Search

The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics., Antibody responses to SARS-CoV-2 are critical in the immune response to infection, but the potential cross-reactivity to other human corona viruses is poorly appreciated. Here the authors apply a systems based approach to characterise the antibody response in pre-pandemic cohorts and assess heterotypic reactivity to SARS-CoV-2.

Summary Immunoglobulin G (IgG) antibodies that activate Fc-mediated immune functions have been correlated with vaccine efficacy, but it is difficult to unravel the relative roles of multiple IgG and Fc receptor (FcR) features that have the capacity to influence IgG-FcR complex formation but vary on a personalized basis. Here, we develop an ordinary differential-equation model to determine how personalized variability in IgG subclass concentrations and binding affinities influence IgG-FcγRIIIa complex formation and validate it with samples from the HIV RV144 vaccine trial. The model identifies individuals who are sensitive, insensitive, or negatively affected by increases in HIV-specific IgG1, which is validated with the addition of HIV-specific IgG1 monoclonal antibodies to vaccine samples. IgG1 affinity to FcγRIIIa is also prioritized as the most influential parameter for dictating activation broadly across a population. Overall, this work presents a quantitative tool for evaluating personalized differences underlying FcR activation, which is relevant to ongoing efforts to improve vaccine efficacy., Graphical abstract, Highlights Fc-mediated immune functions have been correlated with protection in HIV vaccine trials A model reveals personalized mechanisms that drive variation in FcγR activation The model predicts individuals who are sensitive to changes in IgG1 concentration IgG1 affinity to FcγR best dictates activation across a heterogeneous population, Fc-mediated immune functions have been identified as a correlate of protection in vaccine trials for HIV and other pathogens. Lemke et al. present a quantitative tool to understand how personalized differences in antibody and Fc receptor features contribute to variation in FcR activation after vaccination.

A remarkable feature of motor control is the ability to coordinate movements across distinct body parts into a consistent, skilled action. To reach and grasp an object, 'gross' arm and 'fine' dexterous movements must be coordinated as a single action. How the nervous system achieves this coordination is currently unknown. One possibility is that, with training, gross and fine movements are co-optimized to produce a coordinated action; alternatively, gross and fine movements may be modularly refined to function together. To address this question, we recorded neural activity in the primary motor cortex and dorsolateral striatum during reach-to-grasp skill learning in rats. During learning, the refinement of fine and gross movements was behaviorally and neurally dissociable. Furthermore, inactivation of the primary motor cortex and dorsolateral striatum had distinct effects on skilled fine and gross movements. Our results indicate that skilled movement coordination is achieved through emergent modular neural control.

SUMMARY Skilled movements rely on a coordinated cortical and subcortical network, but how this network supports motor recovery after stroke is unknown. Previous studies focused on the perilesional cortex (PLC), but precisely how connected subcortical areas reorganize and coordinate with PLC is unclear. The dorsolateral striatum (DLS) is of interest because it receives monosynaptic inputs from motor cortex and is important for learning and generation of fast reliable actions. Using a rat focal stroke model, we perform chronic electrophysiological recordings in motor PLC and DLS during long-term recovery of a dexterous skill. We find that recovery is associated with the simultaneous emergence of reliable movement-related single-trial ensemble spiking in both structures along with increased cross-area alignment of spiking. Our study highlights the importance of consistent neural activity patterns across brain structures during recovery and suggests that modulation of cross-area coordination can be a therapeutic target for enhancing motor function post-stroke., In brief Guo et al. find that recovery of movement control after motor cortical stroke is associated with reliable neural activation and coordinated activity in both perilesional cortex (PLC) and dorsolateral striatum (DLS). Neural organization occurs simultaneously in PLC and DLS. Their results highlight the importance of distributed network changes after stroke., Graphical Abstract

Sleep is known to be important for promoting recovery after brain injuries such as stroke. Yet, it remains unclear how such injuries affect neural processing during sleep and how to precisely enhance sleep-dependent memory processing during recovery. Using an experimental model of focal cortical stroke in rats along with long-term electrophysiological monitoring of neural firing and sleep microarchitecture, here we show that sleep-dependent neural processing is altered after stroke induction. Specifically, we found that the precise coupling of spindles to global slow- oscillations (SO), a phenomenon that is known to be important for memory consolidation, appeared to be disrupted by a pathological increase in “isolated” local delta waves. The transition from this pathological to a more physiological sleep state – with both a reduction in isolated delta waves and increased spindle coupling to SO – was associated with sustained performance gains after task training during recovery. Interestingly, post-injury sleep processing could be pushed towards a more physiological state via a pharmacological reduction of tonic GABA. Together, our results suggest that sleep processing after cortical brain injuries may be impaired due to an increase in local delta waves and that restoration of physiological processing is important for recovery of task performance.

Bacterial vaginosis is a condition associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus-dominant vaginal microbiota to a polymicrobial microbiota, consistently colonized by strains of Gardnerella vaginalis. Metronidazole is the first-line treatment; however, treatment failure and recurrence rates remain high. To understand complex interactions between Gardnerella vaginalis and Lactobacillus involved in efficacy, here we develop an ordinary differential equation model that predicts bacterial growth as a function of metronidazole uptake, sensitivity, and metabolism. The model shows that a critical factor in efficacy is Lactobacillus sequestration of metronidazole, and efficacy decreases when the relative abundance of Lactobacillus is higher pre-treatment. We validate results in Gardnerella and Lactobacillus co-cultures, and in two clinical cohorts, finding women with recurrence have significantly higher pre-treatment levels of Lactobacillus relative to bacterial vaginosis–associated bacteria. Overall results provide mechanistic insight into how personalized differences in microbial communities influence vaginal antibiotic efficacy., Bacterial vaginosis (BV) is typically caused by a shift in the vaginal microbiota from a Lactobacillus-dominant community to one colonised by strains of Gardenerella vaginalis and treatment with the antibiotic metronidazole (MNZ) often results in failure and recurrence. Here, the authors use modelling and in vitro assays to show that sequestration of MNZ by Lactobacillus is critical in reducing efficacy and women with a higher pre-treatment Lactobacillus/Gardnerella ratio are more likely to recur.

Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have predominantly mild or asymptomatic infections, but the underlying immunological differences remain unclear. Here, we describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children are similar to their parents at all timepoints. All family members have salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincide with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child have IgG antibody against the S1 protein and virus-neutralizing activity detected. Using a systems serology approach, we demonstrate higher levels of SARS-CoV-2-specific antibody features of these family members compared to healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may not identify exposed children, with implications for epidemiological and clinical studies across the life-span., Children with SARS-CoV-2 infection are more likely to have mild symptoms and may be asymptomatic, but underlying reasons remain unclear. Here, the authors show cellular, cytokine and antibody response to SARS-CoV-2 infection in three children who repeatedly tested negative for the virus by PCR, despite high exposure in the household.

SARS-CoV-2, the pandemic coronavirus that causes COVID-19, has infected millions worldwide, causing unparalleled social and economic disruptions. COVID-19 results in higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive coronavirus immunological responses, induced by circulating human coronaviruses, is critical to understand such divergent clinical outcomes. The cross-reactivity of coronavirus antibody responses of healthy children (n=89), adults (n=98), elderly (n=57), and COVID-19 patients (n=19) were analysed by systems serology. While moderate levels of cross-reactive SARS-CoV-2 IgG, IgM, and IgA were detected in healthy individuals, we identified serological signatures associated with SARS-CoV-2 antigen-specific Fcγ receptor binding, which accurately distinguished COVID-19 patients from healthy individuals and suggested that SARS-CoV-2 induces qualitative changes to antibody Fc upon infection, enhancing Fcγ receptor engagement. Vastly different serological signatures were observed between healthy children and elderly, with markedly higher cross-reactive SARS-CoV-2 IgA and IgG observed in elderly, whereas children displayed elevated SARS-CoV-2 IgM, including receptor binding domain-specific IgM with higher avidity. These results suggest that less-experienced humoral immunity associated with higher IgM, as observed in children, may have the potential to induce more potent antibodies upon SARS-CoV-2 infection. These key insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.

Development of primary follicles in vitro benefits from a three-dimensional matrix that is enriched with paracrine factors secreted from feeder cells and mimics the in vivo environment. In this study, we investigated the role of paracrine signaling from adipose-derived stem cells (ADSCs) in supporting primary follicle development in a biomimetic poly(ethylene glycol) (PEG)-based matrix. Follicles co-cultured with ADSCs and follicles cultured in conditioned medium from ADSCs encapsulated in gels (3D CM) exhibited significantly (p < 0.01 and p = 0.09, respectively) improved survival compared to follicles cultured in conditioned medium collected from ADSCs cultured in flasks (2D CM) and follicles cultured without paracrine support. The gene expression of ADSCs suggested that the stem cells maintained their multipotency in the 3D PEG environment over the culture period, regardless of the presence of the follicles, while under 2D conditions the multipotency markers were downregulated. The differences in cytokine signatures of follicles exposed to 3D and 2D ADSC paracrine factors suggest that early cytokine interactions are key for follicle survival. Taken together, the biomimetic PEG scaffold provides a three-dimensional, in vivo-like environment to induce ADSCs to secrete factors which promote early stage ovarian follicle development and survival.

INTRODUCTION: Paracrine signals, such as soluble cytokines and extracellular matrix cues, are essential for the survival and development of multicellular ovarian follicles. While it is well established that hydrogel-based culture systems successfully support the growth of late-stage follicles for fertility preservation, growing small, early-stage ovarian follicles still proves to be challenging. We hypothesized that paracrine factors secreted from neighboring follicles may be crucial for improving the survival of early-stage follicles in vitro. METHODS: To test our hypothesis, we investigated the bi-directional crosstalk of the paracrine signals, such as cell-secreted cytokines, sex hormones and transcription factors (TFs), in follicles encapsulated and cultured for 12 days in alginate in groups of five (5×) and ten (10×). RESULTS: The differential profiles of TF activity and secretome during folliculogenesis were analyzed using TRanscriptional Activity CEllular aRray (TRACER) and data-driven multivariate modeling approach. The mechano- and oxygen-responsive TFs, NF-κB and HIF1, exhibited a unique upregulation signature in 10× follicles. Consistently, levels of proangiogenic factors, such as VEGF-A and angiopoietin-2, were significantly higher in 10× follicles than those in 5× follicles, reaching 269.77 and 242.82 pg/mL on the last day of culture. The analysis of TRACER and secreted cytokines also revealed critical early interactions between cytokines and TFs, correlating with the observed phenotypical and functional differences between conditions. CONCLUSIONS: We identified unique signatures of synergism during successful early-stage ovarian follicle development. These findings bring us closer to understanding of mechanisms underlying the downstream effects of interactions between the extracellular microenvironment and early-stage folliculogenesis in vitro. [Image: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-018-0545-8) contains supplementary material, which is available to authorized users.

