Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial.

AIMS/HYPOTHESIS: Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes. METHODS: In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients. RESULTS: Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders. CONCLUSIONS/INTERPRETATIONS: This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00378508 FUNDING: This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.

Homeopathic pathogenetic trials produce more specific than non-specific symptoms: results from two double-blind placebo controlled trials.

We conducted two parallel, blinded homeopathic pathogenetic trials conducted at two different sites to determine whether symptoms reported by healthy volunteers were significantly different for homeopathic remedies than for placebos. Study 1 used a two-armed design, testing ozone against placebo. Study 2 used a three-armed design, testing ozone and iridium against placebo. We found significantly more remedy-specific symptoms in provers taking ozone or iridium than in provers taking placebo in the three-armed trial and in both trials pooled for ozone and placebo. We, therefore, conclude that homeopathic remedies produce more symptoms typical for a remedy than non-typical symptoms. The results furthermore suggest a somewhat non-classical pattern because symptoms of one remedy appear to be mimicked in the other trial arm. This might be indicative of entanglement in homeopathic systems.

Homeopathic proving symptoms: result of a local, non-local, or placebo process? A blinded, placebo-controlled pilot study.

BACKGROUND: Homeopathic pathogenetic trials (HPTs) (provings) are the pillar of homeopathy. Symptoms experienced by healthy volunteers are used to find the correct medicine for therapy. It is unclear whether these symptoms are specific or due to placebo noise. Furthermore, it is uncertain whether proving effects, if present at all, are due to a local or non-local process OBJECTIVES: To develop a test model which allows for testing if homeopathic proving symptoms are caused by placebo or causative mechanisms, and if these symptoms are due to local or non-local processes. DESIGN: Randomised, blinded, placebo-controlled, parallel-group study, with 1-week baseline and 2-weeks proving period. SUBJECTS: 11 healthy volunteers from two different homeopathic schools. PROVING SUBSTANCE: An homeopathic medicine (Cantharis 30c), blindly chosen from 12 potential medicines, compared to placebo. OUTCOME MEASURE: Number of symptoms typical for the medicine in the experimental and control group during baseline and proving period. RESULTS: During baseline there was no difference in the number of typical or atypical symptoms in either group. During the proving period, both more typical symptoms for Cantharis (P= 0.03) and more atypical symptoms (P= 0.02) were observed compared to baseline. Between-group differences were not significant. Effect sizes for the difference between the proving and control group for typical symptoms was d=0.4, and for atypical symptoms d=0.6. DISCUSSION: This proving model could be valuable in studying the validity of proving symptoms of homeopathic substances in healthy volunteers. CONCLUSION: Homeopathic proving symptoms appear to be specific to the medicine and do not seem to be due to a local process. Since this was a pilot study using a small number of provers, rival hypotheses cannot be ruled out and the study needs replication.

Saccadic eye movement abnormalities in relatives of patients with schizophrenia.

Recent studies note abnormalities in saccadic eye movements of relatives of patients with schizophrenia. The current study examined which aspects of the saccadic system are affected, whether these saccadic abnormalities are associated with schizophrenia spectrum personality symptoms (SSP), and whether such an association is dependent on a family history of schizophrenia. Furthermore, the study examined what proportion of relatives have the saccadic abnormality(ies). Fifty-five first-degree relatives with no DSM-III-R Axis I diagnosis participated in the study. Twenty-one of these relatives experienced SSP symptoms and 34 had no Axis II diagnosis. Sixty-two subjects with no Axis I diagnosis were recruited from the community. Twenty-five experienced SSP symptoms and 37 had no Axis II diagnosis. Prosaccades (saccades toward the target) and antisaccades (saccades made in the opposite direction of the target jump) were examined. Relatives, particularly those with SSP, had difficulties with the antisaccade task as suggested by higher error rates and longer antisaccade latency. Prosaccades were not different in relatives compared to the community subjects, although the effects of field were different in the two groups on some measures. The antisaccade latency was 'abnormal' in only a small proportion (1.6%) of community subjects compared to 14.9% of all relatives (35.3% of SSP relatives and 3.3% of non-SSP relatives). Relatives of patients with schizophrenia have deficits in aspects of the saccadic system involved in generating internally driven saccades and inhibition of unwanted saccades. These deficits implicate frontal ocular motor neuronal circuitry involving frontal cortical and basal ganglia areas. These deficits are associated with SSP symptoms, but not in the absence of a blood relationship to schizophrenia. The relatively high prevalence rate of the abnormality in at-risk subjects may have relevance for use of these measures in linkage analysis.

Relationship of awareness of dyskinesia in schizophrenia to insight into mental illness.

OBJECTIVE: The purpose of this study was to determine whether lack of awareness of motor dysfunction and lack of insight into mental dysfunction are related and to evaluate the longitudinal stability of lack of awareness of abnormal movements in schizophrenia. METHOD: Forty-three patients with schizophrenia and tardive dyskinesia participated in the study. The Scale of Unawareness of Mental Disorder was used to assess insight. All patients still meeting inclusion criteria after 2 years (N = 16) were reevaluated at follow-up. RESULTS: Twenty (46.5%) of the 43 patients had at least moderate unawareness of their tardive dyskinesia. Awareness of tardive dyskinesia was only modestly related to two of the five dimensions of insight into mental disorder assessed. Patients with the deficit syndrome showed significantly less awareness of their tardive dyskinesia than patients without the deficit syndrome. Lack of awareness of tardive dyskinesia was stable over time. CONCLUSIONS: Lack of awareness of tardive dyskinesia is a common feature in schizophrenia and is stable over time. Since patients are often unaware of dyskinesia, direct clinical examination is required to identify early tardive dyskinesia.

Substitution of immediate-release valproic acid for divalproex sodium for adult psychiatric inpatients.

In a prospective open-label study, the substitution of immediate-release valproic acid for divalproex sodium was evaluated in the treatment of 47 adult psychiatric inpatients who had been stabilized on divalproex for at least one month. After two weeks, no significant change in Clinical Global Impressions scale (CGI) scores or in seizure frequency occurred, and serum valproate concentrations decreased by 14.4 percent (p=.001). One patient was restarted on divalproex because of gastrointestinal complaints. Among the 19 patients remaining hospitalized at six months, mean CGI scores did not significantly change. Costs were reduced 83 percent; annual savings per patient was approximately $905. These preliminary results suggest that many chronic psychiatric inpatients stabilized on divalproex may be safely switched to valproic acid.