Brain imaging research: Does the science serve clinical practice?

Brain imaging represents a potent tool to characterize biomarkers, biological traits that are pathognomonic for specific neurological and neuropsychiatric disorders. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are imaging techniques used to identify alterations in the density and distribution of neurotransmitters, neuroreceptors, and transporters in specific regions of the brains of people with these disorders. Brain imaging research currently facilitates the elucidation of dysfunction of dopamine, serotonin, acetylcholine, and other substances in people with Alzheimer's and Parkinson's diseases, schizophrenia, alcoholism and other substance abuse disorders, attention deficit/hyperactivity disorder, and the syndromes of restless legs, Lesch-Nyhan, Rett, and Tourette. Thus, brain imaging research offers great potential for the diagnosis, treatment, prevention, and cure of neurological and neuropsychiatric disorders. Brain imaging research also facilitates new drug development and helps establish therapeutic doses of novel drugs. In particular, studies of specific receptors, such as the dopamine D₂ receptor, before and after the administration of doses of drugs that occupy these D₂ receptors, provide the means to determine receptor occupancy. For example, an optimal dose of D₂ antagonist antipsychotics produces occupancy of 65% to 80% of D₂ receptors, while a greater dose carries a risk of extrapyramidal side effects.     

A study of semantic treatment of three Chinese anomic patients

A treatment combining semantic feature analysis and semantic priming was carried out on three Cantonese-speaking brain-injured individuals with word-finding difficulties. Two of the participants with mild to moderate semantic impairment demonstrated significant progress on naming performance. Treatment effects also generalised to semantically related and unrelated untrained items. However, only one of these two participants was able to maintain the treatment gain for at least one month after the therapy was completed. The third patient with severe semantic deficits did not benefit from the intervention. The different outcomes of these participants to the same intervention were explained in terms of the nature of the treatment approach, the patients' underlying language deficits, and their level of cognitive abilities.     

Potassium Depolarization and Raised Calcium Induces α-Synuclein Aggregates

α-Synuclein is the key aggregating protein in Parkinson’s disease (PD), which is characterized by cytoplasmic protein inclusion bodies, termed Lewy bodies, thought to increase longevity of the host neuron by sequestering toxic soluble α-synuclein oligomers. Previous post-mortem studies have shown relative sparing of neurons in PD that are positive for the Ca²⁺ buffering protein, calbindin, and recent cell culture and in vitro studies have shown that α-synuclein aggregation can be induced by Ca²⁺. We hypothesized that depolarization with potassium resulting in raised Ca²⁺ in a PD cell culture model will lead to the formation of α-synuclein protein aggregates and that the intracellular Ca²⁺ buffer, BAPTA-AM, may suppress their formation. Live cell fluorescence microscopy was performed to monitor changes in intracellular free calcium in HEK293T, SH-SY5Y neuroblastoma or stably transfected HEK293T/α-synuclein cells. Raised intracellular free Ca²⁺ was consistently observed in cells treated with KCl, but not controls. Immunohistochemistry analysis on cells 48–72 h after K⁺ treatment revealed two subsets of cells with either large (>2 μm), perinuclear α-synuclein aggregates or multiple smaller (<2 μm), cytoplasmic accumulations. Cells pre-treated with varying concentrations of trimethadione (TMO), a calcium channel blocker, showed suppression of the Ca²⁺ transient following KCl treatment and no α-synuclein aggregates at TMO concentrations >5 μM. Quantitative analysis revealed a significant increase in the number of cells bearing α-synuclein cytoplasmic inclusions in both HEK293T/α-synuclein and SHSY-5Y cells when transient intracellular raised Ca²⁺ was induced (p = 0.001). BAPTA-AM pre-loading significantly suppressed α-synuclein aggregates (p = 0.001) and the intracellular free Ca²⁺ transient. This study indicates that raised intracellular Ca²⁺ mediated by K⁺ depolarization can lead to α-synuclein aggregation.     

Racial and ethnic disparities in the use of antipsychotic medication: a systematic review and meta-analysis

Objective

To conduct a systematic review and meta-analysis of published evidence on ethnic or racial disparities in the outpatient use versus non-use of antipsychotics and in the outpatient use of newer versus older antipsychotics.

Method

Electronic databases were searched for potentially relevant studies. Two independent reviewers conducted the review in three stages: title review, abstract review and full-text review. Included studies were those that: (a) report measures of disparity in the outpatient use of antipsychotic drugs in clearly defined racial or ethnic groups (b) have a primary focus on ethnic or racial disparities, and (c) have adjusted for factors known to influence medicine use. Odds ratios were pooled following the inverse-variance method of weighting effect sizes. I ² statistics were calculated to quantify the amount of variation that is likely due to heterogeneity between studies. Funnel plots were produced and Egger’s statistic was calculated to assess potential publication bias.

Results

No significant differences were found in the odds of using any antipsychotics among African Americans (OR = 1.01, CI = 0.99–1.02) compared with non-African Americans and among Latinos (OR = 0.98, CI = 0.86–1.13) compared with non-Latinos. Small to moderate but statistically non-significant disparities were also noted in other ethnic groups: Asians (OR = 1.10, CI = 0.88–1.36), Maoris (OR = 0.78, CI = 0.53–1.13) and Pacific Islanders (OR = 0.97, CI = 0.84–1.11). Among those who received antipsychotic medication, African Americans (OR = 0.62, CI = 0.50–0.78) and Latinos (OR = 0.77, CI = 0.73–0.81) appeared to have lower odds of receiving newer antipsychotics compared with non-African Americans and non-Latinos.

Conclusion

No significant ethnic disparities in the use versus non-use of any antipsychotics were observed, but, among those who received antipsychotic treatment, ethnic minorities were consistently less likely than non-ethnic minorities to be treated with newer antipsychotics.     

Anatomical surgical planning for oral and oropharyngeal primary carcinoma combined with adjuvant treatment where indicated is associated with improved local control

We aimed to find out whether surgical tactics that lead to a reduction in tumour-involved surgical margins also improve local control. We retrospectively reviewed a consecutive case series (n = 162) of previously untreated patients who had operations for squamous cell carcinoma (SCC) of the oral cavity or oropharynx. Extensive use was made of computed tomographic multiplanar imaging to plan primary resections. Nine patients (6%) had tumour at the resection margin. Local control at 36 months was 96%, disease-specific survival (DSS) was 86%, and overall survival (OS) was 77%. Carefully planned primary operation for SCC of the oral cavity and oropharynx to minimise tumour-involved margins combined with conventional adjuvant treatment where indicated, is associated with a high probability of local control and disease-specific survival.     

Primary and secondary nonresponse to infliximab: mechanisms and countermeasures

Introduction: Primary and secondary non-response to infliximab are common in patients with inflammatory bowel disease and remain a management challenge in clinical practice.

Areas covered: This article describes the epidemiology, mechanisms and risk factors for primary and secondary nonresponse to infliximab in patients with inflammatory bowel disease. Data on proactive and reactive therapeutic drug monitoring are examined in this review. An algorithm for evaluation and management of non-response to infliximab is provided. Preventative measures are also discussed. Relevant articles were identified after a literature search using PubMed. Search terms included ‘infliximab’, ‘loss of response’, ‘immunogenicity’, and ‘drug monitoring’. References of identified articles were also reviewed to identify additional references.

Expert opinion: A common cause for primary and secondary non-response include inadequate dosing of infliximab; inadequate dosing can be identified through assessment of drug and anti-drug antibody levels. Therapeutic drug monitoring should be done in patients losing response to infliximab. Use of drug monitoring proactively is still under debate.