Background Neo-adjuvant chemoradiotherapy reduces local recurrence in rectal cancer, but there is a paucity of evidence regarding its role for colon cancer. The aim of this study was to evaluate the feasibility and outcomes of a neo-adjuvant chemoradiotherapy (NCRT) approach for locally recurrent adherent colon cancer (LRACC). Methods All patients with non-metastatic LRACC treated with NCRT and multi-visceral resection (MVR) from January 2000 to July 2010 were included. The primary outcome was the rate of R0 resection (negative microscopic margins). Secondary outcomes were toxicities, post-operative morbidity and mortality, local recurrence, overall survival (OS) and disease-free survival (DFS). Results Fifteen patients were identified. Nine primary cancers were located in the sigmoid and 4 in the left colon. Patients were treated with 45–50 Gy in 25 daily fractions and concurrent 5-FU infusion (225 mg/m 2 /day). En-bloc MVR included between 2 and 5 adjacent organs/structures. All but two resulted in R0 resection. One patient had a complete pathologic response and one had minimal residual tumour cells in the resected specimen. Post-operative major morbidity was 33.3%. No mortality occurred. At a median follow-up of 54 months, there were 2 local, 1 regional, and 2 distant lung recurrences. No grade 3 or 4 acute or late toxicities were observed. 5-year OS and DFS were 90.0% and 63.5% respectively. Conclusions NCRT followed by MVR is a feasible option for the treatment of highly selected LRACC to achieve R0 resection, while maintaining acceptable treatment toxicity. Short-term oncological results appear satisfactory, including good local control.

Purpose To commission the treatment planning system (TPS) RayStation for proton therapy including beam models for spot scanning and for uniform scanning. Methods Tests consist of procedures from ESTRO booklet number 7, the German DIN for constancy checks of TPSs, and extra tests checking the dose perturbation function. The dose distributions within patients were verified in silico by a comparison of 65 clinical treatment plans with the TPS XiO. Dose-volume parameters, dose differences, and three-dimensional gamma-indices serve as measures of similarity. The monthly constancy checks of Raystation have been automatized with a script. Results The basic functionality of the software complies with ESTRO booklet number 7. For a few features minor enhancements are suggested. The dose distribution in RayStation agrees with the calculation in XiO. This is supported by a gamma-index (3 mm/3%) pass rate of >98.9% (median over 59 plans) for the volume within the 20% isodose line and a difference of V 95 of the PTV (median over 59 plans). If spot scanning is used together with a range shifter, the dose level calculated by RayStation can be off by a few percent. Conclusions RayStation can be used for the creation of clinical proton treatment plans. Compared to XiO RayStation has an improved modelling of the lateral dose fall-off in passively delivered fields. For spot scanning fields with range shifter blocks an empirical adjustment of monitor units is required. The computation of perturbed doses also allows the evaluation of the robustness of a treatment plan.

Background Perioperative red blood cell transfusions are required in up to 23 per cent of patients undergoing hepatectomy. Previous research has developed three transfusion risk scores to assess risk of perioperative red blood cell transfusion. Here, the performance of these transfusion risk scores was evaluated in a multicentre cohort of patients who underwent hepatectomy and compared with that of a simplified transfusion risk score. Methods A database of patients undergoing hepatectomy at four specialized centres between 2008 and 2012 was developed. External validity was assessed by discrimination and calibration. Discrimination was evaluated using the area under the receiver operating characteristic (ROC) curve (AUC). Calibration was evaluated by the degree of agreement between predicted and actual red blood cell transfusion probabilities. A simplified transfusion risk score using variables common to the three models was created, and discrimination and calibration were evaluated. Results There were 1287 patients included in this study, with 341 (26·5 per cent) receiving a red blood cell transfusion. Discriminative ability was similar between the three transfusion risk scores, with AUCs of 0·66–0·68 and good calibration. A new three-point risk score was developed based on factors present in all models: haemoglobin 12·5 g/dl or less, primary liver malignancy and major resection (at least 4 segments). Discriminative ability and calibration of the three-point model were similar to those of the three existing models, with an AUC of 0·66. Conclusion The three-point transfusion risk score simplifies assessment of perioperative transfusion risk in hepatectomy without sacrificing predictive ability.

The rate of Ca2+clearance from the neuronal cytoplasm affects the amplitude, duration, and localization of Ca2+signals and influences a variety of Ca2+-dependent functions. We reported previously that activation of protein kinase C (PKC) accelerates Ca2+efflux in rat sensory neurons mediated by the plasma membrane Ca2+-ATPase isoform 4 (PMCA4). Here we show that sarco-endoplasmic reticulum Ca2+-ATPase (SERCA)-mediated Ca2+uptake into intracellular stores is also accelerated by PKC activation. The rate of intracellular Ca2+concentration ([Ca2+]i) clearance was studied after small (m) action potential-induced Ca2+loads in rat dorsal root ganglion neurons. Under these conditions, mitochondrial Ca2+uptake and Na+/Ca2+exchange do not significantly influence [Ca2+]irecovery. Phorbol dibutyrate (PDBu) increased the rate of [Ca2+]iclearance by 71% in a manner sensitive to the selective PKC inhibitors GF109203x (2-[1-(3-dimethylaminopropyl)-1H-indol-3-yl]-3-(1H-indol-3-yl)maleimide) and calphostin. PKC-dependent acceleration was still observed (∼39%) when the PKC-sensitive PMCA isoform was knocked down by expression of an antisense PMCA4 cDNA (AS4). Direct measurement of Ca2+in the endoplasmic reticulum (ER) lumen revealed that PKC increased the rate of store refilling more than twofold after depletion by treatment with cyclopiazonic acid. ER refilling was less complete in PDBu-treated cells, although, in AS4-expressing cells, PDBu accelerated the rate without reducing the ER capacity, suggesting that PMCA and SERCA compete for Ca2+. Thus, activation of PKC accelerates the clearance of Ca2+from the cytoplasm by the concerted stimulation of Ca2+sequestration and Ca2+efflux.

