The olfactory bulbectomy disease model: A Re-evaluation.

The olfactory bulbectomized rodent has long been one of the preferred animal models of depression and certain other neuropsychiatric diseases. In fact, it is considered unparalleled, by some, in the search for antidepressant medication and the literature generated about the model is prodigious. We have revisited the "syndrome" of behavioral sequela following bulbectomy choosing ecologically valid tests likely to be underpinned with evolutionarily preserved neural circuits. Our test battery included measurements of activity, intermale aggression, pleasure seeking, stress/fear and non-spatial memory. The emphasis was on the timetable of syndrome emergence, since this has been understudied and bears on the widely held belief that non-olfactory effects dominate. Our results largely agree with previous reports describing the behavioral syndrome in that we document bulbectomized mice as hyperactive, non-aggressive and fearless. However, we did not find deficits in memory as have frequently been reported in previous studies. Notably, our results revealed that some syndrome behaviors-including the hallmark of hyperactivity-appear immediately or soon after surgery. This rapid appearance casts doubt on the widely held view that compensatory reorganization of limbic and prefrontal cortical areas following bulbectomy underlies the syndrome. Rather, hyperactivity, non-aggressiveness, reduced fear and diminished sucrose preference in the olfactory bulbectomized mouse find ready explanations in the loss of smell that is the immediate and irreversible outcome of bulbectomy. Finally, after a critical consideration of the literature and our results, we conclude that the olfactory bulbectomy model lacks the validity and simplicity previously credited to it. Indeed, we deem this lesion unsuitable as a model of most neuropsychiatric diseases since its effects are at least as complex and misunderstood as the disorders it is purported to model.

Drastic reduction of orthopaedic services at an urban tertiary hospital in South Africa during COVID-19: Lessons for the future response to the pandemic.

BACKGROUND: The COVID-19 pandemic has impacted on the global surgery landscape. OBJECTIVES: To analyse and describe the initial impact of the COVID-19 pandemic on orthopaedic surgery at Groote Schuur Hospital, a tertiary academic hospital in South Africa. METHODS: The number of orthopaedic surgical cases, emergency theatre patient waiting times, and numbers of outpatient clinic visits, ward admissions, bed occupancies and total inpatient days for January - April 2019 (pre-COVID-19) were compared with the same time frame in 2020 (COVID-19). The COVID-19 timeframe included initiation of a national 'hard lockdown' from 26 March 2020, in preparation for an increasing volume of COVID-19 cases. RESULTS: April 2020, the time of the imposed hard lockdown, was the most affected month, although the number of surgical cases had started to decrease slowly during the 3 preceding months. The total number of surgeries, outpatient visits and ward admissions decreased significantly during April 2020 (55.2%, 69.1% and 60.6%, respectively) compared with April 2019 (p<0.05). Trauma cases were reduced by 40% in April 2020. Overall emergency theatre patient waiting time was 30% lower for April 2020 compared with 2019. CONCLUSIONS: COVID-19 and the associated lockdown has heavily impacted on both orthopaedic inpatient and outpatient services. Lockdown led to a larger reduction in the orthopaedic trauma burden than in international centres, but the overall reduction in surgeries, outpatient visits and hospital admissions was less. This lesser reduction was probably due to local factors, but also to a conscious decision to avoid total collapse of our surgical services.

Low 30-day mortality in South African orthopaedic patients undergoing surgery at an academic hospital during the first wave of the COVID-19 pandemic: It was safe to perform orthopaedic procedures at our hospital during the first COVID-19 peak.

