Protracted respiratory failure in a case of global spinal syringomyelia and Chiari malformation following administration of diazepam: illustrative case.

BACKGROUND: Syringomyelia is defined as dilation of the spinal cord's central canal and is often precipitated by skull base herniation disorders. Although respiratory failure (RF) can be associated with skull base abnormalities due to brainstem compression, most cases occur in pediatric patients and quickly resolve. The authors report the case of an adult patient with global spinal syringomyelia and Chiari malformation who developed refractory RF after routine administration of diazepam. OBSERVATIONS: A 31-year-old female presented with malnutrition, a 1-month history of right-sided weakness, and normal respiratory dynamics. After administration of diazepam prior to magnetic resonance imaging (MRI), she suddenly developed hypercapnic RF followed MRI and required intubation. MRI disclosed a Chiari malformation type I and syrinx extending from C1 to the conus medullaris. After decompressive surgery, her respiratory function progressively returned to baseline status, although 22 months after initial benzodiazepine administration, the patient continues to require nocturnal ventilation. LESSONS: Administration of central nervous system depressants should be closely monitored in patients with extensive syrinx formation given the potential to exacerbate diminished central respiratory drive. Early identification of syrinx in the context of Chiari malformation and hemiplegia should prompt clinical suspicion of underlying respiratory compromise and early involvement of intensive care consultants.

BK channel modulation by positively charged peptides and auxiliary γ subunits mediated by the Ca2+-bowl site.

The large-conductance, Ca2+-, and voltage-activated K+ (BK) channel consists of the pore-forming α (BKα) subunit and regulatory ß and γ subunits. The γ1-3 subunits facilitate BK channel activation by shifting the voltage-dependence of channel activation toward the hyperpolarization direction by about 50-150 mV in the absence of Ca2+. We previously found that the intracellular C-terminal positively charged regions of the γ subunits play important roles in BK channel modulation. In this study, we found that the intracellular C-terminal region of BKα is indispensable in BK channel modulation by the γ1 subunit. Notably, synthetic peptide mimics of the γ1-3 subunits' C-terminal positively charged regions caused 30-50 mV shifts in BKα channel voltage-gating toward the hyperpolarization direction. The cationic cell-penetrating HIV-1 Tat peptide exerted a similar BK channel-activating effect. The BK channel-activating effects of the synthetic peptides were reduced in the presence of Ca2+ and markedly ablated by both charge neutralization of the Ca2+-bowl site and high ionic strength, suggesting the involvement of electrostatic interactions. The efficacy of the γ subunits in BK channel modulation was reduced by charge neutralization of the Ca2+-bowl site. However, BK channel modulation by the γ1 subunit was little affected by high ionic strength and the positively charged peptide remained effective in BK channel modulation in the presence of the γ1 subunit. These findings identify positively charged peptides as BK channel modulators and reveal a role for the Ca2+-bowl site in BK channel modulation by positively charged peptides and the C-terminal positively charged regions of auxiliary γ subunits.

Functional MRI-Guided Motor Cortex and Deep Brain Stimulation for Intractable Facial Pain: A Novel, Personalized Approach in 1 Patient.

BACKGROUND: Facial neuropathic pain syndromes such as trigeminal neuralgia are debilitating disorders commonly managed by medications, vascular decompression, and/or ablative procedures. In trigeminal neuralgia cases unresponsive to these interventions, trigeminal deafferentation pain syndrome (TDPS) can emerge and remain refractory to any further attempts at these conventional therapies. Deep brain stimulation (DBS) and motor cortex stimulation are 2 neuromodulatory treatments that have demonstrated efficacy in small case series of TDPS yet remain largely underutilized. In addition, functional MRI (fMRI) is a tool that can help localize central processing of evoked stimuli such as mechanically triggered facial pain. In this study, we present a case report and operative technique in a patient with TDPS who underwent fMRI to guide the operative management and placement of dual targets in the sensory thalamus and motor cortex. OBJECTIVE: To evaluate the safety, efficacy, and outcome of a novel surgical approach for TDPS in a single patient. METHODS: The fMRI and operative technique of unilateral DBS targeting the ventroposteromedial nucleus of the thalamus and facial motor cortex stimulator placement through a single burr hole is illustrated as well as the patient's clinical outcome. RESULTS: In less than 1 year, the patient had near complete resolution of his facial pain with no postoperative complications. CONCLUSION: We present the first published case of successful treatment of TDPS using simultaneous DBS of the ventroposteromedial and motor cortex stimulation. fMRI can be used as an effective imaging modality to guide neuromodulation in this complex disorder.

