Rethinking the association between overweight/obesity and ADHD in children: a longitudinal and psychosocial perspective.

OBJECTIVE: This study examines the association between attention-deficit/hyperactivity disorder (ADHD) and overweight/obesity in a large-scale longitudinal study of children, while controlling for a range of psychosocial factors. METHOD: Data were obtained from Growing Up in Ireland, a nationally representative and longitudinal study of approximately 6500 children who were assessed at 9 and 13 years of age. Body mass index (BMI) was determined using measured height and weight, ADHD status was determined by parent reports of professional diagnoses and ADHD symptoms were measured using the Strengths and Difficulties Questionnaire (SDQ). RESULTS: The associations between ADHD status, ADHD symptoms (SDQ) and BMI category at age 9 and 13 years were evaluated using logistic regression. Adjustments were made for child factors (sex, developmental coordination disorder, emotional symptoms, conduct problems, birth weight and exercise) and parental factors (socio-economic status, parental BMI, parental depression, and maternal smoking and alcohol use during pregnancy). Logistic regression indicated that ADHD status was not associated with BMI category at 9 or at 13 years of age, but children with ADHD at 9 years were significantly more likely to be overweight/obese at 13 years than those without ADHD. However, when other child and parental factors were adjusted for, ADHD status was no longer significantly associated with weight status. Female sex, low levels of exercise, overweight/obese parents and prenatal smoking during pregnancy consistently increased the odds of childhood overweight/obesity. CONCLUSIONS: While ADHD and overweight/obesity co-occur in general populations, this relationship is largely explained by a variety of psychosocial factors.

Sensory modulation and negative affect in children at familial risk of ADHD.

BACKGROUND/AIMS: Sensory modulation difficulties are commonly reported in patients with ADHD, however there has been little focus on the development of these difficulties in young children at a higher risk of later ADHD diagnosis. This study investigated whether children with a familial history of ADHD show greater sensory modulation difficulties. We also explored whether sensory modulation was linked to negative affectivity, which has been highlighted as a potential early marker of ADHD. METHODS: Parents of children under 6 years with a family history of ADHD (n = 65) and no family history (n = 122) completed questionnaires on sensory modulation and temperament. RESULTS: Children from families with ADHD were reported to display extreme patterns of hyperresponsiveness and hyporesponsiveness, relative to controls. No differences emerged for the sensory seeking domain. Some children within the high-risk group reported high scores across all three sensory modulation patterns. Regression analysis revealed that hyperresponsiveness predicted higher levels of negative affect. CONCLUSIONS/IMPLICATIONS: This study is the first to report greater sensory modulation difficulties in children at familial risk of ADHD. Future research should establish whether children with sensory modulation and temperament difficulties in early childhood are more vulnerable to developing ADHD.

An Exploration of Sleep and Family Factors in Young Children at Familial Risk for ADHD.

Objective: The aim of the current study was to examine relations between sleep problems and family factors and early markers of ADHD in young children with and without a familial risk for ADHD.Methods: Differences in sleep behavior and family functioning in children under 6 years with (n = 72) and without (n = 139) a familial risk for ADHD were investigated. The influence of family and sleep factors on the development of early temperament markers of ADHD (effortful control and negative affect) was explored. Parents/caregivers completed questionnaires on family functioning, child sleep behavior, and general regulatory behaviors.Results: A significant difference was observed between high-risk and low-risk groups for family functioning in the infant/toddler (<3 years) and preschool (>3 years) cohorts. Parents of infants/toddlers in the high-risk group reported poorer infant sleep. However, there were no sleep differences reported for the preschool cohort. Family functioning was found to predict effortful control, while sleep quality predicted negative affect.Conclusion: The results of this study highlight potential family and sleep issues for young children with a familial history of ADHD and the potential influence of these factors on early temperament markers of ADHD. Future research should explore these relations further in order to better establish whether early sleep and family interventions could mitigate later ADHD symptomatology.

