PubMed Health⌕ Search

Biomedical subjects

J P Cobb

Publications and source records attributed to J P Cobb.

At least 19 recordsLinked to original sources
PubMed2003

Analysis of the referral pattern to a supraregional bone and soft tissue tumour service.

AIM: To investigate the sources of delay in diagnosis and determine if there was a similar diagnostic error rate as found by the Musculoskeletal Tumour Society, which subsequently altered patients' management and affected outcome. PATIENTS AND METHODS: A prospective review of 100 consecutive patients referred to our institution analysed causes for delay in referral and whether prior investigations or procedures had complicated further management. RESULTS: Patients were symptomatic for 14.8 months (range, 0-26 months) prior to consultation with their GP. A further 13.5 months (range, 0.5-120 months) elapsed before referral by the local hospital (94) or GP (6) to the bone and soft tissue service. A significant delay in referral of more than a month occurred in 72 patients. Those patients with malignant disease were symptomatic for 7.6 months (range, 0.5-11 months) prior to seeking medical advice with a further 7.5 months (range, 0-13 months) elapsing prior to onward referral at their local hospital. From the study group, 63 patients were subjected to complex imaging studies (bone scan, CT, MRI) prior to referral; 34 biopsies or surgery were performed in 34 cases by referring teams, 16 of which complicated subsequent management. CONCLUSIONS: If a high suspicion of a soft tissue or bone tumour is suspected from the history, examination and plain radiograph, then early referral to a specialist centre is recommended where relevant, high-quality investigations can be arranged in a short time leading to a planned biopsy, confirmation of diagnosis and definitive treatment at an earlier stage.

Adult↗
PubMed2001

Sepsis-induced apoptosis causes progressive profound depletion of B and CD4+ T lymphocytes in humans.

Patients with sepsis have impaired host defenses that contribute to the lethality of the disorder. Recent work implicates lymphocyte apoptosis as a potential factor in the immunosuppression of sepsis. If lymphocyte apoptosis is an important mechanism, specific subsets of lymphocytes may be more vulnerable. A prospective study of lymphocyte cell typing and apoptosis was conducted in spleens from 27 patients with sepsis and 25 patients with trauma. Spleens from 16 critically ill nonseptic (3 prospective and 13 retrospective) patients were also evaluated. Immunohistochemical staining showed a caspase-9-mediated profound progressive loss of B and CD4 T helper cells in sepsis. Interestingly, sepsis did not decrease CD8 T or NK cells. Although there was no overall effect on lymphocytes from critically ill nonseptic patients (considered as a group), certain individual patients did exhibit significant loss of B and CD4 T cells. The loss of B and CD4 T cells in sepsis is especially significant because it occurs during life-threatening infection, a state in which massive lymphocyte clonal expansion should exist. Mitochondria-dependent lymphocyte apoptosis may contribute to the immunosuppression in sepsis by decreasing the number of immune effector cells. Similar loss of lymphocytes may be occurring in critically ill patients with other disorders.

Adolescent↗
PubMed2001

Nitric oxide synthase inhibition as therapy for sepsis: a decade of promise.

BACKGROUND: Inhibition of nitric oxide synthase (NOS) has held promise as a novel and important therapeutic target for sepsis for over a decade. However, the question as to whether an inhibitor of NOS will prove to be efficacious in human septic shock remains unanswered. METHODS: Review of the pertinent English-language medical literature. RESULTS: Observations of the induction of NOS (iNOS, NOS2) by proinflammatory cytokines led to the hypothesis that nitric oxide (NO) relaxes vascular smooth muscle, thereby producing vasodilation and hypotension in sepsis. Other effects of NO in vascular tone may be manifested by refractoriness to vasopressors or myocardial dysfunction. However, such negative effects of NO are balanced by the role of NO in maintaining microvascular perfusion and host defenses against invading pathogens. Initial animal studies of septic shock modulated by the administration of competitive inhibitors of NOS demonstrated that NOS inhibition might be beneficial therapy for clinical septic shock. However, subsequent animal studies have produced variable results, and a phase III clinical trial of a nonselective NOS inhibitor has failed to show benefit for therapy of septic shock. CONCLUSION: A better understanding of the effects of NOS and its inhibitors is needed as is an understanding of the underlying pathophysiology of sepsis. Moreover, a nontoxic, short-acting, titratable, specific inhibitor of NOS2 has yet to be identified and tested. Until then, efforts should be designed to describe more completely the role of NO in the pathophysiology of sepsis.

