Activation of androgen receptor-expressing neurons in the posterior medial amygdala is associated with stress resistance in dominant male hamsters.

Social stress is a negative emotional experience that can increase fear and anxiety. Dominance status can alter the way individuals react to and cope with stressful events. The underlying neurobiology of how social dominance produces stress resistance remains elusive, although experience-dependent changes in androgen receptor (AR) expression is thought to play an essential role. Using a Syrian hamster (Mesocricetus auratus) model, we investigated whether dominant individuals activate more AR-expressing neurons in the posterior dorsal and posterior ventral regions of the medial amygdala (MePD, MePV), and display less social anxiety-like behavior following social defeat stress compared to subordinate counterparts. We allowed male hamsters to form and maintain a dyadic dominance relationship for 12 days, exposed them to social defeat stress, and then tested their approach-avoidance behavior using a social avoidance test. During social defeat stress, dominant subjects showed a longer latency to submit and greater c-Fos expression in AR+ cells in the MePD/MePV compared to subordinates. We found that social defeat exposure reduced the amount of time animals spent interacting with a novel conspecific 24 h later, although there was no effect of dominance status. The amount of social vigilance shown by dominants during social avoidance testing was positively correlated with c-Fos expression in AR+ cells in the MePV. These findings indicate that dominant hamsters show greater neural activity in AR+ cells in the MePV during social defeat compared to their subordinate counterparts, and this pattern of neural activity correlates with their proactive coping response. Consistent with the central role of androgens in experience-dependent changes in aggression, activation of AR+ cells in the MePD/MePV contributes to experience-dependent changes in stress-related behavior.

The outcomes of acute periprosthetic joint infection following unicompartmental knee replacement managed with early debridement, Antibiotics, and implant retention.

BACKGROUND: Periprosthetic joint infection (PJI) following unicompartmental knee replacement (UKR) is an uncommon, yet serious, complication. There is a paucity of evidence regarding the effectiveness of Debridement-Antibiotics-and-Implant-Retention (DAIR) in this setting. The aim of this study is to investigate the effectiveness of DAIR for acute UKR PJI. METHOD: Between 2006 and 2019, 5195 UKR were performed at our institution. Over this period, sixteen patients underwent DAIR for early, acute PJI. All patients met MSIS PJI diagnostic criteria. The median age at DAIR was 67 years (range 40-73) and 12 patients were male (75.0%). The median time to DAIR was 24 days (range 6-60). Patients were followed up for a median of 6.5 years (range1.4-10.5) following DAIR. RESULTS: 0.3% (16/5195) of UKR in our institution had a DAIR within 3 months. 15 of 16 patients (93.8%) were culture positive, with the most common organism MSSA (n = 8, 50.0%). Patients were treated with an organism-specific intravenous antibiotic regime for a median of 6 weeks, followed by oral antibiotics for a median duration of 6 months. The Kaplan-Meier survivor estimate for revision for PJI was 57% (95%CI: 28-78%) at five years, and survivor estimate for all cause revision 52% (95%CI: 25-74%).The median Oxford Knee Score for patients with a viable implant at final follow-up was 45 points (range 39-46). CONCLUSION: Early, acute PJI after UKR is rare. DAIR had a moderate success rate, with infection-free survivorship of 57% at 5 years. Those successfully treated with DAIR had excellent functional outcome and implant survival.

Incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infection in European hospitals: the COMBACTE-NET ARTHR-IS multi-centre study.