BACKGROUND:  Initial local and global evidence suggests that SARS-CoV-2-infected patients who undergo surgery, and those who become infected perioperatively, have an increased mortality risk post surgery. OBJECTIVES: To analyse and describe the 30-day mortality, presurgical COVID-19 status and hospital-acquired SARS-CoV-2 infection rates of patients, both SARS-CoV-2-positive and negative, undergoing orthopaedic surgery at a tertiary academic hospital in South Africa (SA) during the first COVID-19 peak. METHODS: This single-centre, observational, prospective study included patients who underwent orthopaedic procedures from 1 April 2020 (beginning of the COVID-19 case increase in SA) to 31 July 2020 (first COVID-19 peak in SA). All patients were screened for COVID-19 and were confirmed positive if they had a positive laboratory quantitative polymerase chain reaction test for SARS-CoV-2 RNA on a nasopharyngeal or oral swab. Thirty-day mortality, presurgical COVID-19 status and hospital-acquired SARS-CoV-2 infection were assessed. RESULTS:  Overall, a total of 433 operations were performed on 346 patients during the timeframe. Of these patients, 65.9% (n=228) were male and 34.1% (n=118) were female. The mean (standard deviation) age was 42.5 (16.8) years (range 9 - 89). Of the patients, 5 (1.4%) were identified as COVID-19 patients under investigation (PUI) on admission and tested positive for SARS-CoV-2 before surgery, and 1 (0.3%) contracted SARS-CoV-2 perioperatively; all survived 30 days post surgery. Twenty-nine patients were lost to follow-up, and data were missing for 6 patients. The final analysis was performed excluding these 35 patients. Of the 311 patients included in the final 30-day mortality analysis, 303 (97%) had a follow-up observation ≥30 days after the operation. The overall 30-day mortality for these patients was 2.5% (n=8 deaths). None of the recorded deaths were of screened COVID-19 PUI. CONCLUSIONS: We report a low 30-day mortality rate of 2.5% (n=8) for patients undergoing orthopaedic surgery at our hospital during the first COVID-19 peak. None of the deaths were COVID-19 related, and all patients who tested SARS-CoV-2-positive, before or after surgery, survived. Our overall 30-day mortality rate correlates with several other reports of orthopaedic centres analysing over similar timeframes during the first peak of the COVID-19 pandemic. Regarding mortality and SARS-CoV-2 infection risk, we can conclude that with the appropriate measures taken, it was safe to undergo orthopaedic procedures at our hospital during the first peak of the COVID-19 pandemic in SA.

Key Service Improvements After the Introduction of an Integrated Orthogeriatric Service.

INTRODUCTION: Models of orthogeriatric care have been shown to improve functional outcomes for patients after hip fractures and can improve compliance with best practice guidelines for hip fracture care. METHODS: We evaluated improvements to key performance indicators in hip fracture care after implementation of a formal orthogeriatric service. Compliance with Irish Hip Fracture standards of care was reviewed, and additional outcomes such as length of stay, access to rehabilitation, and discharge destination were evaluated. RESULTS: Improvements were observed in all of the hip fracture standards of care. Mean length of stay decreased from 19 to 15.5 days (mean difference 3.5 days; P < .05). A higher proportion of patients were admitted to rehabilitation (16.7% vs 7.9%, P < .05), and this happened in a timelier fashion (17.8 vs 24.8 days, P < .05). We found that less patients required convalescence post-hip fracture. DISCUSSION: A standardized approach to integrated post-hip fracture care with orthogeriatrics has improved standards of care for patients. CONCLUSION: Introduction of orthogeriatric services has resulted in meaningful improvements in clinical outcomes for older people with hip fractures.

Mutant phenotypes for thousands of bacterial genes of unknown function.

One-third of all protein-coding genes from bacterial genomes cannot be annotated with a function. Here, to investigate the functions of these genes, we present genome-wide mutant fitness data from 32 diverse bacteria across dozens of growth conditions. We identified mutant phenotypes for 11,779 protein-coding genes that had not been annotated with a specific function. Many genes could be associated with a specific condition because the gene affected fitness only in that condition, or with another gene in the same bacterium because they had similar mutant phenotypes. Of the poorly annotated genes, 2,316 had associations that have high confidence because they are conserved in other bacteria. By combining these conserved associations with comparative genomics, we identified putative DNA repair proteins; in addition, we propose specific functions for poorly annotated enzymes and transporters and for uncharacterized protein families. Our study demonstrates the scalability of microbial genetics and its utility for improving gene annotations.

Enhanced chlorhexidine skin penetration with 1,8-cineole.

