Clinical responses with T lymphocytes targeting malignancy-associated κ light chains

BACKGROUND. Treatment of B cell malignancies with adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan–B cell marker, also depletes normal B cells and causes severe hypogammaglobulinemia. Here, we developed a strategy to target B cell malignancies more selectively by taking advantage of B cell light Ig chain restriction. We generated a CAR that is specific for the κ light chain (κ.CAR) and therefore recognizes κ-restricted cells and spares the normal B cells expressing the nontargeted λ light chain, thus potentially minimizing humoral immunity impairment.METHODS. We conducted a phase 1 clinical trial and treated 16 patients with relapsed or refractory κ⁺ non-Hodgkin lymphoma/chronic lymphocytic leukemia (NHL/CLL) or multiple myeloma (MM) with autologous T cells genetically modified to express κ.CAR (κ.CARTs). Other treatments were discontinued in 11 of the 16 patients at least 4 weeks prior to T cell infusion. Six patients without lymphopenia received 12.5 mg/kg cyclophosphamide 4 days before κ.CART infusion (0.2 × 10⁸ to 2 × 10⁸ κ.CARTs/m²). No other lymphodepletion was used.RESULTS. κ.CART expansion peaked 1–2 weeks after infusion, and cells remained detectable for more than 6 weeks. Of 9 patients with relapsed NHL or CLL, 2 entered complete remission after 2 and 3 infusions of κ.CARTs, and 1 had a partial response. Of 7 patients with MM, 4 had stable disease lasting 2–17 months. No toxicities attributable to κ.CARTs were observed.CONCLUSION. κ.CART infusion is feasible and safe and can lead to complete clinical responses.TRIAL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00881920","term_id":"NCT00881920"}}NCT00881920.FUNDING. National Cancer Institute (NCI) grants 3P50CA126752 and 5P30CA125123 and Leukemia and Lymphoma Society (LLS) Specialized Centers of Research (SCOR) grant 7018.     

Barriers and facilitators to diabetes self‐management: Perspectives of older community dwellers and health professionals in China

Little is known about self‐management among people with Type 2 diabetes living in mainland China. Understanding the experiences of this target population is needed to provide socioculturally relevant education to effectively promote self‐management. The aim of this study was to explore perceived barriers and facilitators to diabetes self‐management for both older community dwellers and health professionals in China. Four focus groups, two for older people with diabetes and two for health professionals, were conducted. All participants were purposively sampled from two communities in Shanghai, China. Six barriers were identified: overdependence on but dislike of western medicine, family role expectations, cuisine culture, lack of trustworthy information sources, deficits in communication between clients and health professionals, and restriction of reimbursement regulations. Facilitators included family and peer support, good relationships with health professionals, simple and practical instruction and a favourable community environment. The findings provide valuable information for diabetes self‐management intervention development in China, and have implications for programmes tailored to populations in similar sociocultural circumstances.     

Frontal white matter biochemical abnormalities in late-life major depression detected with proton magnetic resonance spectroscopy

OBJECTIVE: Neuroanatomical abnormalities have been identified in patients with late-life mood disorders by using magnetic resonance imaging. This study examined the biochemical correlates of late-life major depression in the frontal gray and white matter by using single-voxel proton spectroscopy. METHOD: Twenty elderly patients with major depression and 18 comparison subjects similar in age and gender to the patients were scanned on a 1.5-T magnetic resonance scanner with head coil. Voxels were placed in the left dorsolateral white matter and bilaterally in the anterior cingulate gray matter. Absolute levels of N-acetylaspartate, choline, myo-inositol, and creatine were estimated with the LC-Model algorithm. Ratios of metabolite to creatine levels were computed from the absolute values. RESULTS: myo-Inositol/creatine and choline/creatine ratios were significantly higher in the frontal white matter in the major depression group than in the comparison group. The groups had no significant differences in the metabolite ratios in the gray matter. CONCLUSIONS: Biochemical changes in the white matter may provide some of the neurobiological substrates to late-life major depression.     

Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BP_ND) in patients with ADHD and to assess associations of SERT BP_ND between the brain regions. 25 medication‐free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [¹¹C]DASB. SERT BP_ND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BP_ND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BP_ND and age in the ADHD and the healthy control group, we confirmed an age‐related decline in brain SERT binding in the thalamus and insula (R² = 0.284, R² = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792–802, 2017. © 2016 Wiley Periodicals, Inc.     