BACKGROUND: The aim of this study was to estimate the incidence, associated disease burden and healthcare utilization due to Staphylococcus aureus prosthetic joint infections (SA-PJI) after primary hip and knee arthroplasty in European centres. METHODS: This study was conducted in patients who underwent primary hip and knee arthroplasty in 19 European hospitals between 2014 and 2016. The global incidence of PJI and SA-PJI was calculated. The associated disease burden was measured indirectly as infection-related mortality plus loss of function. For healthcare utilization, number and duration of hospitalizations, number and type of surgical procedures, duration of antibiotic treatments, and number of outpatient visits were collected. Subgroup and regression analyses were used to evaluate the impact of SA-PJI on healthcare utilization, controlling for confounding variables. RESULTS: The incidence of PJI caused by any micro-organism was 1.41%, and 0.40% for SA-PJI. Among SA-PJI, 20.7% were due to MRSA with substantial regional differences, and were more frequent in partial hip arthroplasty (PHA). Related deaths and loss of function occurred in 7.0% and 10.2% of SA-PJI cases, respectively, and were higher in patients with PHA. Compared with patients without PJI, patients with SA-PJI had a mean of 1.4 more readmissions, 25.1 more days of hospitalization, underwent 1.8 more surgical procedures, and had 5.4 more outpatient visits, controlling for confounding variables. Healthcare utilization was higher in patients who failed surgical treatment of SA-PJI. CONCLUSIONS: This study confirmed that the SA-PJI burden is high, especially in PHA, and provided a solid basis for planning interventions to prevent SA-PJI.

Resistant fabric warming is a viable alternative to forced-air warming to prevent inadvertent perioperative hypothermia during hemiarthroplasty in the elderly.

BACKGROUND: Surgical site infection (SSI) is associated with inadvertent perioperative hypothermia (IPH). This can be prevented by active patient warming. However, results from comparisons of warming techniques are conflicting. They are based mostly on elective surgery, are from small numbers of patients, and are dominated by the market leader, forced-air warming (FAW). Furthermore, the definition of hypothermia is debatable and systematic reviews of warming systems conclude that a stricter control of temperature is required to study the benefits of warming. AIM: To analyse core temperatures in detail in a large subset of elderly patients who took part in a randomized trial of patient warming following hemiarthroplasty who had received constant zero-flux thermometry to record their temperature. METHODS: Regression models with a fixed effect for warming group and covariates related to temperature were compared for 257 participants randomized to FAW or resistant fabric warming (RFW) from a prior clinical trial. FINDINGS: Those in the RFW group were -0.08°C cooler and had a cumulative hypothermia score -1.87 lower than those in the FAW group. There was no difference in the proportion of hypothermic patients at either <36.5°C or <36.0°C. CONCLUSIONS: This is the first study to provide accurate temperature measurements in patients undergoing a procedure predominantly under regional rather than general anaesthetic. It shows that RFW is a viable alternative to FAW for preventing IPH during hemiarthroplasty. Further studies are needed to measure the benefits of patient warming in terms of clinically important outcomes.

Evaluation of acid-phase digestion as a pretreatment to enhance co-digestion of source separated organics and municipal sewage sludges.

This work assessed if acid-phase digestion could improve volatile solids (VS) destruction and methane yield when co-digesting municipal sewage sludges (primary and waste activated sludge) and source separated organics (SSO). The SSO was made up of food waste and the organic fraction of municipal solid waste. Two laboratory-scale acid-phase digesters and three laboratory-scale methane-phase digesters were employed in order to determine the impacts of SSO co-digestion with municipal sludges both with and without acid-phase digestion as a pretreatment step. Reactors were operated at 35 °C using volatile solids loading rates of 34.2-44.1 g VS/LR-day for acid-phase digesters and 1.2-2.4 1 g VS/LR-day for methane-phase digesters. Solids retention times ranging from 1.2 to 1.5 day and 20.7 to 23.2 days were employed for acid-phase and methane-phase digesters, respectively. VS destruction ranged from 62% to 67%, with reactors receiving SSO achieving higher VS destruction. Results also show that reactors receiving SSO were able to handle organic loading increases of at least 39% without showing signs of overloading. Microbial community analysis revealed that SSO had a noticeable impact on acid-phase digestion with Megasphaera emerging as the most abundant genus.

Reducing Implant Infection in Orthopaedics (RIIiO): Results of a pilot study comparing the influence of forced air and resistive fabric warming technologies on postoperative infections following orthopaedic implant surgery.