Animals↗
PubMed2001

The heat shock paradox: does NF-kappaB determine cell fate?

Cellular injury induces an adaptive response whether the insult is physical (e.g., heat, radiation), chemical (e.g., reactive oxygen species), infectious (e.g., bacteria), or inflammatory (e.g., lipopolysaccharide). Recent data indicate that the interactions of these responses are not predictable and that sequence permutations can have opposite effects on outcome after injury. Our overarching hypothesis is that interactions among stress responses contribute to the fate of cells, tissues, and organisms and that modulation of these interactions can have important affects on both function and survival. For example, whereas it is well known that a prior heat shock stress can protect cells against inflammatory stress both in vitro and in vivo, we and others have shown that induction of a subsequent heat stress in cells 'primed' by inflammation can precipitate cell death by apoptosis. We call this seemingly paradoxical ability of heat shock to induce cytoprotection and cytotoxicity the heat shock paradox. The molecular mechanisms by which cells integrate responses to these and other stresses are poorly understood. We present data linking the heat shock paradox to the activity of the acute-phase transcription factor nuclear factor kappa B (identifying an 'NF-kappaB paradox') and hypothesize that the mechanism is linked to the downstream effects of induction of NF-kappaB's endogenous inhibitor, IkappaBalpha, a putative heat shock protein.

Acute-Phase Reaction↗
PubMed2001

A prospective, randomized study comparing percutaneous with surgical tracheostomy in critically ill patients.

OBJECTIVE: To determine the relative cost-effectiveness of percutaneous dilational tracheostomy (PDT) and surgical tracheostomy (ST) in critically ill patients. DESIGN: Prospective randomized study. SETTING: Medical, surgical, and coronary intensive care units at Barnes-Jewish Hospital, a tertiary care medical center. PATIENTS: Eighty critically ill mechanically ventilated patients requiring elective tracheostomy. INTERVENTIONS: Randomization to either PDT performed in the intensive care unit or ST performed in the operating room. MEASUREMENTS AND MAIN RESULTS: Treatment groups were well matched with respect to age (PDT, 65.44 +/- 2.82 [mean +/- se] years; ST, 61.4 +/- 2.89 years, p = Ns), gender (PDT, 45% males; ST, 47.5% males, p = NS), severity of illness (Acute Physiology and Chronic Health Evaluation II score: PDT, 16.87 +/- 0.84; ST, 17.88 +/- 0.92, p = NS), and principle diagnosis. PDT was performed more quickly (PDT, 20.1 +/- 2.0 mins; ST, 41.7 +/- 3.9 mins, p < .0001) and was associated with lower patient charges than ST (total patient charges: PDT, 1,569 dollars +/- 157 dollars vs. ST, 3,172 dollars +/- 114 dollars; equipment/supply charges: PDT, 688 dollars +/- 103 dollars vs. ST, 1,526 dollars +/- 87 dollars; professional charges: PDT, 880 dollars +/- 54 dollars vs. ST, 1,647 dollars +/- 50 dollars; p < .0001 for all). There were no differences in days intubated before tracheostomy (PDT, 12.7 +/- 1.1 days; ST, 15.6 +/- 1.9, p = .20), intensive care unit length of stay (PDT, 24.5 +/- 2.5 days; ST, 28.5 +/- 3.1 days, p = .33), or hospital length of stay (PDT 49.7 +/- 4.2 days; ST, 43.7 +/- 3.5 days, p = .28) when we compared these two techniques. CONCLUSIONS: PDT is a cost-effective alternative to ST. The reduction in patient charges associated with PDT in this study resulted from the procedure being performed in the intensive care unit, thus eliminating the need for operating room facilities and personnel. PDT may become the procedure of choice for electively establishing tracheostomy in the appropriately selected patient who requires long-term mechanical ventilation.