A time-resolved, in-chamber x-ray pinhole imager for Z.

We have commissioned a new time-resolved, x-ray imaging diagnostic for the Z facility. The primary intended application is for diagnosing the stagnation behavior of Magnetized Liner Inertial Fusion (MagLIF) and similar targets. We have a variety of imaging systems at Z, both time-integrated and time-resolved, that provide valuable x-ray imaging information, but no system at Z up to this time provides a combined high-resolution imaging with multi-frame time resolution; this new diagnostic, called TRICXI for Time Resolved In-Chamber X-ray Imager, is meant to provide time-resolved spatial imaging with high resolution. The multi-frame camera consists of a microchannel plate camera. A key component to achieving the design goals is to place the instrument inside the Z vacuum chamber within 2 m of the load, which necessitates a considerable amount of x-ray shielding as well as a specially designed, independent vacuum system. A demonstration of the imaging capability for a series of MagLIF shots is presented. Predictions are given for resolution and relative image irradiance to guide experimenters in choosing the desired configuration for their experiments.

Intraoperative Sepsis: A Simulation Case for Anesthesiology Residents.

Introduction: Sepsis is a major cause of morbidity and mortality in medicine and is managed in ICUs daily. Critical care training is a vital part of anesthesiology residency, and understanding the presentation, management, and treatment of septic shock is fundamental to intraoperative patient care. Methods: This simulation involved a 58-year-old man undergoing surgical debridement of a peripancreatic cyst with hemodynamic instability and septic shock. We conducted the simulation yearly for clinical anesthesia year 2 residents (n = 26) in 1-hour sessions with three to five learners at a time. The simulation covered the six Anesthesiology Milestones related to sepsis and septic shock as outlined in the Anesthesiology Milestones Project. Results: To date, 155 anesthesiology residents have completed the simulation. Commonly missed critical actions included failure to recognize the need for invasive lines, provide appropriate volumes of fluid resuscitation, inquire about blood cultures and antibiotics, and recognize the need for the patient to remain intubated. Most participants could appropriately diagnose and treat intraoperative septic shock, but all had moments of action or inaction to discuss and improve upon, and all learned from this scenario. Discussion: Simulation is an optimal way to practice the more rare and life-threatening clinical events in medicine. Even though septic shock is commonly managed in the ICU, it is relatively uncommon for it to develop acutely in the OR. This simulation is an effective and educational way to discuss the most recent sepsis/septic shock definition and review evidence-based guidelines for treatment.

Beyond mistreatment: Learner neglect in the clinical teaching environment.

Medical student mistreatment has been recognized as a deterrent to education as it interferes with the learning process and contributes to student burnout and attrition. Medical schools and leaders in undergraduate medical education have expended tremendous effort in addressing this phenomenon in hopes of eradicating mistreatment. However, there is a spectrum of behaviors that negatively impact the learning environment beyond that which is considered frank mistreatment. In this conceptual article, the authors propose the concept of learner neglect for the consideration by educators and researchers. This is a term for a range of behaviors exhibited intentionally or unintentionally by a supervisor that prevent a learner from reaching his or her potential. While the behaviors may overlap with mistreatment, they do not always fit within the definition of mistreatment. This concept is illustrated in the context of optimal and suboptimal teaching behaviors that commonly occur within the ecosystem of clinical education. Descriptions and examples are provided for both intentional and unintentional learner neglect. The authors hypothesize possible short- and long-term impacts of learner neglect, describe contributors to its prevalence, and offer questions for key stakeholders to consider in an effort to recognize, study, and ameliorate this issue within medical education programs.

