Learning whom not to trust across early and middle adolescence: A longitudinal neuroimaging study to trusting behavior involving an uncooperative other.

Longitudinal changes in trusting behavior across adolescence and their neural correlates were examined. Neural regions of interest (ROIs) included the medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (dACC), left anterior insula (AI), bilateral ventral striatum (VS), and right dorsal striatum (DS). Participants (wave 1 age: M = 12.90) played the investor in a Trust Game with an uncooperative trustee three times (1-year interval). Analyses included 77 primarily Dutch participants (33 females). Participants decreased their investments with wave. Furthermore, activity was heightened in mPFC, dACC, and DS during investment and repayment, and in right VS (investment) and AI (repayment). Finally, DS activity during repayment increased with wave. These findings highlight early-middle adolescence as an important period for developing sensitivity to uncooperative behavior.

The development of adolescent trust behavior.

Interpersonal trust shows developmental changes during adolescence. The current study used a longitudinal design to examine the development of trust behavior, the presence of gender differences in these developmental trajectories, and the association between individual differences in these developmental trajectories and perspective-taking abilities. The participants played a trust game with a hypothetical trustworthy partner and a trust game with a hypothetical untrustworthy partner in 3 consecutive years (Mage = 12.55 years, Mage = 13.54 years, and Mage = 14.54 years). Concerning the development of trust behavior, the results showed an age-related increase in initial trust behavior and indicated increasingly adaptive trust behavior with age during untrustworthy interactions, whereas no evidence was found for age-related changes in the adaptation of trust during trustworthy interactions. Gender differences were found for the development of initial trust behavior (with boys showing a stronger increase with age than girls), whereas no support was found for the presence of gender differences in the developmental trajectories of adaptive trust behavior during trustworthy and untrustworthy interactions. Furthermore, no evidence was found for perspective-taking abilities to explain individual differences in the development of initial trust behavior or in the development of adaptive trust behavior during trustworthy and untrustworthy interactions. The results provide evidence that, during adolescence initial trust behavior increased with age, more for boys than for girls, and that both boys and girls showed a stronger adaptive response to the untrustworthy partner but not to the trustworthy partner.

The effect of incorrect prior information on trust behavior in adolescents.

During adolescence, social cognition and the brain undergo major developments. Social interactions become more important, and adolescents must learn that not everyone can be trusted equally. Prior knowledge about the trustworthiness of an interaction partner may affect adolescents' expectations about the partner. However, the expectations based on prior knowledge can turn out to be incorrect, causing the need to respond adaptively during the interaction. In the current fMRI study, we investigated the effect of incorrect prior knowledge on adolescent trust behavior and on the neural processes of trust. Thirty-three adolescents (Mage = 17.2 years, SDage = 0.5 years) played two trust games with partners whose behavior was preprogrammed using an algorithm that modeled trustworthy behavior. Prior to the start of both games, participants received information suggesting that the partner in one game was untrustworthy (raising incorrect expectations) and the partner in the other game trustworthy (raising correct expectations). Results indicated that participants adapted their trust behavior following incorrect prior expectations. No evidence for a change in trust behavior was shown when prior expectations were correct. fMRI analyses revealed that when receiving the partner's response, activity in the dorsolateral prefrontal cortex and in the superior parietal gyrus were increased when participants had incorrect expectations about the partner compared to when participants had correct expectations. When making trust decisions, no significant differences in neural activity were found when comparing the two games. This study provides insight into how adolescent trust behavior and neural mechanisms are affected by expectations and provides an increased understanding of the factors that influence adolescent social interactions.

Quantitative examination of early diabetes by light-emitting diodes light-induced pupillary light reflex.