Cost-Benefit Analysis↗
PubMed2001

Injury in the era of genomics.

The traditional approach to the study of biology employs small-scale experimentation that results in the description of a molecular sequence of known function or relevance. In the era of the genome the reverse is true, as large-scale cloning and gene sequencing come first, followed by the use of computational methods to systematically determine gene function and regulation. The overarching goal of this new approach is to translate the knowledge learned from a systematic, global analysis of genomic data into a complete understanding of biology. For investigators who study shock, the specific goal is to increase understanding of the adaptive response to injury at the level of the entire genome. This review describes our initial experience using DNA microarrays to profile stress-induced changes in gene expression. We conclude that efforts to apply genomics to the study of injury are best coordinated by multi-disciplinary groups, because of the extensive expertise required.

Forecasting↗
PubMed2001

Complex systems analysis: a tool for shock research.

For the past century, students of shock have focused research efforts to illuminate specific mechanisms that cause, or fail as a consequence of, circulatory collapse. Although clinical strategies aimed at supporting or restoring individual organ systems have proven effective, many patients succumb to more generalized multiple organ system failure. We suggest that general biological systems failure cannot be interpreted through reliance on reductionist science. We propose that complex systems analysis is an essential tool for shock research and we evaluate its application to genomic technologies.

Animals↗
PubMed2000

iNOS gene expression modulates microvascular responsiveness in endotoxin-challenged mice.

Septic shock is characterized by vasodilation and decreased responsiveness to vasoconstrictors. Recent studies suggest this results from nitric oxide (NO) overproduction after expression of the calcium-independent isoform of NO synthase (iNOS) in smooth muscle cells. However, direct evidence linking iNOS (NOS2) expression and decreased microvascular responsiveness after septic stimuli is lacking. In the present study, we determined the effect of bacterial lipopolysaccharide (LPS, 20 mg/kg, IP) on smooth muscle contraction and endothelial relaxation in mesenteric resistance arteries from wild-type and iNOS knockout mice. Four hours after challenge with LPS or saline in vivo, concentration-dependent responses to norepinephrine (NE) and acetylcholine (NE+ACh) were measured in cannulated, pressurized vessels ex vivo. In vessels from wild-type mice, NE-induced contraction was markedly impaired after LPS, and pretreatment with the iNOS inhibitor aminoguanidine (AG) partly restored the NE contraction. In contrast, NE contraction in microvessels from iNOS knockout mice was unaffected by LPS. ACh-induced relaxation was unaffected by LPS in vessels from either genotype. These data provide direct evidence that iNOS gene expression mediates the LPS-induced decrease in microvascular responsiveness to vasoconstrictors. Moreover, the observation that AG did not fully restore NE contraction after LPS, whereas iNOS gene deficiency did, suggests that iNOS expression plays a central role in the development of the NO-independent effect of LPS on microvascular responsiveness. Finally, our data indicate that LPS or iNOS expression has little effect on endothelium-dependent relaxation, and eNOS activity does not appear to play a role in the decreased smooth muscle responsiveness after LPS in this model. The full text of this article is available at http://www.circresaha.org.

Acetylcholine↗
PubMed2000

Plate fixation of prostheses after segmental resection for bone tumours.