The cells and conductance mediating cholinergic neurotransmission in the murine proximal stomach.

KEY POINTS: Enteric neurotransmission is essential for gastrointestinal (GI) motility, although the cells and conductances responsible for post-junctional responses are controversial. The calcium-activated chloride conductance (CaCC), anoctamin-1 (Ano1), was expressed by intramuscular interstitial cells of Cajal (ICC-IM) in proximal stomach and not resolved in smooth muscle cells (SMCs). Cholinergic nerve fibres were closely apposed to ICC-IM. Conductances activated by cholinergic stimulation in isolated ICC-IM and SMCs were determined. A CaCC was activated by carbachol in ICC-IM and a non-selective cation conductance in SMCs. Responses to cholinergic nerve stimulation were studied. Excitatory junction potentials (EJPs) and mechanical responses were evoked in wild-type mice but absent or greatly reduced with knockout/down of Ano1. Drugs that block Ano1 inhibited the conductance activated by carbachol in ICC-IM and EJPs and mechanical responses in tissues. The data of the present study suggest that electrical and mechanical responses to cholinergic nerve stimulation are mediated by Ano1 expressed in ICC-IM and not SMCs. ABSTRACT: Enteric motor neurotransmission is essential for normal gastrointestinal (GI) motility. Controversy exists regarding the cells and ionic conductance(s) that mediate post-junctional neuroeffector responses to motor neurotransmitters. Isolated intramuscular ICC (ICC-IM) and smooth muscle cells (SMCs) from murine fundus muscles were used to determine the conductances activated by carbachol (CCh) in each cell type. The calcium-activated chloride conductance (CaCC), anoctamin-1 (Ano1) is expressed by ICC-IM but not resolved in SMCs, and CCh activated a Cl- conductance in ICC-IM and a non-selective cation conductance in SMCs. We also studied responses to nerve stimulation using electrical-field stimulation (EFS) of intact fundus muscles from wild-type and Ano1 knockout mice. EFS activated excitatory junction potentials (EJPs) in wild-type mice, although EJPs were absent in mice with congenital deactivation of Ano1 and greatly reduced in animals in which the CaCC-Ano1 was knocked down using Cre/loxP technology. Contractions to cholinergic nerve stimulation were also greatly reduced in Ano1 knockouts. SMCs cells also have receptors and ion channels activated by muscarinic agonists. Blocking acetylcholine esterase with neostigmine revealed a slow depolarization that developed after EJPs in wild-type mice. This depolarization was still apparent in mice with genetic deactivation of Ano1. Pharmacological blockers of Ano1 also inhibited EJPs and contractile responses to muscarinic stimulation in fundus muscles. The data of the present study are consistent with the hypothesis that ACh released from motor nerves binds muscarinic receptors on ICC-IM with preference and activates Ano1. If metabolism of acetylcholine is inhibited, ACh overflows and binds to extrajunctional receptors on SMCs, eliciting a slower depolarization response.

Effects of new-generation TMEM16A inhibitors on calcium-activated chloride currents in rabbit urethral interstitial cells of Cajal.

Interstitial cells of Cajal (ICC) isolated from the rabbit urethra exhibit Ca2+-activated Cl- currents (I ClCa) that are important for the development of urethral tone. Here, we examined if TMEM16A (ANO1) contributed to this activity by examining the effect of "new-generation" TMEM16A inhibitors, CACCinh-A01 and T16Ainh-A01, on I ClCa recorded from freshly isolated rabbit urethral ICC (RUICC) and on contractions of intact strips of rabbit urethra smooth muscle. Real-time quantitative PCR experiments demonstrated that TMEM16A was highly expressed in rabbit urethra smooth muscle, in comparison to TMEM16B and TMEM16F. Single-cell RT-PCR experiments revealed that only TMEM16A was expressed in freshly isolated RUICC. Depolarization-evoked I ClCa in isolated RUICC, recorded using voltage clamp, were inhibited by CACCinh-A01 and T16Ainh-A01 with IC50 values of 1.2 and 3.4 µM, respectively. Similarly, spontaneous transient inward currents (STICs) recorded from RUICC voltage clamped at -60 mV and spontaneous transient depolarizations (STDs), recorded in current clamp, were also inhibited by CACCinh-A01 and T16Ainh-A01. In contrast, spontaneous Ca2+ waves in isolated RUICC were only partially reduced by CACCinh-A01 and T16Ainh-A01. Finally, neurogenic contractions of strips of rabbit urethra smooth muscle (RUSM), evoked by electric field stimulation (EFS), were also significantly reduced by CACCinh-A01 and T16Ainh-A01. These data are consistent with the idea that TMEM16A is involved with CACCs in RUICC and in contraction of rabbit urethral smooth muscle.