BACKGROUND: Active warming during surgery prevents perioperative hypothermia but the effectiveness and postoperative infection rates may differ between warming technologies. AIM: To establish the recruitment and data management strategies needed for a full trial comparing postoperative infection rates associated with forced air warming (FAW) versus resistive fabric warming (RFW) in patients aged >65 years undergoing hemiarthroplasty following fractured neck of femur. METHODS: Participants were randomized 1:1 in permuted blocks to FAW or RFW. Hypothermia was defined as a temperature of <36°C at the end of surgery. Primary outcomes were the number of participants recruited and the number with definitive deep surgical site infections. FINDINGS: A total of 515 participants were randomized at six sites over a period of 18 months. Follow-up was completed for 70.1%. Thirty-seven participants were hypothermic (7.5% in the FAW group; 9.7% in the RFW group). The mean temperatures before anaesthesia and at the end of surgery were similar. For the primary clinical outcome, there were four deep surgical site infections in the FAW group and three in the RFW group. All participants who developed a postoperative infection had antibiotic prophylaxis, a cemented prosthesis, and were operated under laminar airflow; none was hypothermic. There were no serious adverse events related to warming. CONCLUSION: Surgical site infections were identified in both groups. Progression from the pilot to the full trial is possible but will need to take account of the high attrition rate.

Cross-sectional study of the prevalence, causes and management of hospital-onset diarrhoea.

BACKGROUND: The National Health Service in England advises hospitals collect data on hospital-onset diarrhoea (HOD). Contemporaneous data on HOD are lacking. AIM: To investigate prevalence, aetiology and management of HOD on medical, surgical and elderly-care wards. METHODS: A cross-sectional study in a volunteer sample of UK hospitals, which collected data on one winter and one summer day in 2016. Patients admitted ≥72 h were screened for HOD (definition: ≥2 episodes of Bristol Stool Type 5-7 the day before the study, with diarrhoea onset >48 h after admission). Data on HOD aetiology and management were collected prospectively. FINDINGS: Data were collected on 141 wards in 32 hospitals (16 acute, 16 teaching). Point-prevalence of HOD was 4.5% (230/5142 patients; 95% confidence interval (CI) 3.9-5.0%). Teaching hospital HOD prevalence (5.9%, 95% CI 5.1-6.9%) was twice that of acute hospitals (2.8%, 95% CI 2.1-3.5%; odds ratio 2.2, 95% CI 1.7-3.0). At least one potential cause was identified in 222/230 patients (97%): 107 (47%) had a relevant underlying condition, 125 (54%) were taking antimicrobials, and 195 (85%) other medication known to cause diarrhoea. Nine of 75 tested patients were Clostridium difficile toxin positive (4%). Eighty (35%) patients had a documented medical assessment of diarrhoea. Documentation of HOD in medical notes correlated with testing for C. difficile (78% of those tested vs 38% not tested, P<0.001). One-hundred and forty-four (63%) patients were not isolated following diarrhoea onset. CONCLUSION: HOD is a prevalent symptom affecting thousands of patients across the UK health system each day. Most patients had multiple potential causes of HOD, mainly iatrogenic, but only a third had medical assessment. Most were not tested for C. difficile and were not isolated.

Correlation of histological and microbiological findings in septic and aseptic knee implant failure.

INTRODUCTION: The Musculoskeletal Infection Society (MSIS) has defined specific clinical and laboratory criteria for the diagnosis of periprosthetic joint infection (PJI). In this study we assessed the diagnostic utility of MSIS microbiological and histological criteria for PJI in 138 cases of septic and aseptic knee implant failure. MATERIALS AND METHODS: Intra-operative samples from 60 cases of knee septic implant failure (SIF) and 78 cases of aseptic implant failure (AIF), defined on the basis of clinical, laboratory and operative findings/surgical management, were analysed microbiologically and histologically. Findings were correlated with the final clinical diagnosis and the specificity, sensitivity, accuracy, positive and negative predictive value of MSIS microbiological and histological criteria for knee PJI were assessed. RESULTS: 80% of SIF cases showed culture of the same organism from two or more samples (ie MSIS microbiological criteria for definite PJI); 8.3% grew an organism from one sample, and 11.7% showed no growth from any sample. 23.1% of AIF cases grew an organism from one sample and 76.9% showed no growth from any sample. MSIS histological criteria for PJI identified 96.7% of SIF cases. The sensitivity, specificity, accuracy and positive and negative predictive value of MSIS histological criteria for PJI were 96.7%, 100%, 98.6%, 100% and 97.5%, respectively. MSIS microbiological and histological criteria identified all AIF cases. CONCLUSIONS: Knee PJI is more often identified by current MSIS histological than microbiological criteria. A significant proportion of SIF cases show either no growth or growth of an organism from only one sample. AIF is identified by both MSIS microbiological and histological criteria. Correlation of clinical, radiological and laboratory findings is required for the diagnosis of knee PJI.