This study investigated the concept of using plates to attach endoprostheses to bone after segmental resection for bone tumours in an animal model. Titanium alloy plates integrated with the prosthesis and coated with hydroxyapatite were attached to bone by screws. This type of uncemented fixation relied on the induction of periosteal bone formation into and around the plates to secure the implant to bone. Two, three, and six-slotted plate designs were investigated. On retrieval, each plate was securely fixed by new bone. Bone apposition on the external surface of the plates occurred through a combination of periosteal bone production, invasion of bone through slots in the plate, and bone growth over the ends of the plates. Most plates became incorporated into a remodelled cortex. Higher bone turnover rates (microm day(-1)) were seen in bone in the slots of the plate compared with normal cortical bone turnover (p < 0.05). Significantly higher rates of turnover were measured beneath slotted parts of the plates compared with regions below the unslotted parts (p < 0.05). The cross-sectional area of bone surrounding the six-plate implant design was significantly higher than that of the three-plate (p < 0.05) and two-plate (p < 0.05) designs. In addition, significantly more bone formed adjacent to the six-plated implant design compared with that in the contralateral limb (p = 0.002). However, no significant difference was found when the total cortical area around the three-plated design was compared with that of the contralateral limb (p = 0.63). In contrast, significantly less bone was measured adjacent to the two-plate design than in the untreated limb (p = 0.001). Image analysis also demonstrated increased cortical porosity adjacent to the six-plate design compared with the three-plate (p = 0.004) and two-plate (p < 0.05) designs. Finite element analysis demonstrated that the six and three-plate designs increased the second moment of area compared with that in the left tibia (p = 0.003 and 0.066, respectively). However, the attachment of the more flexible two-plate design did not significantly increase the second moment of area compared with that in the contralateral limb (p = 0.235). It was concluded that due to both mechanical and biological effects, the hydroxyapatite-coated plate designs generated new bone that enhanced fixation and encouraged plate integration into the load-bearing structure of the cortex. This method of fixation may be an alternative to the use of intramedullary cemented stems in patients requiring bone tumour implants and may be the only way to preserve the joint in difficult cases where only short segments of bone remain.

Animals↗
PubMed2000

Molecular biology of multiple organ dysfunction syndrome: injury, adaptation, and apoptosis.

Injury will equal or surpass communicable disease in the year 2020 as the number one cause of lost disability-adjusted life-years worldwide. The major cause of "late death" after trauma is organ dysfunction, commonly as a complication of shock or sepsis. The pathophysiology of injury-induced organ dysfunction is poorly characterized but has been linked to systemic inflammation as a result of infection (either obvious or occult) or massive tissue injury (systemic inflammatory response syndrome, SIRS). Subsequent complications of organ dysfunction, including death, may also stem from immunosuppression characteristic of what has been called the counter-regulatory anti-inflammatory response syndrome (CARS). At the cellular level, injurious stimuli trigger adaptive stress responses that include changes in gene expression. Multiple organ dysfunction syndrome (MODS) is the summation of these stress responses to severe systemic injury, integrated at the cellular, organ, and host levels. We hypothesize that a complete understanding at the molecular level of the stress responses induced by injury will aid in the development of therapeutic strategies for treating MODS in the critically ill surgical patient. This paper reviews recent data from our Cellular Injury and Adaptation Laboratory relevant to our understanding of MODS pathophysiology, particularly as it relates to stress-induced cell death by apoptosis. Our data suggest that inhibition of stress-induced apoptosis may improve survival after severe injury.

Adaptation, Biological↗
PubMed2000

Cementless fixation for primary segmental bone tumor endoprostheses.

To combat the high incidence of aseptic loosening for young patients and for patients with failed implants after resection for bone tumors, intramedullary cementless fixation of massive tumor implants was investigated. These implants consist of a hydroxyapatite coated titanium stem. To date, 47 of these prostheses have been inserted for the treatment of primary bone tumors. Radiographs indicate that the stems are osseointegrated. Radiolucent lines have not been seen between the implant and the bone. Bone remodeling changes have been observed. In several cases in which the implant was not seated properly on the transaction site, bone grew to the shoulder of the implant. Bone remodeling was particularly evident in stems that were coated over their entire surface. In these cases, the implant induced local bone resorption so that the bone around the midstream region became thinner, with resorption of cortical bone on the periosteal surface and maintenance of bone on the endosteal surface adjacent to the stem. This effect was attributed to stress shielding, and a three-dimensional finite element model using loading data obtained from a telemetry study indicated that, where the stem was bonded to the bone over the entire surface, stresses in the outer cortex became reduced. In the finite element model, reducing the region of hydroxyapatite coating to approximately 1/3 of the stem length reduced the extent of the low-stress area in the outer cortex. Subsequently, prostheses have been coated with hydroxyapatite over only approximately 1/3 of their stem. This method of fixing the massive endoprosthesis to the bone is thought to be successful in the short-term and offers an alternative to cemented fixation.

