Physical sleeping environment is related to insomnia risk and measures of readiness in US army special operations soldiers.

BACKGROUND: US military service members have characteristically poor sleep, even when 'in garrison' or at one's home base. The physical sleeping environment, which is often poor in military-provided housing or barracks, may contribute to poor sleep quality in soldiers. The current study aimed to assess whether the sleeping environment in garrison is related to sleep quality, insomnia risk and military readiness. METHODS: Seventy-four US army special operations soldiers participated in a cross-sectional study. Soldiers were queried on their sleeping surface comfort and the frequency of being awakened at night by excess light, abnormal temperatures and noise. Subjective sleep quality and insomnia symptoms were also queried, via the Pittsburgh Sleep Quality Index and Insomnia Severity Index, respectively. Lastly, measures of soldier readiness, including morale, motivation, fatigue, mood and bodily pain, were assessed. RESULTS: Soldiers reporting temperature-related and light-related awakenings had poorer sleep quality higher fatigue and higher bodily pain than soldiers without those disturbances. Lower ratings of sleeping surface comfort were associated with poorer sleep quality and lower motivation, lower morale, higher fatigue and higher bodily pain. Each 1-point increase in sleeping surface comfort decreased the risk for a positive insomnia screen by 38.3%, and the presence of temperature-related awakenings increased risk for a positive insomnia screen by 78.4%. Those living on base had a poorer sleeping environment than those living off base. CONCLUSION: Optimising the sleep environment-particularly in on-base, military-provided housing-may improve soldier sleep quality, and readiness metrics. Providers treating insomnia in soldiers should rule out environment-related sleep disturbances prior to beginning more resource-intensive treatment.

Alpha-substituted gamma-butyrolactones: new class of anticonvulsant drugs.

Alkyl-Substituted gamma-butyrolactones were synthesized and tested for their convulsant and anticonvulsant actions in mice and guinea pigs. The alpha-substituted compounds, alpha, alpha-dimethyl-, and alpha-ethyl-alpha-methyl-gamma-butyrolactone were anticonvulsant compounds with a spectrum of activity similar to that of ethosuximide. In contrast, beta-substituted compounds were convulsant agents similar to picrotoxinin. The alpha-substituted-gama-butyrolactones represent a new class of anticonvulsant drug with experimental and clinical potential.

The alcohol withdrawal syndrome.

The alcohol withdrawal syndrome (AWS) is a common management problem in hospital practice for neurologists, psychiatrists and general physicians alike. Although some patients have mild symptoms and may even be managed in the outpatient setting, others have more severe symptoms or a history of adverse outcomes that requires close inpatient supervision and benzodiazepine therapy. Many patients with AWS have multiple management issues (withdrawal symptoms, delirium tremens, the Wernicke-Korsakoff syndrome, seizures, depression, polysubstance abuse, electrolyte disturbances and liver disease), which requires a coordinated, multidisciplinary approach. Although AWS may be complex, careful evaluation and available treatments should ensure safe detoxification for most patients.

Platinum(iv) oxaliplatin-peptide conjugates targeting memHsp70+ phenotype in colorectal cancer cells.

Novel Pt(iv) tumour penetrating peptide (TPP) conjugates are reported. They are the first example of metallodrugs to target a membrane bound heat shock protein 70 positive (memHSP70+) phenotype in cancer cells. The conjugates exhibit superior cytotoxicity as compared to oxaliplatin alone in Pt resistant colorectal cancer cells with relatively high memHSP70+ expression. Substitution of TPP in Pt(iv) peptide conjugates with scrambled peptide (ScP) essentially abolishes the observed cytotoxicity.

Tirapazamine with cisplatin in patients with advanced non-small-cell lung cancer: a phase II study.