Effects of a Six-Month Multi-Ingredient Nutrition Supplement Intervention of Omega-3 Polyunsaturated Fatty Acids, vitamin D, Resveratrol, and Whey Protein on Cognitive Function in Older Adults: A Randomised, Double-Blind, Controlled Trial.

OBJECTIVES: To investigate the impact of a six-month multi-ingredient nutrition supplement intervention (Smartfish®), containing omega-3 polyunsaturated fatty acids (PUFAs), vitamin D, resveratrol, and whey protein, on cognitive function in Irish older adults. DESIGN: Double-blind, randomised controlled trial (ClinicalTrials.gov: NCT02001831). A quantitative, mixed-model design was employed in which the dependent variable (cognitive function) was analysed with a between-subjects factor of group (placebo, intervention) and within-subjects factor of testing occasion (baseline, three-months, six-months). SETTING: Community-based intervention including assessments conducted at University College Dublin, Ireland. PARTICIPANTS: Thirty-seven community-dwelling older adults (68-83 years; mean (x̄)= 75.14 years; standard deviation (SD)= 3.64; 18 males) with normal cognitive function (>24 on the Mini Mental State Examination) were assigned to the placebo (n= 17) or intervention (n= 20) via a block randomisation procedure. INTERVENTION: Daily consumption for six-months of a 200mL liquid juice intervention comprising 3000mg omega-3 PUFAs [1500mg docosahexaenoic acid (DHA) and 1500mg eicosapentaenoic acid (EPA)], 10µg vitamin D3, 150mg resveratrol and 8g whey protein isolate. The placebo contained 200mL juice only. MEASUREMENTS: A standardised cognitive assessment battery was conducted at baseline and follow-ups. Individual test scores were z-transformed to generate composite scores grouped into cognitive domains: executive function, memory, attention and sensorimotor speed. Motor imagery accuracy and subjective awareness of cognitive failures variables were computed from raw scores. RESULTS: A hierarchical statistical approach was used to analyse the data; first, by examining overall cognitive function, then by domain, and then by individual test scores. Using mixed between-within subjects, analyses of variance (ANOVAs), no significant differences in overall cognitive function or composite cognitive domains were observed between groups over time. The only significant interaction was for Stroop Color-Word Time (p< 0.05). The intervention group demonstrated reduced task completion time at three- and six-month follow-ups, indicating enhanced performance. CONCLUSION: The present nutrition intervention encompassed a multi-ingredient approach targeted towards improving cognitive function, but overall had only a limited beneficial impact in the older adult sample investigated. Future investigations should seek to establish any potential clinical applications of such targeted interventions with longer durations of supplementation, or in populations with defined cognitive deficits.

The impact of caring for an adult with intellectual disability and psychiatric comorbidity on carer stress and psychological distress.

BACKGROUND: Given that carers of individuals with intellectual disability (ID) and carers of individuals with psychiatric disorders experience elevated levels of stress and psychological distress, carers of individuals with both ID and a comorbid psychiatric disorder are potentially at even greater risk for psychological difficulties. The aim of the present study was to investigate the psychological well-being of carers of adults with a dual diagnosis compared with carers of adults with intellectual disability alone. METHOD: Four-hundred and forty-two questionnaires were sent to four community services and seventy-five family carers of adults with intellectual disability responded. Psychological well-being of carers was assessed using the Questionnaire on Resources and Stress - Friedrich edition (QRS-F) and the General Health Questionnaire (GHQ). Comorbid psychopathology for their family member with ID was assessed using the Reiss Screen for Maladaptive Behaviour (RSMB). RESULTS: Twenty-four percent of the individuals with ID were reported to have comorbid psychopathology. Between-group analyses compared carers of people with ID and comorbid psychopathology to carers of people with ID alone. Regression analyses examined the relationship between psychopathology and other care-related variables to carer stress and psychological distress. Carers of people with ID and comorbid psychopathology were found to have significantly higher levels of stress and psychological distress than carers of people with ID alone. Autism was found to be the only significant predictor of both stress and psychological distress among measures of psychopathology. CONCLUSIONS: Additional comorbid psychopathology in individuals with intellectual disability has a significant impact on their carers' psychological well-being.