Cerebral venous sinus thrombosis (CVST) is a rare and potentially deadly condition. Common etiologies include hypercoagulable diseases, low flow states, dehydration, adjacent infectious processes, oral contraceptives, hormonal replacement therapy, pregnancy, and puerperium. Symptoms include nausea, seizures, severe focal neurological deficits, coma, and headache (the most common presenting symptom). Anticoagulation is the mainstay of treatment for CVST. Transvenous clot lysis can be performed using injected thrombolytic agents and specialized catheters for clot retrieval.

Background: Compression fractures are common in patients with osteoporosis and cancer. In particular, vertebral compression fractures are crippling, and pose an additional risk of cord compression. Although a number of nonmedical options such as bracing and exercise programs may help these patients, the combination of constant, severe pain and spinal instability was until recently almost invariably synonymous with painful gradual deterioration and a poor quality of life. Vertebroplasty, and more recently kyphoplasty, are minimally invasive procedures that aim at limiting or reversing painful collapse of the vertebrae, while providing stability to the treated segment of the spine. As these new options are highly effective and involve minimal risk, it is important that physicians be familiar with them. Objective: This paper reviews the demographics of vertebral compression fractures, both osteoporotic and neoplastic, the technical aspects of vertebroplasty and kyphoplasty, and current results and outcomes. ...

Following acute multiple trauma, hypothalamic stimulation of the sympathetic nervous system and adrenal glands causes an increase in circulating corticoids and catecholamines, or a stress response. In individuals with severe traumatic brain injury or a Glasgow Coma Scale score of 3-8, this response can be exaggerated and episodic. A term commonly used by nurses caring for these individuals to describe this phenomenon is storming. Symptoms can include alterations in level of consciousness, increased posturing, dystonia, hypertension, hyperthermia, tachycardia, tachypnea, diaphoresis, and agitation. These individuals generally are at a low level of neurological activity with minimal alertness, minimal awareness, and reflexive motor response to stimulation, and the storming can take a seemingly peaceful individual into a state of chaos. Diagnosis is commonly made solely on clinical assessment, and treatment is aimed at controlling the duration and severity of the symptoms and preventing additional brain injury. Storming can pose a challenge for the nurse, from providing daily care for the individual in the height of the storming episode and treating the symptoms, to educating the family. Careful assessment of the individual leads the nurse to the diagnosis and places the nurse in the role of moderator of the storming episode, including providing treatment and evaluating outcomes.

Cancer is the hyperactive state of cell growth in which the multiplication and division of cells occur abnormally. Malignant cancer to the brain frequently begins and ends with the loss of self or quality of life. Cancer of the central nervous system can be in the form of a primary or secondary brain tumor commonly known as metastatic cancer. Primary brain tumors can be benign or malignant on the basis of the cell type or location within the brain. Metastatic cancer has a primary source of origin, from which it has traveled to the brain by direct extension (tumors arising from the skull or vertebral column), or most commonly by hematogenous spread (through the blood supply, lymphatic system, or cerebral spinal fluid). As the cancer grows, the individual can experience headache, seizures, or focal neurologic deficits, all impinging on quality of life. This article addresses malignant central nervous system cancer including metastatic cancer and malignant gliomas (anaplastic astrocytoma, grade III, and glioblastoma multiforme, grade IV). Epidemiology, diagnostic workup, treatment, and outcome also are reviewed.

Quality of life issues remain at the forefront for individuals with life-threatening disease, such as metastatic cancer. The pain of metastatic bone cancer can severely hamper an individual's quality of life. Percutaneous vertebroplasty offers a minimally invasive way to reinforce bony elements, provide substantial improvement in pain control, allow for mobilization, and overall improve quality of life in these patients.

The object of this study was to find what degenerative changes are present in the ankle (talotibiofibular) joints in former elite high jumpers at least 10 years after their retirement from competition, whether there are differences between takeoff and swinging leg, and whether correlations between any particular training history parameters, former injuries, and the degenerative changes can be recognized.A cross-sectional case control study with matched controls for radiological outcomesThe Orthopedic Department at the University of Heidelberg, Germany.The subjects were 40 male high jumpers (required personal best at least 2.18m), featured in the lists of top athletes kept by the German Athletics Association (DLV) from 1972 to 1986. All radiological findings were compared with X-rays of male age, and BMI-matched controls.All underwent clinical and radiological examinations. In addition to eliciting data on the training history with the aid of a questionnaire, we assessed symptoms affecting the ankle by means of the Freiburg Ankle Score and the Kitaoka Score and scored the radiological findings according to Bargon and Scranton and MacDermott.Differences between takeoff and swinging leg were small (Freiburg takeoff leg 93/swinging leg 95, Kitaoka takeoff 89/swinging leg 93 points on a 100 points scale) in both clinical scores, but statistically significant (p0.005). The more jumps were performed during the active phase, the worse the radiological scores (r(s) = 0.4, p = 0.01). Radiological differences between takeoff and swinging leg were not found. Comparison with controls revealed no radiological differences between athletes and age- and BMI-matched men (all p-values0.40). It was found that one takeoff and one swinging leg ankle was affected by grade 2 arthritis (Bargon). Scranton grade 3 was found in four takeoff and in three swinging legs. No further correlations with training history data were found. Athletes who reported injuries in the past tended to have poorer radiological scores, although statistically not significant. None of the athletes had an instable ankle.The talotibiofibular joints in former high jumpers showed only slight signs of wear and tear with no clinically relevant side-related differences; severe arthrosis with narrowing of the joint space was rare. The risk of arthrosis connected with high-jumping seems not to be elevated.