The afatinib resistance of in vivo generated H1975 lung cancer cell clones is mediated by SRC/ERBB3/c-KIT/c-MET compensatory survival signaling.

We generated afatinib resistant clones of H1975 lung cancer cells by transient exposure of established tumors to the drug and collected the re-grown tumors. Afatinib resistant H1975 clones did not exhibit any additional mutations in proto-oncogenes when compared to control clones. Afatinib resistant H1975 tumor clones expressed less PTEN than control clones and in afatinib resistant clones this correlated with increased basal SRC Y416, ERBB3 Y1289, AKT T308 and mTOR S2448 phosphorylation, decreased expression of ERBB1, ERBB2 and ERBB3 and increased total expression of c-MET, c-KIT and PDGFRß. Afatinib resistant clones were selectively killed by knock down of [ERBB3 + c-MET + c-KIT] but not by the individual or doublet knock down combinations. The combination of the ERBB1/2/4 inhibitor afatinib with the SRC family inhibitor dasatinib killed afatinib resistant H1975 cells in a greater than additive fashion; other drugs used in combination with dasatinib such as sunitinib, crizotinib and amufatinib were less effective. [Afatinib + dasatinib] treatment profoundly inactivated ERBB3, AKT and mTOR in the H1975 afatinib resistant clones and increased ATG13 S318 phosphorylation. Knock down of ATG13, Beclin1 or eIF2α strong suppressed killing by [ERBB3 + c-MET + c-KIT] knock down, but were only modestly protective against [afatinib + dasatinib] lethality. Thus afatinib resistant H1975 NSCLC cells rely on ERBB1- and SRC-dependent hyper-activation of residual ERBB3 and elevated signaling, due to elevated protein expression, from wild type c-MET and c-KIT to remain alive. Inhibition of ERBB3 signaling via both blockade of SRC and ERBB1 results in tumor cell death.

Celecoxib enhances [sorafenib + sildenafil] lethality in cancer cells and reverts platinum chemotherapy resistance.

The present studies sought to determine whether the lethality of the drug combination [sorafenib + sildenafil] could be enhanced by the anti-inflammatory agent celecoxib, using ovarian cancer and other tumor cell lines as models. Also, in a dose dependent fashion celecoxib enhanced [sorafenib + sildenafil] lethality in multiple ovarian cancer cell lines. In a dose dependent fashion celecoxib enhanced the ability of [sorafenib + sildenafil] to reduce expression of multiple chaperone proteins in parallel with lower levels of the drug efflux pumps ABCB1 and ABCG2. Over-expression of GRP78 and HSP27 maintained pump expression in the presence of drugs. Cell killing by the 3 drug combination was mediated by mitochondrial / caspase 9 -dependent apoptotic signaling and by RIP-1 / caspases 2 and 4 / AIF -dependent necroptotic signaling. Pre-treatment of intrinsically resistant primary ovarian cancer cells with [celecoxib + sorafenib + sildenafil] significantly enhanced tumor cell killing by a subsequent cisplatin exposure. Similar data were obtained in some cancer cell lines, but not all, using the related platinum containing drugs, oxaliplatin and carboplatin. As our prior publications have also validated in vivo the combinations of [celecoxib + sildenafil] and [sorafenib + sildenafil] as cytotoxic to multiple tumor cell types, combined with the present findings, we would argue that the combination of celecoxib/sorafenib/sildenafil should be explored in a new phase I trial in ovarian cancer.