Characterizing adult attention-deficit/hyperactivity-disorder and comorbid borderline personality disorder: ADHD symptoms, psychopathology, cognitive functioning and psychosocial factors.

OBJECTIVE: To characterize adults with comorbid attention-deficit/hyperactivity-disorder (ADHD) and borderline personality disorder (BPD) with regard to ADHD symptoms, psychopathology, cognitive functioning and psychosocial factors. METHOD: A between-group design compared a group of individuals diagnosed with ADHD (n=40) with a group diagnosed with BPD and who also met the criteria for ADHD (ADHD+BPD) (n=20). RESULTS: Significant differences were observed for both childhood and current impulsivity symptoms, whereby ADHD+BPD exhibited increased impulsivity; no differences on self-report and cognitive measures of impulsivity were reported. The ADHD+BPD group scored significantly higher on measures of depression, anxiety and numerous other axis I and II conditions. The ADHD+BPD group scored significantly lower on most measures of intellectual functioning and attention, however largely not on those relating to response inhibition. Furthermore, group differences were observed for psychosocial factors, including education, substance use and criminal record. CONCLUSION: Comorbid ADHD and BPD is characterized by more symptoms of impulsivity, additional psychopathology, comparatively lower intellectual and attentional functioning and increased psychosocial difficulties.

Adults with attention deficit hyperactivity disorder: an investigation of age-related differences in behavioural symptoms, neuropsychological function and co-morbidity.

BACKGROUND: The outcomes of attention deficit hyperactivity disorder (ADHD) have been studied extensively in the first decades of life, but less is known about ADHD in adulthood. Hence we investigated cross-sectional age-related differences in behavioural symptoms, neuropsychological function and severity of co-morbid disorders within a clinically referred adult ADHD population. METHOD: We subdivided 439 referrals of individuals with ADHD (aged 16-50 years) into four groups based on decade of life and matched for childhood ADHD severity. We compared the groups on measures of self- and informant-rated current behavioural ADHD symptoms, neuropsychological performance, and self-rated co-morbid mood and anxiety symptoms. RESULTS: There was a significant age-related reduction in the severity of all ADHD symptoms based on informant-ratings. In contrast, according to self-ratings, inattentive symptoms increased with age. Neuropsychological function improved across age groups on measures of selective attention and response inhibition. There was a mild correlation between the severity of depression symptoms and increasing age. CONCLUSIONS: This observational study suggests that, in adulthood, ADHD symptoms as measured using informant-ratings and neuropsychological measures continue to improve with increasing age. However the subjective experience of people with ADHD is that their symptoms worsen. This dichotomy may be partially explained by the presence of co-morbid affective symptoms. The main limitation of the study is that it is cross-sectional rather than longitudinal, and the latter design would provide more conclusive evidence regarding age-related changes in an adult ADHD population.

Change in PASAT performance correlates with change in P3 ERP amplitude over a 12-month period in multiple sclerosis patients.

OBJECTIVE: To examine the correlation between the change in PASAT and the change in P3 event-related potentials (ERPs) over a 12-month period in multiple sclerosis (MS) patients, and to compare the 12-month change in the P3 ERP between MS patients and controls. METHODS: Forty-four subjects (27 MS patients, 17 controls) completed visual and auditory two-stimulus oddball and three-stimulus oddball tasks at Month 0 and Month 12. Data were recorded from a 128-scalp channel electroencephalography array. Data from scalp channels were converted into continuous interpolated images (incorporating the entire scalp and time). Amplitude, topographical differences and correlations were then tested using statistical parametric mapping. RESULTS: The change in visual and auditory P3a correlated significantly with the change in PASAT score (r=0.56, p<0.001 and r=0.48, p=0.003, respectively). Visual P3b and P3a showed greater decrease in 12 months in MS patients relative to controls. Visual P3b, auditory P3b and auditory P3a amplitudes had significantly decreased in MS patients after 12-month period. CONCLUSIONS: Change in visual and auditory P3a ERP amplitudes correlate with change in PASAT scores in MS patients. Visual modality is more sensitive to changes in P3 ERP amplitudes over 12-month period. SIGNIFICANCE: P3 ERPs may have utility in monitoring the change in cognitive functioning in MS.

