a triple enzyme mixture, and single cell suspensions were prepared. Thy 1.2+ lymphocytes were isolated by incubating cells with monoclonal anti-Thy 1.2 antibody-coated magnetic beads. Lymphocyte-bead complexes were extracted with a magnet and cultured in medium containing IL-2 (100 units/ml) for 1-3 weeks. Perioperative IL-2 immunotherapy led to a three- to four-fold increase in WIL yield. WIL from IL-2-treated mice also demonstrated enhanced cytolysis of the autologous tumor and bound to activated endothelial cells with greater avidity than did the controls. We conclude that perioperative IL-2 therapy augments the yield, as well as the cytolytic and adhesive properties, of wound-infiltrating lymphocytes.

Animals↗
PubMed1991

A reappraisal of the causes of hemoptysis.

We reviewed the records of 264 patients who underwent fiberoptic bronchoscopy for unexplained hemoptysis to determine the various causes of hemoptysis. Bronchogenic carcinoma (29%), bronchitis (23%), and idiopathic hemoptysis (22%) accounted for the majority of causes of hemoptysis. In contrast to older studies, the incidence of hemoptysis secondary to tuberculosis and bronchiectasis has decreased. Although our patient population is predominantly male and elderly, our data may well be representative of more recent epidemiologic trends in causes of hemoptysis.

Adult↗
PubMed1990

Phase II studies of ifosfamide alone and in combination in cancer of the cervix.

A series of phase II studies using ifosfamide (IFX) as a single agent and in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer have been coordinated at the West Midlands CRC Clinical Trials Unit (Birmingham, UK). The aims of these studies were to identify single agents and combination regimens that may be of value for palliation and have potential for use as neoadjuvant and adjuvant therapy at the time of primary treatment. A total of 79 patients with disease non-amenable to radical local therapy were treated with single-agent IFX or the BIP combination. In 30 patients treated with single-agent IFX, 10 objective responses (30%) were seen, with 1 complete response. In 49 patients treated with BIP, 34 objective responses (69%) were seen, with 10 complete responses (20%). Toxicity included alopecia, nausea and vomiting, myelosuppression, infection, reduction in renal function and disturbance of consciousness. These data indicate that IFX is highly active in cervix cancer and, in combination with bleomycin and cisplatin, can be used for effective palliation and cytoreduction in greater than 70% of patients. IFX-containing regimens have potential for use as neoadjuvant and adjuvant therapy in patients at high risk of recurrence with conventional treatment. These hypotheses are currently being tested in prospective randomised trials.

Adult↗