This study investigated the abnormal pupillary light reflex in patients with early diabetes mellitus (DM) without retinopathy by using a custom-made noninvasive portable pupilometer. The pupilometer recorded and analyzed the pupillary light reflex. Two light intensities, 0.2 cd and 1.2 cd, and four wavelengths of stimulus light-white (400 nm-800 nm), red (640 ± 5 nm), green (534 ± 5 nm), and blue (470 ± 5 nm)-were used to stimulate the pupil for 10 ms. The pupillary response was recorded for 15 s. A total of 40 healthy people and 40 people with DM without retinopathy participated in the experiment at the National Taiwan University Hospital. The mean and standard deviation of DM duration were 4.5 years and 3.9 years. Of the 16 indices, the duration that pupil restores from its minimum size to half of its resting size (DRP), maximum pupil restoration velocity (MRV), and average restoration velocity (ARV) exhibited the most significant differences between the healthy people and those with DM. Compared with healthy participants, DRP was 16.33% higher, and MRV and ARV were 17.45% and 4.58% lower, respectively, in those with DM. This might be attributable to the sympathetic nervous system (SNS) controlling the dilator muscle during the dark-adapted period and relaxing the pupil; the SNS had few degenerated nerve endings in people with DM. The three aforementioned indices might be used to evaluate the severity of autonomic neuropathy in early DM.

A case of GNE myopathy mimicking hereditary motor neuropathy.

A 36-year-old woman who presented with upper limb distal weakness since the age of 15 years, with gradual progression to the lower limbs, is reported. Hereditary motor neuropathy was initially suspected based on distal weakness and hyporeflexia; however, whole exome sequencing accidentally revealed a compound heterozygous variant in the GNE gene, and ultrasound revealed increased homogeneous echogenicity in the involved muscles, which is characteristic of myopathic changes. Muscle magnetic resonance imaging revealed fatty infiltration in all limb muscles, sparing the triceps brachii, vastus lateralis and vastus medialis. Muscle biopsy revealed intracytoplasmic rimmed vacuole, supporting the diagnosis of GNE myopathy.

The effect of bitter melon (Mormordica charantia) in patients with diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Mormordica charantia (bitter melon) has been investigated for lowering plasma glucose in patients with diabetes mellitus (DM). Previous data has offered inconclusive and inconsistent results about the benefits of bitter melon in patients with DM. Our current project aims to determine whether bitter melon has a favorable effect in lowering plasma glucose in patients with DM. METHODS: We searched PubMed, EMBASE and the Cochrane Library from inception to July 2013 without any language restrictions for randomized controlled trials (RCTs) evaluating bitter melon to no treatment in patients with type 1 or type 2 diabetes. Study selection, data extraction and validity of each article were independently assessed by two investigators. Articles were appraised for proper random sequence generation, allocation concealment, blinding, selective reporting and completeness of outcomes reporting to assess the risk for biases. The glycemic results of each RCT were analyzed to yield weighted mean differences (WMDs) and 95% confidence intervals (CIs). RESULTS: A total of four RCTs, each with 40-66 participants, followed between 4 and 12 weeks were identified in this meta-analysis. Overall risk of bias for each article included was determined to be unclear. In total, 208 participants with type 2 DM (mean age of 56.5 years) were evaluated. Compared with no treatment, bitter melon did not significantly lower A1C (WMD -0.13%, 95% CI -0.41 to 0.16) nor fasting plasma glucose (FPG) 47 (WMD 2.23 mg dl(-1), 95% CI -14.91 to 19.37). CONCLUSIONS: Bitter melon supplementation compared with no treatment did not show significant glycemic improvements on either A1c or FPG.Nutrition & Diabetes advance online publication, 15 December 2014; doi:10.1038/nutd.2014.42.