A high-density ERP study reveals latency, amplitude, and topographical differences in multiple sclerosis patients versus controls.

OBJECTIVE: To quantify latency, amplitude and topographical differences in event-related potential (ERP) components between multiple sclerosis (MS) patients and controls and to compare ERP findings with results from the paced auditory serial addition test (PASAT). METHODS: Fifty-four subjects (17 relapsing remitting (RRMS) patients, 16 secondary progressive (SPMS) patients, and 21 controls) completed visual and auditory oddball tasks while data were recorded from 134 EEG channels. Latency and amplitude differences, calculated using composite mean amplitude measures, were tested using an ANOVA. Topographical differences were tested using statistical parametric mapping (SPM). RESULTS: In the visual modality, P2, P3 amplitudes and N2 latency were significantly different across groups. In the auditory modality, P2, N2, and P3 latencies and N1 amplitude were significantly different across groups. There were no significant differences between RRMS and SPMS patients on any ERP component. There were topographical differences between MS patients and controls for both early and late components for the visual modality, but only in the early components for the auditory modality. PASAT score correlated significantly with auditory P3 latency for MS patients. CONCLUSIONS: There were significant ERP differences between MS patients and controls. SIGNIFICANCE: The present study indicated that both early sensory and later cognitive ERP components are impaired in MS patients relative to controls.

ADHD symptom presentation and trajectory in adults with borderline and mild intellectual disability.

BACKGROUND: This study examined symptoms and lifetime course of Attention Deficit Hyperactivity Disorder (ADHD) in adults with borderline and mild Intellectual Disability (ID). METHOD: A total of 48 adults with ID and ADHD were compared with 221 adults with ADHD without ID using the informant Barkley scale for childhood and adulthood symptoms. RESULTS: The ADHD/ID group presented with greater severity of (adult and childhood) symptoms compared with the non-ID group. For the ADHD/non-ID group, most symptoms improved significantly from childhood to adulthood, whereas only two symptoms changed significantly for the ID group. Principal component analysis revealed scattered loading of different items into five components for the ADHD/ID group that were not consistent with the classic clusters of inattentive, hyperactive and impulsive symptoms. A negative correlation was found between severity of symptoms and IQ. CONCLUSIONS: ADHD in adults with ID may have a more severe presentation and an uneven and less favourable pattern of improvement across the lifespan in comparison with adults without ID.

Social and emotional functioning following bilateral and unilateral neurosurgical prefrontal cortex lesions.

Alterations in emotional and social functioning such as impaired ability to recognize emotions in others, a lack of empathy and poor insight have commonly been reported following prefrontal cortex damage. This study sought to investigate the subtleties of such difficulties in 34 individuals with discrete unilateral and bilateral neurosurgical lesions encroaching on the orbitofrontal, medial, and dorsolateral regions of the prefrontal cortex. A specifically devised self- and informant report measure, the social-emotional questionnaire was used to examine five factors of functioning: emotion recognition; empathy; social conformity; antisocial behaviour; and sociability. There were some specific significant differences between the clinical and control groups' informant-ratings in certain domains of social and emotional functioning. Individuals with damage involving the orbitofrontal region were reported to display elevated levels of antisocial behaviour. Individuals with bilateral orbitofrontal lesions were rated as showing significantly reduced social and emotional functioning in comparison with individuals with unilateral lesions and controls. In addition, individuals with bilateral lesions had significantly less insight overall regarding their social-emotional abilities. The right unilateral lesion group showed significantly less insight into their abilities to recognize emotion in others in comparison with the left unilateral group. In conclusion, these results suggest that specific social-emotional and insight deficits may form separate constellations of impairment. The findings also indicate that marked changes in social and emotional functioning are more likely following bilateral damage, and unilateral lesions do not inevitably lead to impairments.