Risk for broad-spectrum neuropsychiatric disorders after mild traumatic brain injury in a cohort of US Air Force personnel.

BACKGROUND: Military personnel are at increased risk for traumatic brain injury (TBI) from combat and non-combat exposures. Sequelae of moderate-to-severe TBI are well described, but the literature remains conflicted regarding whether mild TBI (mTBI) results in lasting brain injury and functional impairments. This study assessed risk for a range of neuropsychiatric disorders presenting after mTBI while adjusting for the potential confounds of depression and post-traumatic stress disorder (PTSD). METHODS: A historical prospective association study was conducted utilising electronic demographic, medical and military-specific data for over 49,000 active duty US Air Force service members (Airmen). This study utilised diagnostic codes considered by an expert panel to be indicative of mTBI to identify cases. Cox proportional hazards modelling calculated HRs for neuropsychiatric outcomes while controlling for varying lengths of follow-up and potentially confounding variables. RESULTS: Airmen with mTBI were at increased risk for specific neuropsychiatric disorders compared with a similarly injured non-mTBI control group. HRs for memory loss/amnesia, cognitive disorders, schizophrenia, PTSD, and depression were significantly elevated and remained so for at least 6 months post-mTBI, even after eliminating those with previous neuropsychiatric diagnoses. CONCLUSIONS: mTBI was positively associated with neuropsychiatric disorders in this population of primarily young adult males; with increased HRs 6 months post-mTBI. The results support that mTBI is distinguished from moderate-to-severe TBI in terms of risk for developing neuropsychiatric disorders. Further, these findings suggest the importance of screening for psychiatric and cognitive disorders post-mTBI in general medical practice.

Molecular mechanisms underlying the effect of the novel BK channel opener GoSlo: involvement of the S4/S5 linker and the S6 segment.

GoSlo-SR-5-6 is a novel large-conductance Ca(2+)-activated K(+) (BK) channel agonist that shifts the activation V1/2 of these channels in excess of -100 mV when applied at a concentration of 10 µM. Although the structure-activity relationship of this family of molecules has been established, little is known about how they open BK channels. To help address this, we used a combination of electrophysiology, mutagenesis, and mathematical modeling to investigate the molecular mechanisms underlying the effect of GoSlo-SR-5-6. Our data demonstrate that the effects of this agonist are practically abolished when three point mutations are made: L227A in the S4/S5 linker in combination with S317R and I326A in the S6C region. Our data suggest that GoSlo-SR-5-6 interacts with the transmembrane domain of the channel to enhance pore opening. The Horrigan-Aldrich model suggests that GoSlo-SR-5-6 works by stabilizing the open conformation of the channel and the activated state of the voltage sensors, yet decouples the voltage sensors from the pore gate.

Ketamine for procedural sedation by a doctor-paramedic prehospital care team: a 4-year description of practice.

BACKGROUND: Ketamine is a widely used drug that, depending on the dose administered, may be used as an analgesic or as a sedative or anaesthetic agent. A number of features make it attractive for prehospital use. At Essex and Herts Air Ambulance Trust, as with other services and under the guidance of a standard operating procedure, ketamine is used for both procedural sedation and as an anaesthetic agent for rapid sequence intubation. Guidelines exist that define levels of sedation and detail minimum standards of monitoring and personnel required for each level. METHODS: We conducted a retrospective review from 4 years of our mission database for patients who had received ketamine for procedural sedation from the doctor-paramedic helicopter emergency medical service team. Other data relevant to the patient or the mission were also collected. RESULTS: A total of 212 cases of ketamine used for procedural sedation were identified. In all, 111 (52.4%) were for fracture manipulations and 52 (24.5%) were to facilitate extrication. An overall 12.7% of patients were paediatric (less than 18 years) and 160 (75.5%) were male. The helicopter emergency medical service team was with the patient for a mean of 24.4 min after the 999 call and spent a mean of 44.6 min on scene before departing for the hospital, which, in 75% of cases, was by means of a helicopter. A full set of monitoring was documented as having been used in 59 (27.8%) cases. CONCLUSION: We describe the use of ketamine over a 4-year period for prehospital procedural sedation. Minimum standards for patient monitoring were documented in only around a quarter of cases.