The role of histology in the diagnosis of spondylodiscitis: correlation with clinical and microbiological findings.

AIMS: The aim of this study was to determine the diagnostic utility of histological analysis in spinal biopsies for spondylodiscitis (SD). PATIENTS AND METHODS: Clinical features, radiology, results of microbiology, histology, and laboratory investigations in 50 suspected SD patients were evaluated. In 29 patients, the final (i.e. treatment-based) diagnosis was pyogenic SD; in seven patients, the final diagnosis was mycobacterial SD. In pyogenic SD, the neutrophil polymorph (NP) infiltrate was scored semi-quantitatively by determining the mean number of NPs per (×400) high-power field (HPF). RESULTS: Of the 29 pyogenic SD patients, 17 had positive microbiology and 21 positive histology (i.e. one or more NPs per HPF on average). All non-SD patients showed less than one NP per HPF. The presence of one or more NPs per HPF had a diagnostic sensitivity of 72.4%, specificity 100%, accuracy 100%, positive predictive value (PPV) 81.0%, and negative predictive value (NPV) 61.9%. Sensitivity, specificity, and accuracy were greater using the criterion of positive histology and/or microbiology than positive histology or microbiology alone. Granulomas were identified histologically in seven mycobacterial SD patients, and positive microbiology was detected in four. CONCLUSION: The diagnosis of pyogenic SD was more often confirmed by positive histology (one or more NPs per HPF on average) than by microbiology, although diagnostic sensitivity was greater when both histology and microbiology were positive. Cite this article: Bone Joint J 2019;101-B:246-252.

Fracture-related infection: A consensus on definition from an international expert group.

Fracture-related infection (FRI) is a common and serious complication in trauma surgery. Accurately estimating the impact of this complication has been hampered by the lack of a clear definition. The absence of a working definition of FRI renders existing studies difficult to evaluate or compare. In order to address this issue, an expert group comprised of a number of scientific and medical organizations has been convened, with the support of the AO Foundation, in order to develop a consensus definition. The process that led to this proposed definition started with a systematic literature review, which revealed that the majority of randomized controlled trials in fracture care do not use a standardized definition of FRI. In response to this conclusion, an international survey on the need for and key components of a definition of FRI was distributed amongst all registered AOTrauma users. Approximately 90% of the more than 2000 surgeons who responded suggested that a definition of FRI is required. As a final step, a consensus meeting was held with an expert panel. The outcome of this process led to a consensus definition of FRI. Two levels of certainty around diagnostic features were defined. Criteria could be confirmatory (infection definitely present) or suggestive. Four confirmatory criteria were defined: Fistula, sinus or wound breakdown; Purulent drainage from the wound or presence of pus during surgery; Phenotypically indistinguishable pathogens identified by culture from at least two separate deep tissue/implant specimens; Presence of microorganisms in deep tissue taken during an operative intervention, as confirmed by histopathological examination. Furthermore, a list of suggestive criteria was defined. These require further investigations in order to look for confirmatory criteria. In the current paper, an overview is provided of the proposed definition and a rationale for each component and decision. The intention of establishing this definition of FRI was to offer clinicians the opportunity to standardize clinical reports and improve the quality of published literature. It is important to note that the proposed definition was not designed to guide treatment of FRI and should be validated by prospective data collection in the future.

Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of 100 cases.