233 Background: Immune checkpoint inhibitors, such as nivolumab, have rapidly gained in popularity and use since their development and subsequent FDA approval. With an ever burgeoning list of indications for its use, we evaluated its use within our tertiary care center as well as its impact on our healthcare system to investigate the quality of care these patients received as well as the extent of the benefit that they received from this novel therapy. Methods: Charts were collected of patients at SUNY Upstate Cancer Center who were started on treatment with Nivolumab between March 4, 2015 and June 1, 2016. This returned a total of 88 (eighty-eight) patients who underwent chart review process for this IRB-exempt retrospective study. Patients who were lost to follow-up or received their oncology care outside of the Upstate Regional Cancer Center were excluded from the final analysis, leaving 83 (eighty-three) patients on whom the final analyses were performed. Statistical analyses were performed using Microsoft Excel and Apple Numbers. Results: Nivolumab was predominantly used as second or third line therapy (45% and 34%) respectively; while it was used as first line therapy in 4% of patients. Performance status was only documented in 53% of patients within two weeks of Nivolumab initiation. Fifty-eight percent of our patients were admitted to the hospital after Nivolumab initiation. Only 50% of those patients received a palliative care consultation. Twenty-six percent of our patients were admitted with an adverse effect to Nivolumab. Nearly 25% of our patients had multiple hospitalizations. Nivolumab was discontinued in 67% of our patients after an average of eight cycles. Conclusions: Nivolumab has been a relatively well tolerated novel treatment for a multitude of malignancies. However, constant re-evaluation of patients for appropriateness of treatment is needed. It is unclear how much quality of life these patients are gaining, as many patients had to discontinue therapy and had numerous hospitalizations. Palliative care remains an important intervention in this patient population that is under-utilized.

PURPOSE: A study was performed to compare the performance of automatic speech recognition (ASR) with conventional transcription. MATERIALS AND METHODS: 100 CT reports were generated by using ASR and 100 CT reports were dictated and written by medical transcriptionists. The time for dictation and correction of errors by the radiologist was assessed and the type of mistakes was analysed. The text recognition rate was calculated in both groups and the average time between completion of the imaging study by the technologist and generation of the written report was assessed. A commercially available speech recognition technology (ASKA Software, IBM ViaVoice) running on a personal computer was used. RESULTS: The time for the dictation using digital voice recognition was 9.4 +/- 2.3 min compared to 4.5 +/- 3.6 min with an ordinary Dictaphone. The text recognition rate was 97% with digital voice recognition and 99% with medical transcriptionists. The average time from imaging completion to written report finalization was reduced from 47.3 hours with medical transcriptionists to 12.7 hours with ASR. The analysis of misspellings demonstrated (ASR vs. medical transcriptionists): 3 vs. 4 for syntax errors, 0 vs. 37 orthographic mistakes, 16 vs. 22 mistakes in substance and 47 vs. erroneously applied terms. CONCLUSIONS: The use of digital voice recognition as a replacement for medical transcription is recommendable when an immediate availability of written reports is necessary.

Gossypol, a polyphenolic compound which depletes cellular energy by inhibition of several intracellular dehydrogenases, has been shown to have antiproliferative activity against human glial tumor cell lines in vitro and in nude mouse xenografts. Human trials of gossypol as a male contraceptive have demonstrated safety of long-term administration. We studied the activity of Gossypol 10 mg PO bid in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study. We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent.

We hypothesized that substance P and capsaicin would cause the release of prostaglandin E2(PGE2) from intrapulmonary bronchi isolated from Sprague-Dawley rats. Substance P (1 μM) caused the release of PGE2, measured with enzyme immunoassay, from the isolated airway segments; PGE2 release was inhibited by the neurokinin (NK)1-receptor antagonist, RP-67580, by inhibition of cyclooxygenase with meclofenamate, and by removal of the epithelium. The release of PGE2 caused by capsaicin (1 μM) was similar in magnitude to that caused by substance P. The capsaicin-induced release of PGE2was inhibited by desensitization of sensory nerves with capsaicin and by RP-67580, meclofenamate, and epithelial denudation. We conclude that activation of NK1 receptors on epithelium causes release of PGE2, which most likely represents the ultimate mediator of airway smooth muscle relaxation, produced by exogenous neuropeptides and by activation of the sensory nerve inhibitory system. Epithelial damage, such as that seen in asthmatic airways, would disrupt this protective system in the lungs, which could contribute to the development of airway disease.

BACKGROUND Although it is used widely, the value of gallium imaging in managing Hodgkin's disease remains unclear. METHODS A retrospective review of gallium imaging and treatment outcome in 60 patients with Hodgkin's disease treated between January 1990 and July 1995 was conducted. The minimum follow-up was 1 year. RESULTS Based on gallium imaging, 46 patients were in complete remission (CR) after initial treatment, 10 were in partial remission (PR), and 4 had persistent or progressive disease (NR). Ten of 29 patients (34%) with gallium CR after chemotherapy subsequently recurred, compared with no recurrences in 17 patients receiving initial radiotherapy or combined chemoradiation. Eight of ten patients received further therapy after gallium PR, and nine patients remained disease free at last follow-up. Survival did not differ in patients achieving a gallium CR or PR. CONCLUSIONS Gallium-67 imaging may help confirm the presence of active Hodgkin's disease, but was unreliable in defining disease remission after chemotherapy in this study population. Patients with a gallium PR may still have a good prognosis after additional therapy. Cancer 1998;82:754-9. ©; 1998 American Cancer Society.