BACKGROUND: Chlorhexidine (CHG) penetrates poorly into skin. The purpose of this study was to compare the depth of CHG skin permeation from solutions containing either 2% (w/v) CHG and 70% (v/v) isopropyl alcohol (IPA) or 2% (w/v) CHG, 70% (v/v) IPA and 2% (v/v) 1,8-cineole. METHODS: An ex-vivo study using Franz diffusion cells was carried out. Full thickness human skin was mounted onto the cells and a CHG solution, with or without 2% (v/v) 1,8-cineole was applied to the skin surface. After twenty-four hours the skin was sectioned horizontally in 100 µm slices to a depth of 2000 µm and the concentration of CHG in each section quantified using high performance liquid chromatography (HPLC). The data were analysed with repeated measures analysis of variance. RESULTS: The concentration of CHG in the skin on average was significantly higher (33.3% [95%, CI 1.5% - 74.9%]) when a CHG solution which contained 1,8-cineole was applied to the skin compared to a CHG solution which did not contain this terpene (P = 0.042). CONCLUSIONS: Enhanced delivery of CHG can be achieved in the presence of 1,8-cineole, which is the major component of eucalyptus oil. This may reduce the numbers of microorganisms located in the deeper layers of the skin which potentially could decrease the risk of surgical site infection.

Evidence for the role of corticotropin-releasing factor in major depressive disorder.

Major depressive disorder (MDD) is a devastating disease affecting over 300 million people worldwide, and costing an estimated 380 billion Euros in lost productivity and health care in the European Union alone. Although a wealth of research has been directed toward understanding and treating MDD, still no therapy has proved to be consistently and reliably effective in interrupting the symptoms of this disease. Recent clinical and preclinical studies, using genetic screening and transgenic rodents, respectively, suggest a major role of the CRF1 gene, and the central expression of CRF1 receptor protein in determining an individual's risk of developing MDD. This gene is widely expressed in brain tissue, and regulates an organism's immediate and long-term responses to social and environmental stressors, which are primary contributors to MDD. This review presents the current state of knowledge on CRF physiology, and how it may influence the occurrence of symptoms associated with MDD. Additionally, this review presents findings from multiple laboratories that were presented as part of a symposium on this topic at the annual 2014 meeting of the International Behavioral Neuroscience Society (IBNS). The ideas and data presented in this review demonstrate the great progress that has been made over the past few decades in our understanding of MDD, and provide a pathway forward toward developing novel treatments and detection methods for this disorder.

Complete Genome Sequence of Cupriavidus basilensis 4G11, Isolated from the Oak Ridge Field Research Center Site.

Cupriavidus basilensis 4G11 was isolated from groundwater at the Oak Ridge Field Research Center (FRC) site. Here, we report the complete genome sequence and annotation of Cupriavidus basilensis 4G11. The genome contains 8,421,483 bp, 7,661 predicted protein-coding genes, and a total GC content of 64.4%.

Molybdenum Availability Is Key to Nitrate Removal in Contaminated Groundwater Environments.

The concentrations of molybdenum (Mo) and 25 other metals were measured in groundwater samples from 80 wells on the Oak Ridge Reservation (ORR) (Oak Ridge, TN), many of which are contaminated with nitrate, as well as uranium and various other metals. The concentrations of nitrate and uranium were in the ranges of 0.1 µM to 230 mM and <0.2 nM to 580 µM, respectively. Almost all metals examined had significantly greater median concentrations in a subset of wells that were highly contaminated with uranium (≥126 nM). They included cadmium, manganese, and cobalt, which were 1,300- to 2,700-fold higher. A notable exception, however, was Mo, which had a lower median concentration in the uranium-contaminated wells. This is significant, because Mo is essential in the dissimilatory nitrate reduction branch of the global nitrogen cycle. It is required at the catalytic site of nitrate reductase, the enzyme that reduces nitrate to nitrite. Moreover, more than 85% of the groundwater samples contained less than 10 nM Mo, whereas concentrations of 10 to 100 nM Mo were required for efficient growth by nitrate reduction for two Pseudomonas strains isolated from ORR wells and by a model denitrifier, Pseudomonas stutzeri RCH2. Higher concentrations of Mo tended to inhibit the growth of these strains due to the accumulation of toxic concentrations of nitrite, and this effect was exacerbated at high nitrate concentrations. The relevance of these results to a Mo-based nitrate removal strategy and the potential community-driving role that Mo plays in contaminated environments are discussed.

