Monoclonal antibodies against GD2 ganglioside, such as ch14.18, the human–mouse chimeric antibody, have been shown to be effective for the treatment of neuroblastoma. However, treatment is associated with generalized, relatively opiate-resistant pain. We investigated if a point mutation in ch14.18 antibody (hu14.18K332A) to limit complement-dependent cytotoxicity (CDC) would ameliorate the pain behavior, while preserving antibody-dependent cellular cytotoxicity (ADCC). In vitro, CDC and ADCC were measured using europium-TDA assay. In vivo, allodynia was evaluated by measuring thresholds to von Frey filaments applied to the hindpaws after injection of either ch14.18 or hu14.18K332 into wild type rats or rats with deficient complement factor 6. Other rats were pretreated with complement factor C5a receptor antagonist and tested following ch14.18 injection. The mutation reduces the antibody’s ability to activate complement, while maintaining its ADCC capabilities. Injection of hu14.18K322 (1 or 3 mg/kg) produced faster resolving allodynia than that engendered by ch14.18 (1 mg/kg). Injection of ch14.18 (1 mg/kg) into rats with C6 complement deficiency further reduced antibody-induced allodynia, while pre-treatment with complement factor C5a receptor antagonist completely abolished ch14.18-induced allodynia. These findings showed that mutant hu14.18 K322 elicited less allodynia than ch14.18 and that ch14.18-elicited allodynia is due to activation of the complement cascade: in part, to formation of membrane attack complex, but more importantly to release of complement factor C5a. Development of immunotherapeutic agents with decreased complement-dependent lysis while maintaining cellular cytotoxicity may offer treatment options with reduced adverse side effects, thereby allowing dose escalation of therapeutic antibodies.

Among patients with septic shock in US hospitals affected by the 2011 norepinephrine shortage, the most commonly administered alternative vasopressor was phenylephrine. Patients admitted to these hospitals during times of shortage had higher in-hospital mortality.

OBJECTIVE: To describe presenting symptoms and signs according to age group in a cohort of 243 patients with tuberous sclerosis complex (TSC) and identify earlier symptoms and signs that did not lead to immediate diagnosis. PATIENTS AND METHODS: We performed a retrospective chart review for 278 patients with TSC who were examined at Children's Hospital Boston in Massachusetts and at the Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital. The presenting symptom or sign was the first symptom or sign to cause suspicion for TSC and lead to diagnosis. Missed symptoms or signs were those that were documented in the patient's chart but did not immediately lead to diagnosis. RESULTS: There were 243 patients for whom there were sufficient data for inclusion in this study. Patients were diagnosed with TSC at ages ranging from birth to 73 years. The average age at diagnosis was 7.5 years. Of the patients, 81% were diagnosed before the age of 10. Diagnosis during adolescence and adulthood was not uncommon. The most common presenting symptoms and signs included new onset of seizures, history of seizures, infantile spasms, family history of TSC, cardiac rhabdomyomas, and hypopigmented macules. Of the patients, 39% reported missed symptoms or signs of TSC, most commonly seizures (including infantile spasms) and dermatologic features. CONCLUSIONS: Many patients had symptoms or signs of TSC that did not lead to immediate diagnosis. Clinicians should be aware of the myriad potential presenting symptoms and signs of TSC. Early diagnosis may reduce morbidity and mortality.

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Rationale: Vasopressin may be used to treat vasodilatory hypotension in septic shock, but it is not recommended by guidelines as a first-or second-line agent. Little is known about how often the drug is used currently in septic shock.Objectives: We conducted this study to describe patterns of vasopressin use in a large cohort of U.S. adults with septic shock and to identify patient and hospital characteristics associated with vasopressin use.Methods: This was a retrospective cohort study of adults admitted to U.S. hospitals with septic shock in the Premier healthcare database (July 2008 to June 2013). We performed multilevel mixed-effects logistic regression with hospitals as a random effect to identify factors associated with use of vasopressin alone or in combination with other vasopressors on at least 1 day of hospital admission. We calculated quotients of Akaike Information Criteria (AIC) to determine relative contributions of patient and hospital characteristics to observed variation.Measurements and Main Results: Among 584,421 patients with septic shock in 532 hospitals, 100,923 (17.2%) received vasopressin. A total of 6.1% of patients receiving vasopressin received vasopressin alone, and 93.9% received vasopressin in combination with other vasopressors (up to five vasopressors in 15 different combinations). The mean monthly rate of vasopressin use increased from 14.5 to 19.6% over the study period, representing an average annual relative increase of 8% (P , 0.001). The median hospital rate of vasopressin use for septic shock was 11.7% (range, 0-69.7%). Patient demographic and clinical characteristics, including patient age (adjusted odds ratio, 0.71 for age . 85 yr compared with the reference group of age , 50 yr; 95% confidence interval, 0.69-0.74) and acute respiratory dysfunction (adjusted odds ratio, 3.25; 95% confidence interval, 3.20-3.31), were responsible for the majority of observed variation in vasopressin use (quotient of AICs, 0.56). However, hospital of admission also contributed substantially to observed variation (quotient of AICs, 0.37).Conclusions: Approximately one-fifth of patients with septic shock received vasopressin, but rarely as a single vasopressor. The use of vasopressin has increased over time. The likelihood of receiving vasopressin was strongly associated with the specific hospital to which each patient was admitted.