PURPOSE: A phase II study was conducted to evaluate the safety and efficacy of tirapazamine combined with cisplatin for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-four patients with stage IIIB/IV NSCLC were treated with a combination of tirapazamine and cisplatin. Patients received tirapazamine 260 mg/m2 administered intravenously over 2 hours, followed 1 hour later by cisplatin 75 mg/m2 administered over an additional hour, repeated every 21 days. The duration of therapy was meant to be limited to four cycles for nonresponders and eight cycles for responders. RESULTS: Ten of 44 patients (23%) showed a partial response. The estimated median survival for all patients was 37 weeks. Toxicities were treatable and included grade 3 nausea or vomiting (25%), fatigue (27.3%), and muscle cramps (4.5%). No dose reductions were necessary. CONCLUSION: The results show that tirapazamine can safely be added to cisplatin. Both the median survival and response rate observed strongly suggest that tirapazamine with cisplatin is more active than cisplatin alone.

Alpha-spirocyclopentyl- and alpha-spirocyclopropyl-gamma-butyrolactones: conformationally constrained derivatives of anticonvulsant and convulsant alpha,alpha-disubstituted gamma-butyrolactones.

To further study the putative gamma-butyrolactone site of the GABAA/chloride channel complex, constrained derivatives of convulsant and anticonvulsant alpha,alpha-disubstituted gamma-butyrolactones (alpha-spirocyclopropyl- and alpha-spirocyclopentyl-gamma-butyrolactones) were synthesized and evaluated biologically. Most of the spirocyclopropyl agents were anticonvulsants when tested against pentylenetetrazole-induced seizures in mice. These agents effectively displaced 35[S]-tert-butylbicyclophosphorothionate (35[S]-TBPS), a ligand for the picrotoxin binding site of the GABAA/chloride channel, from rat neuronal membranes and affected the GABA-mediated current in hippocampal neurons. The monomethyl-substituted spirocyclopropyl agent with a methyl group cis to the carbonyl (15) potentiates GABA-induced current whereas the trans derivative (16) blocks the current. The only anticonvulsant in the spirocyclopentyl series was the unsubstituted spirocyclopentyl compound 2. All the other substituted spirocyclopentyl targets were inactive in vivo at the highest dose tested except for convulsant 9, which has a trans 2,5-dimethyl-substituted cyclopentyl ring. All the spirocyclopentyl derivatives displaced 35[S]-TBPS from rat neuronal membranes very effectively, and they also all potentiated GABA-induced chloride current except for convulsant 9 which blocked the current. From the data obtained in this investigation, it appears that when the volume occupied above and below the lactone ring is as large as that occupied by spirocyclopentyl agent 9, convulsant activity is observed. Groups with less volume in these areas either are inactive in the behavioral test or have anticonvulsant activity. When bound to the GABAA/chloride channel, the larger molecules may stabilize the closed state of the channel whereas the smaller molecules may stabilize the open state.

Synthesis and structure-activity studies of alkyl-substituted gamma-butyrolactones and gamma-thiobutyrolactones: ligands for the picrotoxin receptor.

A series of gamma-butyrolactones and gamma-thiobutyrolactones possessing a variety of alkyl groups and alkyl-substitution patterns was prepared and evaluated for anticonvulsant and convulsant activity. Behavioral studies performed on these compounds suggest that maximal anticonvulsant activity (against maximal electroshock and pentylenetetrazol) results when three or four carbon atoms are present at the alpha-position. For convulsant potency, a similar dependence on the size of the alkyl chain at the beta-position was observed. Additional gamma-dimethyl groups were found to increase the convulsant potency of a beta-substituted compound and to cause an alpha-substituted anticonvulsant to become a convulsant. In general, sulfur for oxygen heteroatom substitution in the alpha-substituted lactones resulted in improved anticonvulsant potency and spectrum of activity. Binding of these compounds to the picrotoxin site of the GABA receptor complex was demonstrated with a [35S]-tert-butylbicyclophosphorothionate radioligand binding assay. Measurements of brain concentrations for selected compounds supports a hypothesis that correlates binding to the picrotoxin site with the pharmacological effects of these compounds.

Dose escalation and pharmacokinetic study of irinotecan in combination with paclitaxel in patients with advanced cancer.