Defining bowel dose volume constraints for bladder radiotherapy treatment planning.

AIMS: Increases to radiotherapy dose are constrained by normal tissue effects. The relationship between bowel dose volume data and late bowel toxicity in patients with muscle-invasive bladder cancer treated with radical radiotherapy was assessed. MATERIALS AND METHODS: The bowel was contoured retrospectively on radiotherapy plans of 47 patients recruited to the BC2001 trial (CRUK/01/004). The relationship between bowel volume at various dose levels and prospectively collected late bowel toxicity was explored. RESULTS: Fifteen per cent and 6% of patients experienced grade 1 and grade 2 or more late bowel toxicity, respectively. The mean bowel volume was significantly less at doses ≥50 Gy in those treated with reduced high dose volume radiotherapy compared with standard radiotherapy. The probability of late bowel toxicity increased as bowel volume increased (P ≤ 0.05 for dose levels 30-50 Gy). No grade 2 or more late bowel toxicity was observed in patients with bowel volumes under the thresholds given in the model that predict for 25% probability of late bowel toxicity. CONCLUSIONS: There is a dose volume effect for late bowel toxicity in radical bladder radiotherapy. We have modelled the probability of late bowel toxicity from absolute bowel volumes to guide clinicians in assessing radical bladder radiotherapy plans. Thresholds predicting for a 25% probability of late bowel toxicity are proposed as dose volume constraints.

Comparison of patient reported quality of life and impact of treatment side effects experienced with a taxane-containing regimen and standard anthracycline based chemotherapy for early breast cancer: 6 year results from the UK TACT trial (CRUK/01/001).

BACKGROUND: The TACT trial (CRUK/01/001) compared adjuvant sequential FEC-docetaxel (FEC-D) chemotherapy with standard anthracycline-based chemotherapy of similar duration in women with early breast cancer. Results at a median of 5 years suggested no improvement in disease-free survival with FEC-D. Given differing toxicity profiles of the regimens, the impact on quality of life (QL) was explored. METHODS: Patients from 44 centres completed standardised QL questionnaires before chemotherapy, after cycles 4 and 8, at 9, 12, 18 and 24 months and at 6 years follow-up. Patient diaries assessed frequency, associated distress and impact on daily activity of 15 treatment related side effects. FINDINGS: 830 patients (415 FEC-D; 415 controls) contributed assessments during 0-24 months; 362 of whom participated again at 6 years. During chemotherapy, FEC-D impaired global health/QL and depression rates and significantly more QL domains than standard regimens. Novel diary card ratings highlighted significantly more distress and interference with daily activities due to FEC-D side effects compared with standard treatment. In both groups, most QL parameters returned to baseline levels by 2 years and were unchanged at 6 years. INTERPRETATION: Within expected negative effects of chemotherapy on wide ranging QL domains FEC-D patients reported greater toxicity, disruption and distress during treatment with no improvement in disease outcome at 5 years than patients receiving standard anthracycline-based chemotherapy. Findings should inform future patients of relative costs and benefits of adjuvant chemotherapy.

Assessment of a proposed "three-criteria" cocaine addiction model for use in reinstatement studies with rats.

RATIONALE: Relapse is a primary obstacle in the treatment of addiction disorders, and as such, understanding this phenomenon is a major effort of clinical and preclinical studies of cocaine addiction. OBJECTIVE: A recently developed protocol uses laboratory rats to model cocaine addiction by examining three criteria of addiction-like behaviors (persistent seeking in the absence of drug, high motivation for drug, and resistance to punishment during drug seeking) to detect subjects that possess an addiction phenotype. We closely followed this protocol in order to detect rats possessing this addiction phenotype, with the goal of utilizing this model in future studies investigating potential therapies for relapse in human cocaine addicts. RESULTS: The majority of the rats used in this study exhibited multiple characteristics thought to be associated with addiction-like behavior in rats, including robust reinstatement to multiple stimuli and high motivation to obtain cocaine. However, no rats displayed the complete addiction phenotype as previously described, due to a complete lack of addiction-like behavior in all subjects on two of the three addiction criteria (drug seeking in the absence of drug and resistance to punishment). CONCLUSIONS: Our data highlight the independence of behavioral aspects of a rat addiction-like phenotype and suggest that some of these behavioral criteria may be altogether absent in some rat populations. Furthermore, our results suggest a closer review and analysis of some parameters used in this protocol and its global utility.

