The Temozolomide-Doxorubicin paradox in Glioblastoma in vitro-in silico preclinical drug-screening.

Adjuvant Temozolomide is considered the front-line Glioblastoma chemotherapeutic treatment; yet not all patients respond. Latest trends in clinical trials usually refer to Doxorubicin; yet it can lead to severe side-effects if administered in high doses. While Glioblastoma prognosis remains poor, little is known about the combination of the two chemotherapeutics. Patient-derived spheroids were generated and treated with a range of Temozolomide/Doxorubicin concentrations either as monotherapy or in combination. Optical microscopy was used to monitor the growth pattern and cell death. Based on the monotherapy experiments, we developed a probabilistic mathematical framework in order to describe the drug-induced effect at the single-cell level and simulate drug doses in combination assuming probabilistic independence. Doxorubicin was found to be effective in doses even four orders of magnitude less than Temozolomide in monotherapy. The combination therapy doses tested in vitro were able to lead to irreversible growth inhibition at doses where monotherapy resulted in relapse. In our simulations, we assumed both drugs are anti-mitotic; Temozolomide has a growth-arrest effect, while Doxorubicin is able to cumulatively cause necrosis. Interestingly, under no mechanistic synergy assumption, the in silico predictions underestimate the in vitro results. In silico models allow the exploration of a variety of potential underlying hypotheses. The simulated-biological discrepancy at certain doses indicates a supra-additive response when both drugs are combined. Our results suggest a Temozolomide-Doxorubicin dual chemotherapeutic scheme to both disable proliferation and increase cytotoxicity against Glioblastoma.

Associations between Combined Psychological and Lifestyle Factors with Pain Intensity and/or Disability in Patients with Chronic Low Back Pain: A Cross-Sectional Study.

Chronic low back pain (CLBP) is common in primary care, causing disability and economic burden globally. We aimed to compare socio-demographic, health, lifestyle, and psychological factors in people with and without CLBP and correlate them with clinical outcomes in people with CLBP. A total of 253 volunteers with and 116 without CLBP provided sociodemographic information, daily habits, medical history, subjective sleep complaints (Penn State Sleep Questionnaire), low back pain intensity, and disability (Quebec Back Pain Disability Scale), as well as the Zung Self-Rating Scale for self-assessment of depression and Self-Rating Anxiety Scale. CLBP diagnosis was linked with female gender and older age, as well as a higher level of sleep complaints such as sleepiness, OSA and insomnia symptoms, and a higher prevalence of moderate to severe depressive symptoms. The combination of moderate to severe depressive symptoms with obstructive sleep apnea or insomnia symptoms was the most important predictive factor for functional disability in CBLP patients (OR 13.686, 95% CI 4.581-40.885; p < 0.001). In conclusion, depressive symptoms and subjective sleep complaints appear to relate to greater CLBP intensity and/or CLBP-related disability in people with CLBP. A holistic approach is crucial for treating chronic CLBP patients, including psychological and sleep issue assessment and management, to improve their quality of life.

Infections in patients undergoing craniotomy: risk factors associated with post-craniotomy meningitis.

OBJECT The authors performed a prospective study to define the prevalence and microbiological characteristics of infections in patients undergoing craniotomy and to clarify the risk factors for post-craniotomy meningitis. METHODS Patients older than 18 years who underwent nonstereotactic craniotomies between January 2006 and December 2008 were included. Demographic, clinical, laboratory, and microbiological data were systemically recorded. Patient characteristics, craniotomy type, and pre- and postoperative variables were evaluated as risk factors for meningitis RESULTS Three hundred thirty-four procedures were analyzed (65.6% involving male patients). Traumatic brain injury was the most common reason for craniotomy. Almost 40% of the patients developed at least 1 infection. Ventilator-associated pneumonia (VAP) was the most common infection recorded (22.5%) and Acinetobacter spp. were isolated in 44% of the cases. Meningitis was encountered in 16 procedures (4.8%), and CSF cultures were positive for microbial growth in 100% of these cases. Gram-negative pathogens (Acinetobacter spp., Klebsiella spp., Pseudomonas aeruginosa, Enterobacter cloaceae, Proteus mirabilis) represented 88% of the pathogens. Acinetobacter and Klebsiella spp. demonstrated a high percentage of resistance in several antibiotic classes. In multivariate analysis, the risk for meningitis was independently associated with perioperative steroid use (OR 11.55, p = 0.005), CSF leak (OR 48.03, p < 0.001), and ventricular drainage (OR 70.52, p < 0.001). CONCLUSIONS Device-related postoperative communication between the CSF and the environment, CSF leak, and perioperative steroid use were defined as risk factors for meningitis in this study. Ventilator-associated pneumonia was the most common infection overall. The offending pathogens presented a high level of resistance to several antibiotics.

Infections in patients with traumatic brain injury who undergo neurosurgery.

OBJECTIVE: Several factors place victims with traumatic brain injury (TBI) at increased risk for infection. The purpose of this study was to delineate the frequency, types and risk factors for infection in patients with TBI who undergo neurosurgery. MATERIALS AND METHODS: Retrospective surveillance of infections in patients with TBI, aged  ≥18 years who underwent neurosurgery in University of Crete between 1999 and 2005. RESULTS: Two hundred fifty-eight patients (76.7% men) who underwent 342 procedures were included. One hundred forty-two infections occurred, mainly lower respiratory tract infections (44.4% of the number of infections) and surgical site infections (SSIs) (25.4%). In multivariate analysis, SSIs were independently associated with the length of stay (p < 0.001), history of malignancy (p = 0.008), CSF leak (p = 0.012), any concomitant infection (p = 0.010), particularly urinary tract infections (p = 0.001) and the use of lumbar and/or ventricular drains (p = 0.005). Meningitis was independently associated with the total length of stay (p < 0.001), the need for intubation and mechanical ventilation beyond surgery (p = 0.028) and the presence of a lumbar and/or ventricular drain (p < 0.001). CONCLUSIONS: Respiratory tract infections were common in patients with TBI who underwent surgery with Acinetobacter spp. being the emerging offending pathogens. Device-related postoperative communication of the CSF and the environment was a significant risk factor for SSI development and meningitis in particular. Malignancy was an independent risk factor for SSIs. The prevalence of the offending pathogens must be determined institution by institution for the establishment of proper antibiotic treatment on suspicion.

Psychosis-like syndrome associated with intermittent intracranial hypertension caused by a large arachnoid cyst of the left temporal lobe.

Lesions on certain brain areas can cause psychiatric signs. Symptomatic arachnoid cysts can produce a variety of symptoms like headache, seizures, increased ICP, and rarely psychiatric disorders. We report a case of a young woman with a left temporal lobe arachnoid cyst, presented with headache and an atypical psychosis. A 72-h epidural ICP recording revealed incidental elevation of ICP. After a permanent shunt was placed, patient's symptoms improved substantially, and antipsychotic medication was significantly reduced.