Neuropsychological characteristics of adults with comorbid ADHD and borderline/mild intellectual disability.

This study aimed to characterise the neuropsychological functioning of adults with comorbid attention deficit hyperactivity disorder (ADHD) and intellectual disability. Individuals with ADHD and mild-borderline range intelligence (N=59) and individuals with ADHD and normal intellectual functioning (N=95) were compared on attentional and response inhibition tasks. The comorbid group had significantly lower scores on the majority of measures in comparison with the ADHD alone group. These differences remained significant after co-varying for level of intellectual functioning for variables measuring selective attention and errors of commission during sustained attention. This suggests that individuals with comorbid ADHD and intellectual disability may be vulnerable to a 'double deficit' from both disorders in certain aspects of cognitive functioning.

A prospective study of the effects of anterior temporal lobectomy on emotion recognition and theory of mind.

Nineteen patients evaluated facial emotional expressions and performed 'theory of mind' reasoning tasks before and after a temporal lobectomy for medically intractable epilepsy, and results were compared with the performance of 19 healthy controls. Following operation, which in all cases resulted in excision of the entire amygdala, there was no change in the ability to reason about the mental states of others, in line with the suggestion that the anterior temporal lobe is not necessary for theory of mind reasoning. However, following a left anterior temporal lobectomy, patients evaluated fearful facial expressions in a more normative manner. This may reflect the excision of a 'hyper-excitable' amygdala which pre-operatively misinterprets fearful expressions as containing blends of other emotions. Alternatively the results may represent an improvement in function of the right amygdala following the excision of a noxious inhibitory epileptogenic focus on the left. The finding complements earlier demonstrations that damage to the right amygdala is associated with impaired processing of fear; amelioration of right amygdala function may conversely be associated with an improvement.

Differential effects of lesions of the amygdala and prefrontal cortex on recognizing facial expressions of complex emotions.

Humans can detect facial expressions of both simple, basic emotions and expressions reflecting more complex states of mind. The latter includes emotional expressions that regulate social interactions ("social expressions" such as looking hostile or friendly) and expressions that reflect the inner thought state of others ("cognitive expressions" such as looking pensive). To explore the neural substrate of this skill, we examined performance on a test of detection of such complex expressions in patients with lesions of the temporal lobe (n = 54) or frontal lobe (n = 31). Of the temporal group, 18 had unilateral focal lesions of the amygdala and of the frontal group, 14 patients had unilateral lesions of the ventromedial prefrontal cortex-two regions held to be pivotal in mediating social cognitive skills. Damage to either the left or right amygdala was associated with impairment in the recognition of both social and cognitive expressions, despite an intact ability to extract information relating to invariant physical attributes. Lesions to all of the right prefrontal cortex-not just the ventromedial portions-led to a specific deficit in recognizing complex social expressions with a negative valence. The deficit in the group with right prefrontal cortical damage may contribute to the disturbances in social behavior associated with such lesions. The results also suggest that the amygdala has a role in processing a wide range of emotional expressions.

The impact of early and late damage to the human amygdala on 'theory of mind' reasoning.

There is a burgeoning interest in the neural basis of the ability to attribute mental states to others; a capacity referred to as 'theory of mind' (ToM). We examined the effects of lesions of the amygdala which arise at different stages of development on this key aspect of social cognition. Tests of ToM, executive and general neuropsychological function were given to subjects with lesions of the amygdala arising congenitally or in early childhood ('early damage', n = 15), subjects who acquired damage to the amygdala in adulthood ('late damage' n = 11) and matched clinical (n = 14) and healthy comparison groups (n = 38). Subjects with early damage to the amygdala, particularly if the lesion was associated with childhood onset of seizures, were impaired relative to all other groups on more advanced tests of ToM reasoning, such as detecting tactless or ironic comments or interpreting non-literal utterances. These deficits held for subjects with either left or right early amygdala damage and encompassed the understanding of both the beliefs and emotional states of others. In contrast, subjects who acquired damage to the amygdala in adulthood (usually as part of an anterior temporal lobectomy) were not impaired in ToM reasoning relative to both clinical and healthy controls, supporting the position that the amygdala is not part of the neural circuitry mediating the 'on-line' performance of ToM reasoning. In line with theories which claim that ToM is an independent faculty of cognition, we found that the pattern of results held after co-varying for measures of executive function, memory and general intellectual functioning. We discuss the results in the light of recent theories which link early developmental insults to the amygdala with the ToM impairments which are thought to be a core neurocognitive deficit found in disorders such as autism. We conclude that the amygdala may play an important role in the neural systems supporting the normal development of ToM reasoning.