Barriers to accepting and completing latent tuberculosis infection treatment.

Treatment of Latent Tuberculosis Infection (LTBI) is an important component of any TB control strategy. Acceptance and completion of treatment is poor. We undertook this study to identify barriers to acceptance & completion of treatment. Patients attending TB clinics completed a self-administered survey. Medical notes and electronic pharmacy records were reviewed. 143 surveys were completed. 70 (49%) completed treatment. Patients were less likely to accept treatment (p = 0.01, RR 0.781, CI 0.643-0.950) and less likely to complete treatment (p = 0.01, RR 0.640, CI 0.462-0.885) when concerned about the side effects of LTBI medication. Completion of LTBI treatment is sub-optimal. The major barrier identified was fear about side effects caused by LTBI medications.

Phase II trial of docetaxel, cisplatin and 5FU chemotherapy in locally advanced and metastatic penis cancer (CRUK/09/001).

BACKGROUND: Penis cancer is rare and clinical trial evidence on which to base treatment decisions is limited. Case reports suggest that the combination of docetaxel, cisplatin and 5-flurouracil (TPF) is highly active in this disease. METHODS: Twenty-nine patients with locally advanced or metastatic squamous carcinoma of the penis were recruited into a single-arm phase II trial from nine UK centres. Up to three cycles of chemotherapy were received (docetaxel 75 mg m(-2) day 1, cisplatin 60 mg m(-2) day 1, 5-flurouracil 750 mg m(-2) per day days 1-5, repeated every 3 weeks). Primary outcome was objective response (assessed by RECIST). Fourteen or more responses in 26 evaluable patients were required to confirm a response rate of 60% or higher (Fleming-A'Hern design), warranting further evaluation. Secondary endpoints included toxicity and survival. RESULTS: 10/26 evaluable patients (38.5%, 95% CI: 20.2-59.4) achieved an objective response. Two patients with locally advanced disease achieved radiological complete remission. 65.5% of patients experienced at least one grade 3/4 adverse event. CONCLUSION: Docetaxel, cisplatin and 5FU did not reach the pre-determined threshold for further research and caused significant toxicity. Our results do not support the routine use of TPF. The observed complete responses support further investigation of combination chemotherapy in the neoadjuvant setting.

Combining virotherapy and angiotherapy for the treatment of breast cancer.

A breast cancer-selective oncolytic adenovirus was engineered to express antagonists of vascular endothelial growth factor (VEGF) and Notch signaling to combine direct anticancer activity with disruption of tumor-associated angiogenesis. Replication of the parental virus, AdEHE2F, is stimulated by estrogen receptor (ER), E2F1 and hypoxia, and it mediates selective lysis of breast cancer cells in vitro and in vivo. Here, we encoded soluble Flt-1 (sFlt1) and soluble Dll4 (sDll4) under control of the E3 promoter. sFlt1 (the extra-cellular domain of VEGF receptor 1) binds VEGF-A and inhibits stimulation of VEGFR2, decreasing angiogenic stimulus. Conversely, sDll4 (the extracellular domain of Delta-like 4) antagonizes Notch signaling to prevent endothelial maturation. We hypothesized that these agents might show additive or synergistic activity. In vitro, sFlt1 inhibited endothelial cell proliferation and sprouting, whereas sDll4 increased the number of vascular branchpoints. In ER-positive ZR75.1 tumors in vivo AdEHE2F showed the potent direct virotherapy with no augmentation owing to sFlt1 or sDll4; however, in ER-negative MDA-231 tumors efficacy was enhanced by encoding sFlt1 or sDll4, with survival time extending to double that of controls. There was also a dramatic decrease in the total number of tumour blood vessels, as well as the number of perfused vessels, suggesting that improved efficacy reflects combined anti-tumour and anti-vascular effects.