Bone Neoplasms↗
PubMed2000

Rapid onset of intestinal epithelial and lymphocyte apoptotic cell death in patients with trauma and shock.

OBJECTIVE: Apoptosis is a cellular suicide program that can be activated by cell injury or stress. Although a number of laboratory studies have shown that ischemia/reperfusion injury can induce apoptosis, few clinical studies have been performed. The purpose of this study was to determine whether apoptosis is a major mechanism of cell death in intestinal epithelial cells and lymphocytes in patients who sustained trauma, shock, and ischemia/ reperfusion injury. DESIGN: Intestinal tissues were obtained intraoperatively from 10 patients with acute traumatic injuries as a result of motor vehicle collisions or gun shot wounds. A control population consisted of six patients who underwent elective bowel resections. Apoptosis was evaluated by conventional light microscopy, laser scanning confocal microscopy using the nuclear staining dye Hoechst 33342, immunohistochemical staining for active caspase-3, and immunohistochemical staining for cytokeratin 18. SETTING: Academic medical center. PATIENTS: Patients with trauma or elective bowel resections. MEASUREMENTS AND MAIN RESULTS: Extensive focal crypt epithelial and lymphocyte apoptosis were demonstrated by multiple methods of examination in the majority of trauma patients. Trauma patients having the highest injury severity score tended to have the most severe apoptosis. Repeat intestinal samples obtained from two of the trauma patients who had a high degree of apoptosis on initial evaluation were negative for apoptosis at the time of the second operation. Tissue lymphocyte apoptosis was associated with a markedly decreased circulating lymphocyte count in 9 of 10 trauma patients. CONCLUSIONS: Focal apoptosis of intestinal epithelial and lymphoid tissues occurs extremely rapidly after injury. Apoptotic loss of intestinal epithelial cells may compromise bowel wall integrity and be a mechanism for bacterial or endotoxin translocation into the systemic circulation. Apoptosis of lymphocytes may impair immunologic defenses and predispose to infection.

Adolescent↗
PubMed2000

Acyclovir induced coma in the intensive care unit.

A 73-year-old man with multiorgan failure requiring mechanical ventilation and haemodialysis developed herpes labialis infection during his stay in the ICU. This was treated with enteral acyclovir. He developed persistent neurologic impairment soon after acyclovir administration, which, over the course of seven days, progressed to coma, the aetiology of which was unclear. The computed tomograph (CT) of the brain and the cerebrospinal fluid (CSF) examination was normal. The electroencephalogram (EEG) showed generalized slowing. The possibility of acyclovir neurotoxicity was considered and the drug was discontinued. Haemodialysis was instituted and the patient made a complete neurological recovery. We believe that this is the first reported case of coma due to enteral acyclovir.

Acyclovir↗
PubMed2000

Interstitial laser photocoagulation for the treatment of osteoid osteoma.

We report the results of a prospective study of 23 patients in which interstitial laser photocoagulation (ILP) was used to treat an osteoid osteoma. ILP is a technique in which tumour tissue is destroyed by direct heating using low-power laser light energy delivered by thin (400 microm) optical fibres which are introduced percutaneously into the tumour under image guidance. Pain was evaluated before operation and at the latest follow-up using a visual analogue scale with 0 denoting no pain and 10 the worst pain imaginable. The mean follow-up was for 15 months. The results showed that the mean pain score decreased from 7.5 before operation to 0.95 at the latest follow-up. Fourteen patients had no pain and eight had minor discomfort, not requiring analgesia. One patient required a second procedure because placement of the fibre had not been accurate enough and one developed recurrent symptoms eight months after treatment. All patients were satisfied with the operation because of the rapid resolution of pain, the minimally invasive nature of the procedure, and the fact that there was no postoperative restriction of activity.