Reward-related reversal learning after surgical excisions in orbito-frontal or dorsolateral prefrontal cortex in humans.

Neurophysiological studies in primates and neuroimaging studies in humans suggest that the orbito-frontal cortex is involved in representing the reward value of stimuli and in the rapid learning and relearning of associations between visual stimuli and rewarding or punishing outcomes. In the present study, we tested patients with circumscribed surgical lesions in different regions of the frontal lobe on a new visual discrimination reversal test, which, in an fMRI study (O'Doherty, Kringelbach, Rolls, Hornak, & Andrews, 2001), produced bilateral orbito-frontal cortex activation in normal subjects. In this task, touching one of two simultaneously presented patterns produced reward or loss of imaginary money delivered on a probabilistic basis to minimize the usefulness of verbal strategies. A number of types of feedback were present on the screen. The main result was that the group of patients with bilateral orbito-frontal cortex lesions were severely impaired at the reversal task, in that they accumulated less money. These patients often failed to switch their choice of stimulus after a large loss and often did switch their choice although they had just received a reward. The investigation showed that bilateral lesions were required for this deficit, since patients with unilateral orbito-frontal cortex (or medial prefrontal cortex) lesions were not impaired in the probabilistic reversal task. The task ruled out a simple motor disinhibition as an explanation of the deficit in the bilateral orbito-frontal cortex patients, in that the patients were required to choose one of two stimuli on each trial. A comparison group of patients with dorsolateral prefrontal cortex lesions was in some cases able to do the task, and in other cases, was impaired. Posttest debriefing showed that all the dorsolateral prefrontal patients who were impaired at the task had failed to pay attention to the crucial feedback provided on the screen after each trial about the amount won or lost on each trial. In contrast, all dorsolateral patients who paid attention to this crucial feedback performed normally on the reversal task. Further, it was confirmed that the bilateral orbito-frontal cortex patients had also paid attention to this crucial feedback, but in contrast had still performed poorly at the task. The results thus show that the orbital prefrontal cortex is required bilaterally for monitoring changes in the reward value of stimuli and using this to guide behavior in the task; whereas the dorsolateral prefrontal cortex, if it produces deficits in the task, does so for reasons related to executive functions, such as the control of attention. Thus, the ability to determine which information is relevant when making a choice of pattern can be disrupted by a dorsolateral lesion on either side, whereas the ability to use this information to guide behavior is not disrupted by a unilateral lesion in either the left or the right orbito-frontal cortex, but is severely impaired by a bilateral lesion in this region. Because both abilities are important in many of the tasks and decisions that arise in the course of daily life, the present results are relevant to understanding the difficulties faced by patients after surgical excisions in different frontal brain regions.

Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices.