Metabolic adaptations of skeletal muscle to voluntary wheel running exercise in hypertensive heart failure rats.

The Spontaneously Hypertensive Heart Failure (SHHF) rat mimics the human progression of hypertension from hypertrophy to heart failure. However, it is unknown whether SHHF animals can exercise at sufficient levels to observe beneficial biochemical adaptations in skeletal muscle. Thirty-seven female SHHF and Wistar-Furth (WF) rats were randomized to sedentary (SHHFsed and WFsed) and exercise groups (SHHFex and WFex). The exercise groups had access to running wheels from 6-22 months of age. Hindlimb muscles were obtained for metabolic measures that included mitochondrial enzyme function and expression, and glycogen utilization. The SHHFex rats ran a greater distance and duration as compared to the WFex rats (P<0.05), but the WFex rats ran at a faster speed (P<0.05). Skeletal muscle citrate synthase and beta-hydroxyacyl-CoA dehydrogenase enzyme activity was not altered in the SHHFex group, but was increased (P<0.05) in the WFex animals. Citrate synthase protein and gene expression were unchanged in SHHFex animals, but were increased in WFex rats (P<0.05). In the WFex animals muscle glycogen was significantly depleted after exercise (P<0.05), but not in the SHHFex group. We conclude that despite robust amounts of aerobic activity, voluntary wheel running exercise was not sufficiently intense to improve the oxidative capacity of skeletal muscle in adult SHHF animals, indicating an inability to compensate for declining heart function by improving peripheral oxidative adaptations in the skeletal muscle.

Selection for increased voluntary wheel-running affects behavior and brain monoamines in mice.

Selective-breeding of house mice for increased voluntary wheel-running has resulted in multiple physiological and behavioral changes. Characterizing these differences may lead to experimental models that can elucidate factors involved in human diseases and disorders associated with physical inactivity, or potentially treated by physical activity, such as diabetes, obesity, and depression. Herein, we present ethological data for adult males from a line of mice that has been selectively bred for high levels of voluntary wheel-running and from a non-selected control line, housed with or without wheels. Additionally, we present concentrations of central monoamines in limbic, striatal, and midbrain regions. We monitored wheel-running for 8 weeks, and observed home-cage behavior during the last 5 weeks of the study. Mice from the selected line accumulated more revolutions per day than controls due to increased speed and duration of running. Selected mice exhibited more active behaviors than controls, regardless of wheel access, and exhibited less inactivity and grooming than controls. Selective-breeding also influenced the longitudinal patterns of behavior. We found statistically significant differences in monoamine concentrations and associated metabolites in brain regions that influence exercise and motivational state. These results suggest underlying neurochemical differences between selected and control lines that may influence the observed differences in behavior. Our results bolster the argument that selected mice can provide a useful model of human psychological and physiological diseases and disorders.

Prey availability influences the ontogeny and timing of chemoreception-based prey shifting in the striped crayfish snake, Regina alleni.

Striped crayfish snakes (Regina alleni) undergo a dietary shift from dragonfly larvae to crayfish during ontogeny. Godley (1980) suggested that this shift is attributable to crayfish availability rather than an initial preference for dragonfly larvae. We experimentally tested this hypothesis by measuring the chemosensory response of newborn snakes to prey odors at 2 ages and also after they were fed on either dragonfly larvae or crayfish. The results show that R. alleni respond equally to dragonfly larvae, hard crayfish, and soft crayfish before feeding experience. We also show that the maintenance of this preference over fish and control stimuli is subsequently determined by the prey type encountered, through an unusual interaction. Snakes fed dragonfly larvae increased their chemosensory response to both dragonfly larvae and crayfish, whereas snakes fed crayfish increased their response only to crayfish. Our study demonstrates that innate chemosensory responses to prey can be modified by prey availability and that they do not necessarily result from maturation alone. Such plasticity has adaptive value to newborn animals that must fend for themselves from birth and respond to changing environmental conditions.