PURPOSE: Based on preclinical data demonstrating synergy between camptothecin analogues and taxanes, we determined the maximum tolerated dose (MTD) of irinotecan that could be given in combination with a fixed dose of paclitaxel of 75 mg/m2, when both drugs were delivered on a weekly schedule. The pharmacokinetics of this combination were explored to determine whether the sequence of administration affected the elimination of irinotecan. METHODS: For the first cycle patients with advanced cancer were treated with irinotecan given as a 90-min infusion followed immediately by paclitaxel given at a dose of 75 mg/m2 over 1 h. The sequence of drug administration was reversed in subsequent cycles for most patients. Chemotherapy was given weekly for 4 weeks, followed by a 2-week rest. In selected patients, plasma concentrations of irinotecan were determined by high-performance liquid chromatography during the first 24 h of cycle 1 and after the first dose of cycle 2 to determine whether the order of drug administration affected the elimination of irinotecan, or the toxicologic effects of the chemotherapy. RESULTS: A total of 53 cycles were delivered to 21 patients. Reversible neutropenia was dose-limiting. Suppression of the other blood cell elements was modest. There was one partial response in a man with a previously treated cholangiocarcinoma that lasted 26 weeks. Prolonged stabilization of disease (6 months or more) was observed in five of the patients (24%). At the recommended dose of irinotecan (50 mg/m2), transfusions of red cells and platelets were not required. The sequence of drug administration produced no significant differences in the pharmacokinetic parameters of irinotecan or SN-38, which were similar to the values reported when irinotecan is administered alone. The most prominent nonhematologic toxicities were mild diarrhea and fatigue. CONCLUSIONS: The recommended dose of irinotecan on this schedule is 50 mg/m2. The sequence of drug administration affects neither the elimination of irinotecan nor the chemotherapy-related toxicity. This combination is well tolerated and causes minimal clinical side effects.

Anterior thalamus and substantia nigra: two distinct structures mediating experimental generalized seizures.

Injection of gamma-vinyl aminobutyric acid (GVG) into the anterior thalamus protected rats against pentylenetetrazol (PTZ) seizures but not against maximal electroshock (MES) seizures. Injection of GVG into the substantia nigra protected against MES seizures but not against PTZ seizures. Both types of seizures were prevented by injections into both of the above brain regions. These data indicate that separate neuronal circuits mediate PTZ and MES seizures.

Rationale and dose-finding studies of the combination of irinotecan and a taxane on a weekly schedule.

Cisplatin (Platinol)-based chemotherapy has been the standard systemic therapy for both non-small-cell and small-cell lung cancer for the past 2 decades, though the efficacy and benefit remain modest. Recently, several novel agents have been introduced that have single-agent activity comparable to cisplatin and offer the possibility of improved therapy for lung cancer. Camptothecin and taxane derivatives are associated with both different mechanisms of action and nonhematologic toxicities, and have demonstrated additive or synergistic activity when used in combination in preclinical studies. We review pertinent clinical studies of these agents in lung cancer and present our experience in combining irinotecan (Camptosar, CPT-11) with taxanes on a weekly schedule in dose-finding and efficacy studies. When chemotherapy is delivered for 4 consecutive weeks followed by a 2-week rest, hematologic toxicity is dose limiting and most prominent during weeks 3 and 4. Dose intensification is feasible if the schedule is modified so the chemotherapy is given on days 1 and 8, with cycles repeated every 3 weeks. The most common nonhematologic toxicities remain asthenia, neuropathy, and diarrhea. Future studies will explore and better define the role of these drug combinations in the treatment of lung cancer.

Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility.