Long-term efficacy of miglustat in paediatric patients with Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease characterized by progressive neurological manifestations. Oral miglustat was first approved for the treatment of children and adults with NP-C in Europe in 2009. There are still relatively few published data on the long-term efficacy and safety of miglustat in patients with NP-C in clinical practice. We report the effects of up to 6 years of treatment with miglustat 100 mg t.i.d. in five children. Overall, 3/5 patients displayed progressive dysphagia before starting miglustat, and 4/5 showed marked cognitive and/or motor impairment. The mean age at treatment start was 11.6 years, and the median (range) duration of therapy so far is 4 (4.1 to 6.1) years. No treatment dose alterations were required, but therapy was interrupted for 1-3 months at least once in all patients due to supply issues. Swallowing function was stabilised during miglustat therapy, with no significant increase in Han dysphagia scale or aspiration-penetration index scores among four evaluable patients (p > 0.05). Scores on the mini-mental state examination indicated an improvement in cognitive function during the first 3-6 months of miglustat therapy, followed by stabilisation up to 5 years. Ambulatory function remained stable for at least the first 2 years of treatment in most patients, but there was a trend towards deterioration thereafter, possibly related to treatment interruptions. The safety/tolerability profile of miglustat was similar to previous clinical studies, although reports of gastrointestinal disturbances were rare. Overall, miglustat appeared to stabilise key parameters of neurological disease progression.

Stabilization of blood methylmalonic acid level in methylmalonic acidemia after liver transplantation.

Methylmalonic acidemia with complete mutase deficiency (mut(0) type) is an inborn error of metabolism with high mortality and morbidity. LT has been suggested to be a solution to this disease, but elevation of urinary and blood MMA was still observed after LT. In this study, we measured dry blood spot MMA and its precursor propionyl-carnitine (C3-carnitine) for mut(0) patients. The results revealed that when C3-carnitine rose during metabolic stress, MMA rose exponentially (up to 1000 micromol/L) in patients who did not undergo LT. In patients who underwent LT, MMA rose to 100-200 micromol/L when C3-carnitine reached 10-20 micromol/L. However, when C3-carnitine rose further to 40-50 micromol/L, MMA levels just stayed put. Therefore, LT stabilized blood MMA level, though there might be a threshold for blood MMA clearance by the donor liver. This finding should be critical to understand the long-term outcome for LT in methylmalonic acidemia.

Simultaneous detection of mitochondrial DNA depletion and single-exon deletion in the deoxyguanosine gene using array-based comparative genomic hybridisation.

Intragenic exonic deletions, which cannot be detected by direct DNA sequencing, are a common cause of Mendelian disease. Array-based comparative genomic hybridisation (aCGH) is now widely used for the clinical diagnosis of large chromosomal deletions, but not small deletions or analysis of the mitochondrial genome. An oligonucleotide-based microarray that provides high-density coverage of the entire mitochondrial genome and nuclear genes related to mitochondrial disorders has been developed. In this report, the case of an infant referred with tyrosinaemia on newborn screening who developed liver failure is presented. DNA sequencing revealed a heterozygous missense mutation (c.679G>A, p.E227K) in the deoxyguanosine gene (DGUOK). Oligonucleotide aCGH allowed simultaneous detection of an intragenic heterozygous deletion of exon 4 of DGUOK and mitochondrial DNA depletion in blood and liver. Screening of the parents' DNA samples indicated that the patient was compound heterozygous for these mutations. An older sibling who had died from liver failure was then retrospectively diagnosed with the same mutations. This report shows the clinical utility of this oligoarray in the detection of changes in DNA copy number in both the mitochondrial and nuclear genomes, thus greatly improving the molecular diagnosis of mitochondrial disorders caused by nuclear genes involved in mitochondrial DNA biosynthesis.

Deficiency of the carnitine transporter (OCTN2) with partial N-acetylglutamate synthase (NAGS) deficiency.