To analyse the functions of different parts of the prefrontal cortex in emotion, patients with different prefrontal surgical excisions were compared on four measures of emotion: voice and face emotional expression identification, social behaviour, and the subjective experience of emotion. Some patients with bilateral lesions of the orbitofrontal cortex (OFC) had deficits in voice and face expression identification, and the group had impairments in social behaviour and significant changes in their subjective emotional state. Some patients with unilateral damage restricted to the OFC also had deficits in voice expression identification, and the group did not have significant changes in social behaviour or in their subjective emotional state. Patients with unilateral lesions of the antero-ventral part of the anterior cingulate cortex (ACC) and/or medial Brodmann area (BA) 9 were, in some cases, impaired on voice and face expression identification, had some change in social behaviour, and had significant changes in their subjective emotional state. Patients with unilateral lesions of the OFC and of the ACC and/or medial BA 9 were, in some cases, impaired on voice and face expression identification, had some changes in social behaviour, and had significant changes in their subjective emotional state. Patients with dorsolateral prefrontal cortex lesions or with medial lesions outside ACC and medial BA 9 areas (dorsolateral/other medial group) were unimpaired on any of these measures of emotion. In all cases in which voice expression identification was impaired, there were no deficits in control tests of the discrimination of unfamiliar voices and the recognition of environmental sounds. Thus bilateral or unilateral lesions circumscribed surgically within the OFC can impair emotional voice and/or face expression identification, but significant changes in social behaviour and in subjective emotional state are related to bilateral lesions. Importantly, unilateral lesions of the ACC (including some of medial BA 9) can produce voice and/or face expression identification deficits, and marked changes in subjective emotional state. These findings with surgically circumscribed lesions show that within the prefrontal cortex, both the OFC and the ACC/medial BA 9 region are involved in a number of aspects of emotion in humans including emotion identification, social behaviour and subjective emotional state, and that the dorsolateral prefrontal areas are not involved in emotion in these ways.

Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: a phase II trial of the Minnie Pearl Cancer Research Network.

The purpose of this study was to evaluate the activity of single-agent gemcitabine in previously treated patients with carcinoma of unknown primary site. Between January 1997 and October 1998, 39 patients were enrolled in this multicenter Phase II trial performed in the Minnie Pearl Cancer Research Network. Twenty-seven patients (69%) had adenocarcinoma or poorly differentiated adenocarcinoma; 35 patients (90%) had previously received treatment with chemotherapy regimens containing both a platinum agent and a taxane. Only 21% of patients had ever responded to previous therapy. Gemcitabine 1000 mg/m2 was administered intravenously on days 1, 8, and 15 of each 28-day course. Three of 36 evaluable patients (8%) had partial responses, and 9 patients (25%) had minor responses or stable disease with improved symptoms. The median time to progression for patients with partial responses or stable disease/improved symptoms was 5 months. Treatment was well tolerated, with uncommon grade 3 or 4 toxicity. Gemcitabine produced a low objective response rate in this refractory patient population, although approximately one-third of patients experienced symptomatic improvement. Treatment with gemcitabine was well tolerated. Because gemcitabine has activity against a variety of adenocarcinomas, further evaluation of this agent as part of first-line therapy for patients with carcinoma of unknown primary site is appropriate.

Simultaneous CT-13C and VT-15N chemical shift labelling: application to 3D NOESY-CH3NH and 3D 13C,15N HSQC-NOESY-CH3NH.

Based on the HSQC scheme, we have designed a 2D heterocorrelated experiment which combines constant time (CT) 13C and variable time (VT) 15N chemical shift labelling. Although applicable to all carbons, this mode is particularly suitable for simultaneous recording of methyl-carbon and nitrogen chemical shifts at high digital resolution. The methyl carbon magnetisation is in the transverse plane during the whole CT period (1/J(CC) = 28.6 ms). The magnetisation originating from NH protons is initially stored in the 2HzNz state, then prior to the VT chemical shift labelling period is converted into 2HzNy coherence. The VT -15N mode eliminates the effect of 1J(N,CO) and 1,2J(N,CA) coupling constants without the need for band-selective carbon pulses. An optional editing procedure is incorporated which eliminates signals from CH2 groups, thus removing any potential overlap with the CH3 signals. The CT-13CH3,VT-15N HSQC building block is used to construct two 3D experiments: 3D NOESY-CH3NH and 3D 13C,15N HSQC-NOESY-CH3NH. Combined use of these experiments yields proton and heteronuclear chemical shifts for moieties experiencing NOEs with CH3 and NH protons. These NOE interactions are resolved as a consequence of the high digital resolution in the carbon and nitrogen chemical shifts of CH3 and NH groups, respectively. The techniques are illustrated using a double labelled sample of the CH domain from calponin.