BACKGROUND: Chronic gastrointestinal dysmotility greatly impacts the quality of life. Treatment options are limited and generally symptomatic. Neural autoimmunity is an under-recognized etiology. We evaluated immunotherapy as an aid to diagnosing autoimmune gastrointestinal dysmotility (AGID). METHODS: Twenty-three subjects evaluated at the Mayo Clinic for suspected AGID (August 2006-February 2014) fulfilled the following criteria: (1) prominent symptoms of gastrointestinal dysmotility with abnormalities on scintigraphy-manometry; (2) serological evidence or personal/family history of autoimmune disease; (3) treated by immunotherapy on a trial basis, 6-12 weeks (intravenous immune globulin, 16; or methylprednisolone, 5; or both, 2). Response was defined subjectively (symptomatic improvement) and objectively (gastrointestinal scintigraphy/manometry studies). KEY RESULTS: Symptoms at presentation: constipation, 18/23; nausea or vomiting, 18/23; weight loss, 17/23; bloating, 13/23; and early satiety, 4/23. Thirteen patients had personal/family history of autoimmunity. Sixteen had neural autoantibodies and 19 had extra-intestinal autonomic testing abnormalities. Cancer was detected in three patients. Preimmunotherapy scintigraphy revealed slowed transit (19/21 evaluated; gastric, 11; small bowel, 12; colonic, 11); manometry studies were abnormal in 7/8. Postimmunotherapy, 17 (74%) had improvement (both symptomatic and scintigraphic, five; symptomatic alone, eight; scintigraphic alone, four). Nine responders re-evaluated had scintigraphic evidence of improvement. The majority of responders who were re-evaluated had improvement in autonomic testing (six of seven) or manometry (two of two). CONCLUSIONS & INFERENCES: This proof of principle study illustrates the importance of considering an autoimmune basis for idiopathic gastrointestinal dysmotility and supports the utility of a diagnostic trial of immunotherapy.

AQP4 autoantibody assay performance in clinical laboratory service.

OBJECTIVE: To compare performance of contemporary aquaporin-4-immunoglobulin (Ig) G assays in clinical service. METHODS: Sera from neurologic patients (4 groups) and controls were tested initially by service ELISA (recombinant human aquaporin-4, M1 isoform) and then by cell-based fluorescence assays: fixed (CBA, M1-aquaporin-4, observer-scored) and live (fluorescence-activated cell sorting [FACS], M1 and M23 aquaporin-4 isoforms). Group 1: all Mayo Clinic patients tested from January to May 2012; group 2: consecutive aquaporin-4-IgG-positive patients from September 2011 (Mayo and non-Mayo); group 3: suspected ELISA false-negatives from 2011 to 2013 (physician-reported, high likelihood of neuromyelitis optica spectrum disorders [NMOSDs] clinically); group 4: suspected ELISA false-positives (physician-reported, not NMOSD clinically). RESULTS: Group 1 (n = 388): M1-FACS assay performed optimally (areas under the curves: M1 = 0.64; M23 = 0.57 [p = 0.02]). Group 2 (n = 30): NMOSD clinical diagnosis was confirmed by: M23-FACS, 24; M1-FACS, 23; M1-CBA, 20; and M1-ELISA, 18. Six results were suspected false-positive: M23-FACS, 2; M1-ELISA, 2; and M23-FACS, M1-FACS, and M1-CBA, 2. Group 3 (n = 31, suspected M1-ELISA false-negatives): results were positive for 5 sera: M1-FACS, 5; M23-FACS, 3; and M1-CBA, 2. Group 4 (n = 41, suspected M1-ELISA false-positives): all negative except 1 (positive only by M1-CBA). M1/M23-cotransfected cells expressing smaller membrane arrays of aquaporin-4 yielded fewer false- positive FACS results than M23-transfected cells. CONCLUSION: Aquaporin-4-transfected CBAs, particularly M1-FACS, perform optimally in aiding NMOSD serologic diagnosis. High-order arrays of M23-aquaporin-4 may yield false-positive results by binding IgG nonspecifically.

Utility of an immunotherapy trial in evaluating patients with presumed autoimmune epilepsy.