Changes in spectroscopic biomarkers after transcranial direct current stimulation in children with perinatal stroke

Background

Perinatal stroke causes lifelong motor disability, affecting independence and quality of life. Non-invasive neuromodulation interventions such as transcranial direct current stimulation (tDCS) combined with intensive therapy may improve motor function in adult stroke hemiparesis but is under-explored in children. Measuring cortical metabolites with proton magnetic resonance spectroscopy (MRS) can inform cortical neurobiology in perinatal stroke but how these change with neuromodulation is yet to be explored.

Gene therapy in epilepsy

Results from animal models suggest gene therapy is a promising new approach for the treatment of epilepsy. Several candidate genes such as neuropeptide Y and galanin have been demonstrated in preclinical studies to have a positive effect on seizure activity. For a successful gene therapy-based treatment, efficient delivery of a transgene to target neurons is also essential. To this end, advances have been made in the areas of cell transplantation and in the development of recombinant viral vectors for gene delivery. Recombinant adeno-associated viral (rAAV) vectors in particular show promise for gene therapy of neurological disorders due to their neuronal tropism, lack of toxicity, and stable persistence in neurons, which results in robust, long-term expression of the transgene. rAAV vectors have been recently used in phase I clinical trials of Parkinson's disease with an excellent safety profile.
Prior to commencement of phase I trials for gene therapy of epilepsy, further preclinical studies are ongoing including evaluation of the therapeutic benefit in chronic models of epileptogenesis, as well as assessment of safety in toxicological studies.     

The development and testing of an algorithm for diagnosis of active labour in primiparous women

OBJECTIVES: to describe the development and testing of an algorithm for diagnosis of active labour in primiparous women. DESIGN: qualitative and quantitative methods were used. A literature review was first conducted to identify the key cues for inclusion in the algorithm. Focus groups of midwives were then conducted to assess content validity, finally a vignette study assessed the inter-rater reliability of the algorithm. SETTING: midwives from two study sites were invited to participate. Data were collected during 2002 and 2003. PARTICIPANTS: midwives from the first site took part in the focus groups (n=13), completed vignettes (n=19), or both. Midwives from the second site then completed vignettes (n=17). FINDINGS: an algorithm, developed from the key informational cues reported in the literature, was validated in relation to content validity by the findings from the focus groups. Inter-rater reliability was tested using vignettes of admission case histories and was found to be moderate in the first test (K=0.45). However, after modifying the algorithm the kappa score was 0.86, indicating a high level of agreement. KEY CONCLUSIONS: diagnosis of labour may be straightforward on paper but is frequently problematic in practice. This may be because the diagnosis of labour is made in a high pressured environment where conflicting pressures of workload, limited resources and emotional pressures add to the complexity of the judgement. IMPLICATIONS FOR PRACTICE: we offer a valid and reliable decision-support tool as an aid for diagnosis of labour. The evaluation of the implementation of this tool is under way and will determine whether it is effective in reducing unnecessary admissions and improving clinical outcomes for women.     

Maternal blood pressure in pregnancy and stillbirth: a case-control study of third-trimester stillbirth

An immense body of literature on the effects of hypertension on perinatal morbidity and mortality exists, but only a handful of studies have reported adverse outcomes associated with low maternal blood pressure during pregnancy. This study aimed to investigate if there is an increased risk of fetal loss associated with hypotension during pregnancy. A matched case-control study of stillbirth and maternal blood pressure was conducted in which maternal blood pressures for a total of 124 pregnancies culminating in stillbirth were compared with maternal blood pressures in 243 (matched) pregnancies resulting in a liveborn infant. Women whose diastolic blood pressures fell in a borderline range (60 to 70 mm Hg) were consistently at greater risk of stillbirth relative to normotensive pregnancies. Women who had three or more mean arterial pressure values < or = 83 mm Hg during the course of their pregnancy were at nearly twice the risk of stillbirth (odds ratio 1.78; 95% confidence interval [CI] 1.06 to 2.99; P = 0.03). Systolic hypotension was not significantly associated with stillbirth, but proportionately more control women were noted to have systolic hypertension (SBP > or = 130 mmHg) than cases, and the adjusted odds of stillbirth in women who were hypertensive at either their first or last antenatal visit or whose antenatal average SBP was > or = 130 mm Hg were all very close to 0.4 (95% CI 0.37 to 0.43; P = 0.02 to 0.03) relative to normotensives. We concluded that maternal hypotension, particularly borderline hypotension, may be a contributory risk factor for stillbirth. Women with hypertension in pregnancy may now be at a decreased risk of stillbirth as a result of the close care and treatment they receive.