A patient with recurrent episodes of hyperammonaemia (highest ammonia level recorded 229 micromol/L, normal 9-33) leading to altered levels of consciousness was diagnosed with partial N-acetylglutamate synthase (NAGS) deficiency (9% residual activity) at age 5 years and was treated with ammonia-conjugating agents (Ucephan 250 mg/kg per day and later sodium phenylbutyrate 200-250 mg/kg per day) for 15 years. A chronically low serum carnitine level (pretreatment plasma free carnitine 4 nmol/L, normal 37 +/- 8 nmol/L; total carnitine 8 nmol/L, normal 46 +/- 10) was assumed to be secondary and was treated with supplemental carnitine (30-50 mg/kg per day). Hypoglycaemia (blood sugar 35 mg/dl, normal 70-100), cardiomegaly, and fatty liver were also noted at diagnosis. The patient died unexpectedly at age 20 years. In retrospect, it was learned that the patient had stopped his carnitine without medical consultation several weeks prior to his death. Additional molecular investigations identified two mutations (R254X and IVS3 + 1G > A) in the patient's OCTN2 (SLC22A5) gene, consistent with a diagnosis of primary carnitine deficiency due to carnitine transporter defect. R245X is a founder mutation in Southern Chinese populations. It is unknown whether the original NAGS deficiency was primary or secondary, but molecular analysis of the NAGS gene failed to identify mutations. Urea cycle enzyme expression may be affected by fatty acid suppression of an AP-1 binding site in the promoter enhancer region of the urea cycle gene. Regardless, it is clear that the NAGS abnormality has led to delay of recognition of the OCTN2 defect, and modified the clinical course in this patient.

Treatment of Niemann-Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year.

Niemann-Pick disease type C (NP-C) is a lipid storage disorder characterized by the accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system of certain cells in the central nervous system (CNS) and visceral organs. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Miglustat, a small iminosugar molecule approved for the treatment of Gaucher disease, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step in glycosphingolipid synthesis. The physicochemical properties of miglustat allow it to cross the blood-brain barrier and suggest possible benefits in lysosomal storage diseases affecting the CNS. Here, we present findings in two children with NP-C, aged 14 years (patient 1) and 9 years (patient 2), treated with miglustat for 1 year. Before treatment, patient 1 presented with severe difficulties in swallowing and walking, and patient 2 with problems mostly affecting communication and social interaction. Videofluoroscopic studies in patient 1 demonstrated a substantial improvement in swallowing by month 6 of treatment, and ambulation index measurements indicated improved walking. Mini Mental-State Examination (MMSE) assessments in patient 2 showed cognitive improvement by month 6, which was sustained up to month 12. Liver/spleen volume and plasma chitotriosidase activities were stabilized in both cases. There was no weight loss during treatment. Patient 1 experienced severe but self-limiting paresthesia, which was not associated with peripheral neuropathy. We conclude that miglustat can provide therapeutic benefits in CNS symptoms and allows stabilization of systemic disease in childhood-onset NP-C. Further follow-up is crucial to determine the long-term maintenance of these effects.

Contributions of bone maturation measurements to the differential diagnosis of neonatal transient hypothyroidism versus dyshormonogenetic congenital hypothyroidism.

AIM: To a) evaluate the contribution of bone maturation in the diagnosis of neonatal transient hypothyroidism versus dyshormonogenetic congenital hypothyroidism in full-term newborns, and b) use bone maturation to test the hypothesis that neonatal transient hypothyroidism is perinatal in onset. MATERIALS AND METHODS: The study included 20 patients with dyshormonogenetic and 43 with transient hypothyroidism. Thyroid function and measurements of the distal femoral epiphysis area, obtained at the time of first confirmatory diagnosis, were compared between the two groups. The epiphysis area in two control groups with normal thyroid function was also measured and compared with that in patients with transient hypothyroidism, at age 1-3 d (control A), or at the age when normal thyroid function was confirmed (control B). RESULTS: Mean epiphysis area was 0.04 cm2 in patients with dyshormonogenetic versus 0.22 cm2 in patients with transient hypothyroidism (p < 0.0001). An area <0.05 cm2 was limited to patients with dyshormonogenetic hypothyroidism. Conversely, a normal area (>0.2 cm2) was only observed in patients with transient hypothyroidism. Mean epiphysis areas in control A (0.20 cm2) and in patients with transient hypothyroidism were similar (p = 0.37), consistent with perinatal onset of transient hypothyroidism. Mean epiphysis area in control B (0.31 cm2) was significantly greater than in patients with transient hypothyroidism (p < 0.01). CONCLUSIONS: A short duration of hypothyroidism can significantly delay bone maturation. Examination of bone maturation at initial confirmatory evaluation yields important information pertaining to congenital hypothyroidism, not only to predict intellectual development, but also to evaluate the risk of dyshormonogenetic hypothyroidism.