OBJECTIVE: To evaluate a trial of immunotherapy as an aid to diagnosis in suspected autoimmune epilepsy. METHOD: We reviewed the charts of 110 patients seen at our autoimmune neurology clinic with seizures as a chief complaint. Twenty-nine patients met the following inclusion criteria: (1) autoimmune epilepsy suspected based on the presence of ≥ 1 neural autoantibody (n = 23), personal or family history or physical stigmata of autoimmunity, and frequent or medically intractable seizures; and (2) initiated a 6- to 12-week trial of IV methylprednisolone (IVMP), IV immune globulin (IVIg), or both. Patients were defined as responders if there was a 50% or greater reduction in seizure frequency. RESULTS: Eighteen patients (62%) responded, of whom 10 (34%) became seizure-free; 52% improved with the first agent. Of those receiving a second agent after not responding to the first, 43% improved. A favorable response correlated with shorter interval between symptom onset and treatment initiation (median 9.5 vs 22 months; p = 0.048). Responders included 14/16 (87.5%) patients with antibodies to plasma membrane antigens, 2/6 (33%) patients seropositive for glutamic acid decarboxylase 65 antibodies, and 2/6 (33%) patients without detectable antibodies. Of 13 responders followed for more than 6 months after initiating long-term oral immunosuppression, response was sustained in 11 (85%). CONCLUSIONS: These retrospective findings justify consideration of a trial of immunotherapy in patients with suspected autoimmune epilepsy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with suspected autoimmune epilepsy, IVMP, IVIg, or both improve seizure control.

The spectrum of neuromyelitis optica (NMO) in childhood.

The evaluation of inflammatory central nervous system disorders in childhood with predominant involvement of the optic nerves and spinal cord has been greatly enhanced over the last decade with identification of a group of disorders unified by the detection of neuromyelitis optica (NMO)-IgG, an antibody targeting the central nervous system-predominant water channel aquaporin-4. Clinical syndromes are predominated by the relapsing form of NMO but also include encephalopathic variants that can mimic acute disseminated encephalomyelitis. Maintenance immunotherapy is used to prevent relapses in NMO-IgG-seropositive patients. In contrast, NMO-IgG-seronegative children with NMO more commonly have a monophasic course (simultaneous occurrence of optic neuritis and transverse myelitis) and do not require remission-maintaining immunotherapy, but close surveillance is advised. Current clinical, pathological, and pathogenetic knowledge is reviewed with a focus on clinical presentation, neuroimaging findings, serological investigations, and treatment of children with disorders within the spectrum of central nervous system aquaporin-4 autoimmunity.

Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays.

OBJECTIVES: Neuromyelitis optica (NMO) immunoglobulin G (IgG) (aquaporin-4 [AQP4] IgG) is highly specific for NMO and related disorders, and autoantibody detection has become an essential investigation in patients with demyelinating disease. However, although different techniques are now used, no multicenter comparisons have been performed. This study compares the sensitivity and specificity of different assays, including an in-house flow cytometric assay and 2 commercial assays (ELISA and transfected cell-based assay [CBA]). METHODS: Six assay methods (in-house or commercial) were performed in 2 international centers using coded serum from patients with NMO (35 patients), NMO spectrum disorders (25 patients), relapsing-remitting multiple sclerosis (39 patients), miscellaneous autoimmune diseases (25 patients), and healthy subjects (22 subjects). RESULTS: The highest sensitivities were yielded by assays detecting IgG binding to cells expressing recombinant AQP4 with quantitative flow cytometry (77; 46 of 60) or visual observation (CBA, 73%; 44 of 60). The fluorescence immunoprecipitation assay and tissue-based immunofluorescence assay were least sensitive (48%-53%). The CBA and ELISA commercial assays (100% specific) yielded sensitivities of 68% (41 of 60) and 60% (36 of 60), respectively, and sensitivity of 72% (43 of 60) when used in combination. CONCLUSIONS: The greater sensitivity and excellent specificity of second-generation recombinant antigen-based assays for detection of NMO-IgG in a clinical setting should enable earlier diagnosis of NMO spectrum disorders and prompt initiation of disease-appropriate therapies.

Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica.