Adolescent↗
PubMed1999

Prevention of lymphocyte cell death in sepsis improves survival in mice.

Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial to host survival by down-regulating the inflammatory response or, alternatively, harmful by impairing host defenses. To determine the beneficial vs. adverse effects of lymphocyte apoptosis in sepsis, we blocked lymphocyte apoptosis either by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl) fluoromethyl ketone (z-VAD), a broad-spectrum caspase inhibitor, or by use of Bcl-2 Ig transgenic mice that selectively overexpress the antiapoptotic protein Bcl-2 in a lymphoid pattern. Both z-VAD and Bcl-2 prevented lymphocyte apoptosis and resulted in a marked improvement in survival. z-VAD did not decrease lymphocyte tumor necrosis factor-alpha production. Considered together, these two studies employing different methods of blocking lymphocyte apoptosis provide compelling evidence that immunodepression resulting from the loss of lymphocytes is a central pathogenic event in sepsis, and they challenge the current paradigm that regards sepsis as a disorder resulting from an uncontrolled inflammatory response. Caspase inhibitors may represent a treatment strategy in this highly lethal disorder.

Animals↗
PubMed1999

Overexpression of Bcl-2 in transgenic mice decreases apoptosis and improves survival in sepsis.

In sepsis there is extensive apoptosis of lymphocytes, which may be beneficial by down-regulating the accompanying inflammation. Alternatively, apoptosis may be detrimental by impairing host defense. We studied whether Bcl-2, a potent antiapoptotic protein, could prevent lymphocyte apoptosis in a clinically relevant model of sepsis. Transgenic mice in which Bcl-2 was overexpressed in T cells had complete protection against sepsis-induced T lymphocyte apoptosis in thymus and spleen. Surprisingly, there was also a decrease in splenic B cell apoptosis in septic Bcl-2 overexpressors compared with septic HeJ and HeOuJ mice. There were marked increases in TNF-alpha, IL-1beta, and IL-10 in thymic tissue in sepsis in the three species of mice, and the increase in TNF-alpha and IL-10 in HeOuJ mice was greater than that in Bcl-2 mice. Mitotracker, a mitochondrial membrane potential indicator, demonstrated a sepsis-induced loss of membrane potential in T cells in HeJ and HeOuJ mice but not in Bcl-2 mice. Importantly, Bcl-2 overexpressors also had improved survival in sepsis. To investigate the potential impact of loss of lymphocytes on survival in sepsis, Rag-1-/- mice, which are totally deficient in mature T and B cells, were also studied. Rag-1-/- mice had decreased survival compared with immunologically normal mice with sepsis. We conclude that overexpression of Bcl-2 provides protection against cell death in sepsis. Lymphocyte death may be detrimental in sepsis by compromising host defense.

Animals↗
PubMed1999

Osseo-mechanical induction of extra-cortical plates with reference to their surface properties and geometric designs.

The purpose of this investigation was to determine which geometric and surface properties encouraged optimal ingrowth and bonding of bone to an extra-cortical plate. Forty-eight titanium extra-cortical plates were attached onto the left and right femora of adult rabbits. The plates were of six different designs and the osseoconductive effects of four surfaces were examined. A roughened titanium surface, a plasma sprayed HA coating of low crystallinity (57%) and a solution precipitated calcium phosphate coating were compared with a plasma sprayed crystalline hydroxyapatite coating (crystallinity 85%). Thin sections were prepared by grinding and polishing. Bone formation and the interface around the plates were investigated histologically and computer and morphometric analyses were used to quantify new bone formation, bone apposition onto the plate, bone porosity and the condition of the HA coating. The study found that a hydroxyapatite coating (with the exception of the solution precipitated coating) had significantly greater interfacial contact with bone when compared to a roughened titanium surface, and that significantly more bone attached to a crystalline HA coating compared with the HA coating of lower crystallinity although significantly more bone formed in the vicinity of the lower crystalline HA coating. Differences in the bony reaction induced by the various geometric designs were evident and the optimal plate design requires either holes or slots along its length as this encouraged bone ingrowth into the plate.

Animals↗