AIMS: Chronic osteomyelitis may recur if dead space management, after excision of infected bone, is inadequate. This study describes the results of a strategy for the management of deep bone infection and evaluates a new antibiotic-loaded biocomposite in the eradication of infection from bone defects. PATIENTS AND METHODS: We report a prospective study of 100 patients with chronic osteomyelitis, in 105 bones. Osteomyelitis followed injury or surgery in 81 patients. Nine had concomitant septic arthritis. 80 patients had comorbidities (Cierny-Mader (C-M) Class B hosts). Ten had infected nonunions. All patients were treated by a multidisciplinary team with a single-stage protocol including debridement, multiple sampling, culture-specific systemic antibiotics, stabilisation, dead space filling with the biocomposite and primary skin closure. RESULTS: Patients were followed up for a mean of 19.5 months (12 to 34). Infection was eradicated in 96 patients with a single procedure and all four recurrences were successfully managed with repeat surgery. Adverse events were uncommon, with three fractures, six wound leaks and three unrelated deaths. Outcome was not dependant on C-M host class, microbial culture, wound leakage or presence of nonunion. CONCLUSION: This single-stage protocol, facilitated by the absorbable local antibiotic, is effective in the treatment of chronic osteomyelitis. It offers a more patient-friendly treatment compared with other published treatment options. Cite this article: Bone Joint J 2016;98-B:1289-96.

Gram-negative bacteraemia; a multi-centre prospective evaluation of empiric antibiotic therapy and outcome in English acute hospitals.

Increasing antibiotic resistance makes choosing antibiotics for suspected Gram-negative infection challenging. This study set out to identify key determinants of mortality among patients with Gram-negative bacteraemia, focusing particularly on the importance of appropriate empiric antibiotic treatment. We conducted a prospective observational study of 679 unselected adults with Gram-negative bacteraemia at ten acute english hospitals between October 2013 and March 2014. Appropriate empiric antibiotic treatment was defined as intravenous treatment on the day of blood culture collection with an antibiotic to which the cultured organism was sensitive in vitro. Mortality analyses were adjusted for patient demographics, co-morbidities and illness severity. The majority of bacteraemias were community-onset (70%); most were caused by Escherichia coli (65%), Klebsiella spp. (15%) or Pseudomonas spp. (7%). Main foci of infection were urinary tract (51%), abdomen/biliary tract (20%) and lower respiratory tract (14%). The main antibiotics used were co-amoxiclav (32%) and piperacillin-tazobactam (30%) with 34% receiving combination therapy (predominantly aminoglycosides). Empiric treatment was inappropriate in 34%. All-cause mortality was 8% at 7 days and 15% at 30 days. Independent predictors of mortality (p <0.05) included older age, greater burden of co-morbid disease, severity of illness at presentation and inflammatory response. Inappropriate empiric antibiotic therapy was not associated with mortality at either time-point (adjusted OR 0.82; 95% CI 0.35-1.94 and adjusted OR 0.92; 95% CI 0.50-1.66, respectively). Although our study does not exclude an impact of empiric antibiotic choice on survival in Gram-negative bacteraemia, outcome is determined primarily by patient and disease factors.

Death is associated with complement C3 depletion in cerebrospinal fluid of patients with pneumococcal meningitis.

UNLABELLED: Pneumococcal meningitis can lead to death or serious neurological sequelae as a result of the host inflammatory response. We investigated the association between host response protein expression and outcome in patients with pneumococcal meningitis. Cerebrospinal fluid (CSF) was obtained from 80 patients with pneumococcal meningitis (40 nonsurvivors and 40 survivors) and 10 normal controls. Candidate proteins were analyzed for an association with survival. Complement C3 levels were 5-fold lower in nonsurvivors than in survivors (P < 0.05). This C3 reduction was not associated with lower levels in serum, indicating a compartmentalized CSF response. Transferrin levels were significantly higher in CSF (but not serum) from nonsurvivors than in CSF from survivors, suggestive of blood-brain barrier damage. Classical apoptosis proteins caspase 3 and apoptosis-inducing factor were not present in CSF. Expression of creatine kinase BB in clinically infected CSF suggested neuronal necrosis, but there was no clear association between level of expression and clinical outcome. Increased blood-brain barrier permeability and complement C3 depletion may have a role in determining outcome from bacterial meningitis. Therapeutic use of citicoline or caspase inhibitors is unlikely to have beneficial effects in patients with meningitis. IMPORTANCE: We previously identified proteins associated with clinical outcome in patients diagnosed with pneumococcal meningitis in a pilot proteomics study of cerebrospinal fluid (CSF). In this article, we have quantitatively assayed specific proteins identified from this previous proteomics analysis along with proteins associated with cell death by using Western blotting.