OBJECTIVE: To evaluate the efficacy, tolerability, optimal dosing, and monitoring of azathioprine in patients with neuromyelitis optica (NMO). METHODS: This was a chart review and telephone follow-up study of 99 patients with NMO spectrum of disorders (NMOSD) treated with azathioprine (1994-2009). NMOSD were NMO (2006 diagnostic criteria) or partial NMO forms (NMO-immunoglobulin G seropositive). Wilcoxon signed rank test was used to compare pretreatment and postinitiation of azathioprine (posttreatment) annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) score, and visual acuity outcome. Linear regression was used to assess the effects of various factors on ARR change and disability. RESULTS: The median duration of NMOSD symptoms prior to initiation of azathioprine was 2 years (range 1-27); 79 patients were women. Eighty-six patients had NMO and 13 limited NMO versions, including transverse myelitis in 8 and optic neuritis in 5. Median posttreatment follow-up was 22 months. Thirty-eight patients discontinued drug (side effects, 22; no efficacy, 13; lymphoma, 3). Among 70 patients with >12 months follow-up, 48 received ≥2.0 mg/kg/day (ARR: pretreatment, 2.20; posttreatment, 0.52); 22 received <2.0 mg/kg/day (ARR: pretreatment, 2.09; posttreatment, 0.82); 52 received concomitant prednisone (ARR: pretreatment, 2.20; posttreatment, 0.89) and 18 did not (ARR: pretreatment, 1.54; posttreatment, 0.23); p < 0.0001 for each comparison. EDSS was stable or improved despite ongoing attacks in 22 patients (31%). Twenty-six patients tolerated azathioprine and were relapse-free (37%, median follow-up 24 months; range 12-151). Mean corpuscular volume increase influenced ARR change (p = 0.049). CONCLUSIONS: Azathioprine is generally effective and well-tolerated. Early initiation, adequate dosing, and hematologic parameter monitoring may optimize efficacy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that azathioprine is effective for reducing relapse rates and improving EDSS and visual acuity scores in patients with NMO spectrum of disorders.

Paraneoplastic isolated myelopathy: clinical course and neuroimaging clues.

OBJECTIVE: To report the clinical phenotype and outcome of isolated paraneoplastic myelopathy. METHODS: We systematically reviewed clinical, serologic, and MRI data for 31 patients (20 female) who presented with an isolated myelopathy and coexisting cancer: carcinoma (lung, 9; breast, 7; kidney, 2; thyroid, 2; ovary/endometrium, 2), melanoma (2), or other cancer (3), or a paraneoplastic autoantibody with strong cancer association (amphiphysin-immunoglobulin G [IgG], 9; collapsin response-mediator protein 5-IgG, 9; Purkinje-cell cytoplasmic autoantibody type 1, 2; antineuronal nuclear autoantibody [ANNA]-1, 1; ANNA-3, 1). RESULTS: Of 31 patients who presented with a progressive myelopathy, symptom onset was subacute in 16 (52%). The median age was 62 years. CSF abnormalities included elevated protein (>45 mg/dL), 22; pleocytosis, 15; excess oligoclonal bands (normal <4), 7. MRI cord abnormalities identified in 20 patients were longitudinally extensive (>3 vertebral segments), 14; symmetric tract or gray matter-specific signal abnormality, 15 (enhancing in 13). Myelopathy preceded cancer diagnosis in 18 patients (median interval 12 months; range 2-44). After myelopathy onset, 26 patients underwent oncologic treatment, immunosuppressive treatment (median delay to commencing immunotherapy 9.5 months [range 1-54]), or both; only 8 improved (31%). At last neurologic evaluation (median interval after onset 17 months; range 1-165 months), 16 patients (52%) were wheelchair-dependent (median time from onset to wheelchair 9 months [range 1-21]). Ten patients died after a median of 38 months from symptom onset (range 7-152). CONCLUSION: Symmetric, longitudinally extensive tract or gray matter-specific changes on spinal MRI should raise suspicion for a paraneoplastic myelopathy. Resulting disability is often severe. Only a minority of patients improve with treatment.