PDE5 inhibitors enhance celecoxib killing in multiple tumor types.

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer.

Neurologically-related sequelae associated with mild traumatic brain injury.

OBJECTIVE: Mild traumatic brain injury (mTBI) accounts for more than 75% of traumatic brain injuries every year. This study examines the temporal association between non-blast mTBI and the onset of neurologic sequelae to illuminate risks of post-concussive syndrome, epilepsy and chronic pain. METHODS: A large historical prospective study was conducted utilizing electronically-recorded demographic, medical and military-specific data for over half a million active duty US Air Force Airmen. This study utilized diagnostic codes to identify mTBI exposures, two control groups and three post-mTBI time periods. Adjusted hazard ratios (HRs) were calculated using Cox proportional hazards modelling. RESULTS: HRs were higher when mTBI exposed Airmen were compared with the full cohort and lower when compared with the other injured group. When compared to the other injured group, mTBI was positively associated with epilepsy/recurrent seizure outcomes, post-concussive syndrome and pain disorders. HRs tended to be highest within the first 30 days and decreased over time. CONCLUSIONS: Findings support that mTBI may have a prolonged neurological impact. Findings are also likely generalizable to young adult populations with exposure to non-blast related mTBI, including civilians, as those included in this study were young adults with a high prevalence of recreational/sports and motor vehicle injuries.

Pharmacological characterization of TMEM16A currents.

Recent studies have shown that transmembrane protein 16 A (TMEM16A) is a subunit of calcium-activated chloride channels (CACCs). Pharmacological agents have been used to probe the functional role of CACCs, however their effect on TMEM16A currents has not been systematically investigated. In the present study, we characterized the voltage and concentration-dependent effects of 2 traditional CACC inhibitors (niflumic acid and anthracene-9-carboxcylic acid) and 2 novel CACC / TMEM16A inhibitors (CACC(inh)A01 and T16A(inh)A01) on TMEM16A currents. The whole cell patch clamp technique was used to record TMEM16A currents from HE K 293 cells that stably expressed human TMEM16A. Niflumic acid, A-9-C, CACC(inh)A01 and T16A(inh)A01 inhibited TMEM16A currents with IC50 values of 12, 58, 1.7 and 1.5 µM, respectively, however, A-9-C and niflumic acid were less efficacious at negative membrane potentials. A-9-C and niflumic acid reduced the rate of TMEM16A tail current deactivation at negative membrane potentials and A-9-C (1 mM) enhanced peak TMEM16A tail current amplitude. In contrast, the inhibitory effects of CACC(inh)A01 and T16A(inh)A01 were independent of voltage and they did not prolong the rate of TMEM16A tail current deactivation. The effects of niflumic acid and A-9-C on TMEM16A currents were similar to previous observations on CACCs in vascular smooth muscle, strengthening the hypothesis that they are encoded by TMEM16A. However, CACC(inh)A01 and T16A(inh)A01 were more potent inhibitors of TMEM16A channels and their effects were not diminished at negative membrane potentials making them attractive candidates to interrogate the functional role of TMEM16A channels in future studies.

Airmen with mild traumatic brain injury (mTBI) at increased risk for subsequent mishaps.