Absorptive hypercalciuria (a stone-forming condition) is characterized by gut hyperabsorption of calcium, hypercalciuria, and reduced bone density. Inasmuch as these features implicate enhanced calcitriol action in gut and bone, we analyzed the vitamin D receptor (VDR) gene to ascertain whether an abnormality of this gene marks patients with intestinal hyperabsorption of calcium. We have compared the frequency of a restriction fragment length polymorphism (Bsm I) associated with different alleles of the VDR gene in a group of 33 well characterized absorptive hypercalciuric patients and a group of 36 normal race- and age-matched control subjects. There was no difference between the distribution of the VDR alleles in the patient population when compared with the normal population. The coding region of VDR messenger RNA was also normal, as determined by both DNA sequence analysis and chemical mismatch cleavage analysis of copy DNA from 11 index absorptive hypercalciuric patients. On the basis of these results, we propose that the enhanced intestinal calcium absorption invariably seen in absorptive hypercalciuria and attendant symptoms of this disorder are not attributable to mutations of the VDR and are not linked to a common VDR genotype.

This study was initiated to test the hypothesis that histamine can act as an endothelium-derived contracting factor in bovine isolated intrapulmonary vein. The effects of calcium ionophore, calcimycin (A23187), on isometric tension were compared in unstimulated rings of intrapulmonary vein with and without endothelium. A23187 (0.1−10 μM) induced concentration-related contraction when endothelium was present. Destruction of endothelium markedly inhibited A23187-induced contraction. Methylene blue, hemoglobin or N G - methyl - L - arginine significantly enhanced A23187-induced contraction only in venous rings with endothelium consistent with attenuation of the contraction by the concomitant release of endothelium-derived relaxing factor (nitric oxide) [EDRF(NO)]. Histamine H1 receptor antagonists inhibited, and iproniazid enhanced, contraction elicited by A23187. A23187 induced release of greater amounts of histamine from venous rings with than without endothelium. A23187-induced contraction was not mimicked by the mast cell activator, compound 48/80, and was not inhibited by preexposure to compound 48/80 or in the presence of cromolyn or doxantrazole. A23187-induced contraction was not inhibited by pretreatment with indomethacin, phentolamine, lipoxygenase inhibitors or superoxide dismutase. The results indicate that A23187 induces endothelium-dependent contraction in bovine intrapulmonary vein and support histamine as one major mediator involved. The association of destruction of endothelium with an inhibition of both A23187-induced contraction and histamine release is consistent with the endothelium as a source for histamine which can exert a local vasoconstrictor effect in bovine intrapulmonary vein.

BACKGROUND Iproplatin (cis-dichloro-transdihydroxybis-isopropylamine platinum IV; CHIP) is a second generation cisplatin derivative that was developed to retain the antineoplastic effect of cisplatin with fewer toxic effects. Early clinical studies showed moderate activity in some neoplasms, with disappointing results in tumors of the lower gastrointestinal tract. Myelosuppression was the dose-limiting toxic effect in the acute setting. METHODS The authors report a patient with metastatic adenocarcinoma of the colon who received long-term therapy with CHIP. RESULTS The patient achieved complete remission of disease after prolonged treatment with CHIP. The patient subsequently had a myelodysplastic syndrome that rapidly transformed to acute myelogenous leukemia. CONCLUSIONS Acute leukemia may represent a late complication of CHIP therapy.

Granulocytic sarcoma is an extramedullary tumor of malignant granulocytic progenitor cells that accompanies, heralds, or signals relapse of acute myelogenous leukemia (AML), or indicates blastic transformation of a chronic myeloproliferative disorder. We describe a case involving the uterine cervix of a 51-year-old woman that led to the diagnosis of AML. Granulocytic sarcoma can occur in the female genital tract and may be the first clinically significant manifestation of a hematologic malignancy. The salient findings in 28 reported cases from 12 different countries are reviewed. Awareness of this lesion is important for all medical personnel involved in the health care of women.

Among the many topics considered by meta-analysts, one that has received relatively little attention is the statistical integration of multivariate outcome data. This article focuses on a procedure proposed by Kaiser that has been used to integrate the results from different factor analyses. After giving a geometrical description of Kaiser's procedure, the authors illustrate its use with factor analytic studies of the Buss-Durkee Hostility Inventory. The results show that the seven subscales of the Buss-Durkee Hostility Inventory measure two dimensions of aggressiveness, one that can be called covert. The need for further development and application of multivariate data synthesis procedures is also discussed.

Takotsubo syndrome is a reversible neuromyocardial failure that has been thought to be related to an acute catecholamine toxicity of the myocardium brought upon by a stressful event. The neurocritical care unit population is particularly vulnerable for this condition given the acute presentation of neurological emergencies, which most often can be catastrophic. We present a case series of this syndrome and a review of the literature.Our recent experience with three cases that were prospectively identified with the diagnosis of Takotsubo syndrome is reported with clinical presentation, evaluation, and management approach. Review of the literature is presented in the discussion.We present three episodes of Takotsubo neuromyocardial syndrome in two patients that were admitted to our neurointensive care unit that presented with seizures and had typical clinical presentation, echocardiographic and cardiac catheterization findings. All the episodes were treated with vasoactive medications, ventilatory support, afterload and preload reduction, and treatment of the underlying condition. There was complete reversal of their symptoms and findings in each episode.Patients with critical neurological illnesses such as large ischemic or hemorrhagic stroke, status epilepticus, recurrent seizure activities as in our study may be at a higher risk for Takotsubo neuromyocardial syndrome.