Periosteal chondroma at birth.

Periosteal chondroma is a slow-growing, cartilaginous, surface tumor that usually occurs in the second and third decades of life. The youngest reported age at diagnosis is 5 years. Marginal excision is the treatment of choice. We report a case of a periosteal chondroma noted at birth and treated conservatively. This report expands the age range of periosteal chondroma to include neonates and suggests a role for observation in its management.

Differential effects of estrogen in the injured forebrain of young adult and reproductive senescent animals.

Estrogen attenuates neural damage resulting from a variety of experimental injury models in adult female rats. To determine whether estrogens neuroprotective actions are age-specific, the present study compared the effects of estrogen on young adult and reproductive senescent animals subject to excitotoxic injury to the forebrain. NMDA was injected bilaterally into the olfactory bulbs of estrogen and placebo-replaced young adult and reproductive senescent animals. Lysates of the olfactory bulb and its basal forebrain afferent, the horizontal limb of the diagonal band of Broca (hlDBB), harvested 24h later were analyzed for expression of IL-1beta, IL-10, and nerve growth factor (NGF). NMDA injections resulted in local activation of microglia and an increase in IL-1beta. Estrogen replacement decreased IL-1beta expression in young adult females, but paradoxically enhanced its expression in reproductive senescent females. Furthermore, bulb injury increased IL-1beta production in the hlDBB of reproductive senescent animals although estrogen replacement was able to suppress lesion-induced expression of this cytokine. In both, the olfactory bulb and hlDBB, constitutive expression of the anti-inflammatory cytokine IL-10 was significantly higher while that of NGF was almost 50% lower in senescent animals as compared to young adults, indicating that aging preferentially altered Th2-type secretions. The present findings are consistent with our earlier observations that estrogen does not exert trophic effects in the aging forebrain and supports the hypothesis that estrogen treatment to reproductive senescent females may exacerbate neural injury.

Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions.

SETTING: Inpatient medical wards, Department of Medicine, University Teaching Hospital, Lusaka, Zambia. OBJECTIVE: To define the natural history, clinical presentation, and management outcome of microbiologically confirmed cryptococcal meningitis in adult AIDS patients treated under local conditions where antifungal and antiretroviral therapies are not routinely available. DESIGN: A descriptive, longitudinal, observational study. METHODS: All adult patients admitted to the medical wards of the University Teaching Hospital, Lusaka, Zambia with cerebrospinal fluid culture proved, primary cryptococcal meningitis, during a 12 month period were enrolled into the study. The following details were acquired: clinical features, HIV status, laboratory data, treatment accorded, and survival. RESULTS: A total of 230 patients with primary cryptococcal meningitis were studied (median age 32 years; range 15-65 years; 112 males, 118 females). Cryptococcal meningitis was the first AIDS defining illness in 210 (91%) patients. One hundred and thirty of the 230 (56%) patients had received treatment with fluconazole monotherapy and 100 (43%) patients received palliative care only without any antifungal therapy. A 100% case fatality rate was observed in both groups at follow up: by seven weeks in the untreated group and at six months in the fluconazole treated group. The cumulative median survival from time of diagnosis was 19 days (range 1-164 days) for the fluconazole treated group and 10 days (range 0-42 days) for the untreated group. CONCLUSION: Cryptococcal meningitis, under current treatment accorded at the University Teaching Hospital, Lusaka, has a 100% mortality in young Zambian adults with AIDS. The current treatment accorded to Zambian adults with cryptococcal meningitis is inappropriate. An urgent need exists to improve strategies for the clinical management of AIDS patients in poor African countries. The wider ethical and operational issues of making available antifungals to African AIDS patients are discussed.

Pathologic fractures after surgery and radiation for soft tissue tumors.