BACKGROUND: Little is known regarding long-term performance decrements associated with mild Traumatic Brain Injury (mTBI). The goal of this study was to determine if individuals with an mTBI may be at increased risk for subsequent mishaps. METHODS: Cox proportional hazards modeling was utilized to calculate hazard ratios for 518,958 active duty U.S. Air Force service members (Airmen) while controlling for varying lengths of follow-up and potentially confounding variables. Two non-mTBI comparison groups were used; the second being a subset of the original, both without head injuries two years prior to study entrance. RESULTS: Hazard ratios indicate that the causes of increased risk associated with mTBI do not resolve quickly. Additionally, outpatient mTBI injuries do not differ from other outpatient bodily injuries in terms of subsequent injury risk. CONCLUSIONS: These findings suggest that increased risk for subsequent mishaps are likely due to differences shared among individuals with any type of injury, including risk-taking behaviors, occupations, and differential participation in sports activities. Therefore, individuals who sustain an mTBI or injury have a long-term risk of additional mishaps. PRACTICAL APPLICATIONS: Differences shared among those who seek medical care for injuries may include risk-taking behaviors (Cherpitel, 1999; Turner & McClure, 2004; Turner, McClure, & Pirozzo, 2004), occupations, and differential participation in sports activities, among others. Individuals with an mTBI should be educated that they are at risk for subsequent injury. Historical data supported no lingering effects of mTBI, but more recent data suggest longer lasting effects. This study further adds that one of the longer term sequelae of mTBI may be an increased risk for subsequent mishap.

Sesterterpene glycinyl-lactams: a new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia.

Bioassay guided fractionation of three southern Australian marine sponges of the genus Psammocinia, selected for their ability to modulate glycine-gated chloride channel receptors (GlyRs), yielded the rare marine sesterterpenes (-)-ircinianin (1) and (-)-ircinianin sulfate (2), along with the new biosynthetically related metabolites (-)-ircinianin lactam A (3), (-)-ircinianin lactam A sulfate (4), (-)-oxoircinianin (5), (-)-oxoircinianin lactam A (6) and (-)-ircinianin lactone A (7). Acetylation of 1 returned (-)-ircinianin acetate (8). Whole cell patch-clamp electrophysiology on 1-8 established 3 as an exceptionally potent and selective α3 GlyR potentiator, and 6 as a selective α1 GlyR potentiator. The discovery and characterization of sesterterpenes 1-8, and in particular the glycinyl-lactams 3 and 6, provide valuable new insights into GlyR pharmacology. These insights have the potential to inform and inspire the development of new molecular tools to probe GlyR distribution and function, and therapeutics to treat a wide array of GlyR mediated diseases and disorders.

A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.

PURPOSE: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m(2) ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies. RESULTS: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia. CONCLUSIONS: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement.

Risk for addiction-related disorders following mild traumatic brain injury in a large cohort of active-duty U.S. airmen.

OBJECTIVE: Military personnel are at increased risk for traumatic brain injury (TBI) from combat and noncombat exposures. The sequelae of moderate to severe TBI are well described, but little is known regarding long-term performance decrements associated with mild TBI. Furthermore, while alcohol and drug use are well known to increase risk for TBI, little is known regarding the reverse pattern. The authors sought to assess possible associations between mild TBI and addiction-related disorders in active-duty U.S. military personnel. METHOD: A historical prospective study was conducted using electronically recorded demographic, medical, and military data for more than a half million active-duty U.S. Air Force service members. Cases were identified by ICD-9-CM codes considered by an expert panel to be indicative of mild TBI. Outcomes included ICD-9-CM diagnoses of selected addiction-related disorders. Cox proportional hazards modeling was used to calculate hazard ratios while controlling for varying lengths of follow-up and potential confounding variables. RESULTS: Airmen with mild TBI were at increased risk for certain addiction-related disorders compared with a similarly injured non-mild TBI comparison group. Hazards for alcohol dependence, nicotine dependence, and nondependent abuse of drugs or alcohol were significantly elevated, with a consistent decrease over time. CONCLUSIONS: A novel finding of this study was the initial increased risk for addiction-related disorders that decreased with time, thus eroding war fighter performance in a military population. Moreover, these results suggest that mild TBI is distinguished from moderate to severe TBI in terms of timing of the risk, indicating that there is a need for screening and prevention of addiction-related disorders in mild TBI. Screening may be warranted in military troops as well as civilians at both short- and long-term milestones following mild TBI.