Dibutyltin dichloride (DBTC) is an organotin compound used as a model for acute pancreatitis. The aim was to determine the effect of various doses of Na-selenite on the pathogenesis and course of DBTC-induced toxic changes in organs and serum of rats.Experimental pancreatitis was induced by intravenous administration of 6 mg kg(-1) BW DBTC. Na-selenite was applied as a single intravenous dose of 5 mg kg(-1) BW and as daily oral dose of 1 mg kg(-1) BW. Malondialdehyde (MDA) was detected to observe the level of oxidative stress. The tin concentration in bile and urine shows the elimination of DBTC. Organ changes were indicated by serum parameters as well as histology.DBTC causes an acute pancreatitis, cholestasis and liver lesions determined by specific elevated serum parameters and several histological lesions. Na-selenite significantly diminished MDA concentration, lipase, bilirubin and transaminases as well as organ injuries compared to only DBTC-treated rats.The treatment with Na-selenite in the scope of DBTC-induced pancreatitis points to a reduced oxidative stress characterized by diminished MDA serum levels and a milder course of pancreatitis. The generation of DBTC-Na-selenite complexes could also be a mechanism to decrease the toxicity of organotin compounds like DBTC.

Background: Aneurysms associated with vertebrobasilar fenestrations are uncommon. We report on an unusual presentation of such aneurysm with a dedicated arterial pedicle, manifesting with significant intraventricular hemorrhage. Equally important, the aneurysm was managed in a multidisciplinary fashion, which, we think, greatly contributed to a good outcome. Case Description: A 55-year-old man presented in good condition after subarachnoid and massive intraventricular hemorrhage. The aneurysm location and the extent of intraventricular hemorrhage both presented concerns regarding treatment approach. The aneurysm was first treated with transarterial coil obliteration, and intraventricular tissue plasminogen activator (tPA) infusion was given, with rapid resolution of evolving hydrocephalus. The patient had an excellent outcome. Conclusion: To our knowledge, this is the first report of a vertebrobasilar fenestration saccular aneurysm with a dedicated pedicle projecting toward the foramen of Magendie with significant intraventricular hemorrhage. In addition, this patient was successfully managed with endovascular obliteration and intraventricular tPA infusion.

Metastasis to the brain occurs in 20%–40% of cancer patients.1 About 20% of these metastases are located in the posterior fossa, cerebellum, and brainstem. Metastatic disease to periventricular brain tissue can obstruct the flow of cerebrospinal fluid (CSF) produced in the ventricles to the subarachnoid space where it is normally absorbed by arachnoid granulations. This typically causes an obstructive or non-communication hydrocephalus. A shunt has been customarily placed to drain CSF from a lateral ventricle through a pressure regulating valve and into the atrium or peritoneal or pleural cavity. Even though this technique has been successful in relieving the hydrocephalus, it has about a 50% chance of infection or failure from blockage.2 Another option for the treatment of obstructive hydrocephalus is third ventriculostomy, a minimal invasive endoscopic neurosurgical procedure. In performing third ventriculostomy, a hole is created in the floor of the third ventricle, allowing CSF inside the ventricle to drain out to the CSF space surrounding …

Introduction Agomelatine, a melatonergic agonist and 5-HT2c-antagonist, has demonstrated antidepressant efficacy in clinical trials. Aims Aim of VITAL was to document treatment with agomelatine non-interventionally in daily practice over 6 months. Objectives Evaluation of the effectiveness of agomelatine on depressive symptoms, daytime activity, tolerability and compliance in depressed patients under routine conditions. Methods 3005 outpatients aged>18 years were observed by 1169 psychiatrists and general practitioners in Germany over 6 months, treated with agomelatine 25-50 mg once daily. Antidepressant effectiveness was evaluated by Beck Depression Inventory (BDI-II), effects on daytime activity by two questions of Circscreen (patient questionnaire), compliance by standardized questions. ADRs were documented every visit. Results Included patients (BDI-II total score 31.9) improved during 6 months treatment with agomelatine (BDI-II 9.6). Responder rate (≥50% reduction of BDI-II) rose steadily from 11.7% (2 weeks), 62.0% (12 weeks) to 79.0% (6 months). 55.3% of patients were classified as remitters (BDI ≤9) after 6 months. According to CGI, 20.7% had responded after 2 weeks, 81.6% at study-end (CGI-I≤2). At baseline 53.2% were markedly impaired in normal daily activity compared to 16.1% of patients at the end of study. 64.5% at baseline versus 9.1% after 6 months felt sleepy during daytime (Circscreen). 89.6% of 2511 patients at study-end documented good compliance (regular intake). Adverse drug reactions (mainly headache, dizziness) were reported by 3.6%, 0.6% of patients had reversible ALT/AST>3ULN (n=12). Conclusion Antidepressant effectiveness of agomelatine, improvement of daytime activity, good tolerability and good compliance were observed in unselected depressed patients over 6 months.