Pre-existing tumor-sensitized T cells are essential for eradication of established tumors by IL-12 and cyclophosphamide plus IL-12.

The antitumor immune response activated by IL-12, especially by a combination of cyclophosphamide and IL-12 (Cy+IL-12), is clinically significant in certain experimental tumor models, in that a number of well-established (10-20 mm in diameter) s.c. tumors are completely eradicated. Furthermore, Cy+IL-12 treatment is also able to eradicate well-established grossly detectable experimental lung metastases and advanced ascites tumors. Despite the dramatic antitumor effects seen in some tumor models, Cy+IL-12 fails to induce regression of other established tumors. Characterization of tumor immunogenicity shows that all tumors responding to IL-12 and Cy+IL-12 treatments are immunogenic tumors, in that an antitumor immune response is detectable in tumor-bearing hosts upon tumor establishment. In contrast, none of the nonimmunogenic tumor responds to IL-12 and Cy+IL-12 treatments. Analysis of cellular requirements for successful tumor rejection through an adoptive cell transfer approach reveals that the presence of tumor-sensitized, but not naive, T cells is essential for tumor rejection by IL-12 and Cy+IL-12. Transfer of these tumor-sensitized T cells must be conducted before, but not after, IL-12 treatment in order for tumor rejection to occur. The requirement of sensitized T cells is also tumor specific. In mice bearing immunogenic tumors, the presence of pre-existing tumor-sensitized T cells is demonstrated by adoptive cell transfer experiments using purified spleen T cells from these mice. Results from our study show that Cy+IL-12-based immunotherapy of cancer may be highly effective and that pre-existing tumor-sensitized T cells are essential for the success of the therapy.

Factors associated with continued participation in mammography screening.

BACKGROUND: Relatively little is known about factors that predict ongoing participation in mammography screening at regular intervals. Members of managed care plans have access to this preventive service; yet, many still do not receive it routinely. METHODS: Using administrative data from HIP Health Plan of New York, a group model HMO, 24,215 women ages 50-80 years identified as having a screening mammogram during the baseline period were followed for 2 years to determine demographic and utilization factors that might be related to having a subsequent mammogram within the recommended time interval. RESULTS: Of the 24,215 women with an index mammogram, 71.8;pc had a subsequent screening mammogram within 2 years. Women ages 65-74 years and those with Medicare coverage had the highest mammogram rates among the age and coverage categories. Number of primary care and gynecology physician visits was strongly related to having a subsequent mammogram. The average (mean) time between index and subsequent mammogram was 14.4 months. CONCLUSION: The significance of health plan visits in subsequent mammography underscores the importance of physician-patient communication in a managed care plan and the integration of health plan members into the HMO delivery system. Even in this environment with equal access for all types of coverage, Medicaid members were less likely to receive this preventive service.

A randomized intervention to improve ongoing participation in mammography.