Twenty pathologic fractures occurred in 285 patients with soft tissue tumors that were treated with radiation therapy and surgery. Twelve of these fractures occurred in 11 patients from a subpopulation of 163 patients with 168 soft tissue tumors of the thigh (155 soft tissue sarcomas and 13 aggressive fibromatosis). The fractures occurred at a mean of 40.5 months after treatment and were not associated with significant trauma. Risk factors associated with the development of fracture included tumor location within the anterior compartment of the thigh, extensive surgical periosteal stripping, and a marginal or intralesional margin of resection. The dose, timing, and fractionation of radiation therapy were not related to the risk of fracture. A high rate of complications was seen with this series, including fracture nonunion (45%) and deep infection (20%). Prophylactic intramedullary fixation of the femur should be considered for patients undergoing resection of large tumors in the anterior compartment of the thigh requiring extensive periosteal stripping and adjuvant radiation therapy.

Limb salvage surgery with vascular reconstruction.

Vascular reconstruction and limb salvage surgery has been the authors' preferred approach when malignancy involves major vessels of the extremities. Treatment of 16 patients involved resection, with vascular grafting in 14 patients and rotationplasty in two patients. The major vessels were surrounded by tumor in six patients, nearly encased in three patients, invaded by tumor in four patients, and widely contaminated by intralesional surgery in three patients. The tumor stage included one Stage IB, 12 Stage IIB, two Stage IIIB sarcomas, and one multiply recurrent carcinoma. The largest average tumor dimension was 9.5 cm, and the length of grafting was 14 cm. Major nerves were sacrificed in eight (50%) patients, flaps or muscle transfers were done in seven (44%), chemotherapy was administered in nine (56%), radiation therapy was used in four (25%), and pulmonary metastasectomy was done in two (12%). At a mean followup of 56 months, 50% (eight of 16) of patients were alive without disease. Local recurrence was 12% (two of 16 patients), and infection was 12% (two of 16 patients). Limb salvage was achieved in 88% (14 of 16 patients), and functional status was judged good or excellent in 81% (13 of 16 patients). The complication rate observed in this subset of patients is significant, yet local control and the incidence of major complications was acceptable. Results observed from this series and data gathered from the literature clearly indicate that patients can avoid amputation, despite malignant involvement of major vessels to their extremities.

NGF stimulation increases JNK2 phosphorylation and reduces caspase-3 activity in the olfactory bulb of estrogen-replaced animals.

Estrogen receptors are extensively colocalized with neurotrophins and their receptors in the rodent forebrain. We have shown previously that estrogen increases mRNA and protein expression of the nerve growth factor (NGF)-specific tyrosine kinase receptor, trkA, while decreasing expression of the universal neurotrophin receptor p75. In view of the pro-survival roles described for trks and the context-dependent stimulation of survival and cell death pathways activated by p75, differential regulation of these receptors by estrogen is likely to alter neurotrophin-dependent cell signaling. This hypothesis was tested in vivo, using the rodent olfactory bulb as a model. We found that NGF activated the extracellular signal-regulated protein kinase (ERK) equally in estrogen replaced and hormone-deprived animals. However in the case of c-jun-kinase (JNK), a related MAP kinase, pretreatment with estrogen altered NGF activation of a specific isoform of this protein. Specifically, NGF stimulation did not alter JNK1 or JNK2 activation in the estrogen-deprived condition, but significantly increased JNK2 activation in estrogen-replaced animals. Increased JNK2 phosphorylation in the NGF-injected, estrogen- replaced animals was paralleled by decreased activity of caspase-3, an enzyme required for apoptosis. In view of the disparate roles assigned to JNK, this latter finding suggests that estrogen pretreatment may preferentially direct neurotrophin-dependent JNK activation toward regeneration and plasticity rather than cell death.

The role of radiotherapy and limb-conserving surgery in the management of soft-tissue sarcomas in adults.

The treatment of soft-tissue sarcomas has undergone significant changes over the past several decades. Previously, patients were often treated with surgery alone, which frequently necessitated amputation of the affected extremity. Less extensive, limb-sparing operations combined with adjuvant irradiation are now feasible for most patients without compromising the likelihood of cure.