Background The majority of gastrointestinal stromal tumours (GISTs) express gain-of-function mutations in the tyrosine kinase receptor KIT, and less often in platelet derived growth factor receptor α (PDGFRα). Imatinib mesylate is an effective therapy for GISTs, especially in patients with Exon 11 mutations, but has less response in Exon 9 mutation patients. Imatinib is least effective in patients expressing wild-type (WT) KIT and PDGFRα mutations. When used in the neoadjuvant setting, patients typically experience maximal tumor response within a year of initiation and surgical resection is required for potential cure. In this study, we characterized the mutational status in paired samples before and after neoadjuvant imatinib therapy. Methods All patients receiving neoadjuvant imatinib (at a single academic institution), to improve surgical resectability were reviewed retrospectively. Patients were treated with imatinib until deemed to be appropriate surgical candidates at a multidisciplinary case conference. All tumours were sent for molecular analysis before and after resection when possible. Results 17 patients were identified from 2007 to 2012. The time on neoadjuvant imatinib therapy ranged from 31-135 weeks, with a median time of 57 weeks. At time of diagnosis, mutational analysis was possible on 7 samples, all of which were found to have a mutation: 5 in Exon 11, 2 in Exon 9. Of the 6 patients where mutational analysis was possible both prior to imatinib therapy and following surgical resection, 5 retained identical mutations. 1 patient with a jejunal GIST found to express an Exon 9 mutation at diagnosis was found to have WT KIT following imatinib therapy. The greatest median reduction in maximum tumour dimension (MR-MTD) was in the patient with the Exon 9 mutation (54.55%) compared to 9 patients with Exon 11 mutations (39.2%) and 2 patients with WT KIT/PDGFRα (38.0%). Patients with Exon 11 mutations showed the greatest variation in MR-MTD, one growing by 6.7% to another shrinking by 79.4%. Conclusions Most tumors retain the same mutations after neaoadjuvant therapy with imatinib. We identified one patient who had a different non-imatinib sensitive mutation after treatment. In the neoadjuvant setting, the duration of imatinib therapy may be too short for imatinib resistant clones to appear. Disclosure All authors have declared no conflicts of interest.

This study examined the effects of chlorpheniramine, citalopram and fluoxetine on 5-hydroxytryptamine (5-HT)-induced contraction and 5-HT uptake in rat thoracic aortic rings in vitro. Chlorpheniramine and citalopram markedly potentiated 5-HT-induced contraction. Potentiation by fluoxetine was less pronounced. Chlorpheniramine (0.01-1 microM) and citalopram (0.1-1 microM) induced concentration-dependent parallel shifts to the left of the 5-HT concentration-response curves. The potentiation by chlorpheniramine was selective as chlorpheniramine (1 microM) did not potentiate phenylephrine-induced contraction. The potentiation did not depend upon the presence of endothelium, and was not related to H1 receptor antagonism as diphenhydramine and pyrilamine (1 microM) did not similarly enhance 5-HT-induced contractions. Whereas cocaine (1-10 microM) similarly potentiated 5-HT-induced contraction, imipramine (1-10 microM) inhibited, rather than enhanced, contraction elicited by 5-HT. In the presence of 10 microM cocaine, maximally effective concentrations of chlorpheniramine (1 microM) or citalopram (100 nM) did not induce any additional potentiation of 5-HT-induced contraction. Cooling (4 degrees C) markedly inhibited uptake of [3H]5-HT in rings with and without endothelium. Although less marked, imipramine (10 microM), cocaine (1 microM), chlorpheniramine (1 microM) and citalopram (100 nM) inhibited [3H]5-HT uptake in endothelium-intact and endothelium-denuded rings. Fluoxetine also inhibited [3H]5-HT uptake, but the inhibition was only statistically significant in endothelium-intact rings. The monoamine oxidase (MAO) inhibitor, pargyline (10-100 microM), did not significantly affect 5-HT-induced contraction. The results demonstrate that chlorpheniramine, citalopram and to a lesser extent, fluoxetine potentiate 5-HT-induced contraction in rat aorta in which neuronal 5-HT uptake is negligible. The data are consistent with inhibition of non-neuronal 5-HT uptake as at least one mechanism responsible for potentiation of 5-HT-induced contraction in rat aorta by chlorpheniramine, citalopram and fluoxetine.

In vivo integumental transepithelial potential (TEP) in the Eastern red-spotted newt (Notophthalmus viridescens) increases linearly with external [Na+] from 0.1 to 10 mM and is anion independent. Both integumental TEP and osmotic permeability are higher in laboratory-conditioned (LC, terrestrial) than in breeding-condition (BC, aquatic) newts at temperatures of 5-25 degrees. Prolactin (PRL) treatment of LC newts decreased both TEP and rate of water uptake. Arginine vasotocin (AVT) treatment resulted in a substantial increase in water uptake in LC newts, while little or no AVT response was seen in PRL-treated or BC newts. Hypophysectomy (HX) or ergocryptine treatment increased TEP in BC newts, whereas HX + PRL maintained TEP at control levels. Although ergocryptine and HX were without effect on water uptake in BC newts kept at 5 degrees for 9 days, HX + ACTH increased water uptake. HX produced a substantial fall in serum [Na+] in BC newts, while either PRL or ACTH replacement elevated serum [Na+]. Combined ACTH and PRL treatment returned serum [Na+] to control levels. These data suggest that high endogenous prolactin plays a significant role in maintaining serum [Na+] and integumental permeability and transport characteristics in breeding-condition N. viridescens. Although PRL and ACTH are both sodium retaining in the aquatic breeding stage, these two hormones promote opposite effects on the integument; PRL decreases both water uptake and integumental TEP, whereas ACTH (presumably acting through the adrenals) increases water uptake and possibly TEP.

Prolonged driving under monotonous conditions decreases the vigilance of the human controller and his performance of the driving task. Variations of his control activity (vehicle related signals) were measured with the goal of receiving criteria for a warning device, which could improve the active safety of today's traffic. The investigations were performed on a rural circuit and on a driving simulator: the control variable for decreasing vigilance was the electro-encephalogram of the test subjects. Factor analysis and canonical correlation were used to investigate the relation between both data sets. The EEG parameters showed a frontal displacement under prolonged driving: thus a decreasing vigilance could be confirmed. Simultaneously the subjects' control activity in the tracking task became coarser. The accelerator pedal activity—which is a relatively free control variable—decreased with the test duration despite constant driving speed. This was explained with increased risk-acceptance at decreased performance or decreased vigilance.