OBJECTIVE: To test the effectiveness of interventions intended to increase rates of regular breast cancer screening, according to recommended guidelines. STUDY DESIGN: A randomized controlled trial of 2 outreach interventions (a mail reminder and a telephone reminder plus appointment scheduling) compared with a routine publicity campaign to encourage continued participation in mammography screening. PARTICIPANTS AND METHODS: Participants were 1908 women aged 50 to 75 years continuously enrolled in a large group-model HMO during the study who underwent a bilateral mammogram during the first quarter of 1994 and no subsequent mammogram during the next 18 to 21 months. Data were obtained from health plan administrative data files supplemented by medical chart review. Women were randomly assigned to receive (1) a mail reminder, (2) a telephone reminder, or (3) routine publicity on mammography for all women. The outcome measure was a mammogram received after the intervention period and within 2 years of the initial mammogram date. RESULTS: Bivariate and multivariate statistical analyses showed that participation was significantly higher for women contacted by telephone than through routine publicity. Mail reminders were no more effective than a routine publicity campaign. Primary care physician and gynecologist visits increased the likelihood of a subsequent mammogram for women in all intervention groups. CONCLUSIONS: Telephone contact by regular health plan staff was more successful than publicity in encouraging continued participation in mammography screening in women enrolled in a group-model managed health care plan. Because mailings did not influence participation in mammography screening, health plans should be cautious about investing in member mailings without first evaluating their effectiveness in the context of existing outreach efforts.

Self-reported Papanicolaou smears and hysterectomies among women in the United States.

OBJECTIVE: To evaluate the potential overuse of Papanicolaou smears among women who have had a hysterectomy. METHODS: We analyzed two surveys of US women aged 18 years or older, the Behavioral Risk Factor Surveillance System (1992-1997) and the National Health Interview Survey (1993-1994), and one survey of US hospitals (National Hospital Discharge Survey, 1980-1997). We examined the number of women who have had a hysterectomy who had a recent (within 3 years) Papanicolaou smear. We also examined trends in the proportions and rates of hysterectomies by diagnoses and type of procedure that potentially could require a Papanicolaou smear. RESULTS: From the Behavioral Risk Factor Surveillance System, an estimated 21.2% of US women have had a hysterectomy. Among women who have had a hysterectomy, 78.3% had a recent Papanicolaou smear. Among those reporting no hysterectomy, 82.1% had a recent Papanicolaou smear. Estimates from the National Health Interview Survey were similar. From the National Hospital Discharge Survey, an estimated 6.7% to 15.4% of women with a history of hysterectomy would require a subsequent Papanicolaou smear because they had a diagnosis related to cervical neoplasia or because they had undergone a supracervical hysterectomy. For an estimated 10.6-11.6 million of the 12.5 million women who had a hysterectomy and a recent Papanicolaou smear, that test could be considered unnecessary. CONCLUSION: Continued Papanicolaou screening of women without an intact uteri may result in excessive use of resources in time and money with minimal impact on decreasing cervical cancer.

Race-specific results of Papanicolaou testing and the rate of cervical neoplasia in the National Breast and Cervical Cancer Early Detection Program, 1991-1998 (United States).

OBJECTIVE: To describe differences in cervical screening and biopsy results by race or ethnicity from women in the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). METHODS: We examined the percentage of abnormalities detected by Papanicolaou (Pap) tests and the rate of biopsy-diagnosed high-grade precancerous or cancerous lesions by racial or ethnic group. RESULTS: Almost half the 628,085 women screened were members of racial or ethnic minority groups. American Indian or Alaska Native women were more likely than others to report never having had a prior Pap test. American Indian or Alaska Native women had the highest proportion of abnormal Pap tests for first program screens (4.4%), followed by blacks (3.2%), whites (3.0%), Hispanics (2.7%), and Asians or Pacific Islanders (1.9%). Whites had the highest biopsy detection rate of high-grade lesions for first program screens (9.9 per 1000 Pap tests), followed by Hispanics (7.6), blacks (7.1), American Indians or Alaska Natives (6.7), and Asians or Pacific Islanders (5.4). CONCLUSIONS: This program provides important data on the prevalence of cervical neoplasia among diverse populations. Our findings that black women with a high-grade Pap test were less likely to get a work-up are disconcerting and merit further study and ultimate correction.