Paul A. Thompson

Comprehensive Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease

Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, duplication of PKD1, and a high level of unclassified variants (UCV). Present mutation detection levels are 60 to 70%, and PKD1 and PKD2 UCV have not been systematically classified. This study analyzed the uniquely characterized Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by molecular analysis. A cohort of 202 probands was screened by denaturing HPLC, followed by direct sequencing using a clinical test of 121 with no definite mutation (plus controls). A subset was also screened for larger deletions, and reverse transcription-PCR was used to test abnormal splicing. Definite mutations were identified in 127 (62.9%) probands, and all UCV were assessed for their potential pathogenicity. The Grantham Matrix Score was used to score the significance of the substitution and the conservation of the residue in orthologs and defined domains. The likelihood for aberrant splicing and contextual information about the UCV within the patient (including segregation analysis) was used in combination to define a variant score. From this analysis, 44 missense plus two atypical splicing and seven small in-frame changes were defined as probably pathogenic and assigned to a mutation group. Mutations were thus defined in 180 (89.1%) probands: 153 (85.0%) PKD1 and 27 (15.0%) PKD2. The majority were unique to a single family, but recurrent mutations accounted for 30.0% of the total. A total of 190 polymorphic variants were identified in PKD1 (average of 10.1 per patient) and eight in PKD2. Although nondefinite mutation data must be treated with care in the clinical setting, this study shows the potential for molecular diagnostics in ADPKD that is likely to become increasingly important as therapies become available.

Retention of upper limb function in stroke survivors who have received constraint-induced movement therapy: the EXCITE randomised trial

BACKGROUND The aim of constraint-induced movement therapy (CIMT) is to promote use of a limb that is functionally impaired after a stroke. In one form of CIMT to treat upper limb impairment, use of the less severely affected arm is restricted for many hours each weekday over 2 consecutive weeks. The EXCITE trial has previously shown the efficacy of this intervention for patients 3-9 months poststroke who were followed-up for the next 12 months. We assessed the retention of improvements 24 months after the intervention. METHODS In the EXCITE trial, 106 of 222 participants who had mild to moderate poststroke impairments were randomly assigned to receive CIMT rather than usual and customary care. We assessed this group of patients every 4 months for the primary outcome measure of impaired upper limb function, as measured with the Wolf motor function test (WMFT) and the motor activity log (MAL). Health-related quality of life, measured with the stroke impact scale (SIS), was a secondary outcome measure. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT00057018. FINDINGS The effects at 24 months after treatment did not decline from those at 12 months for time taken to complete the WMFT (-0.32 s, 95% CI -3.70 to 3.06), for weight lifted in the WMFT (-1.39 kg, -2.74 to -0.04), for WMFT grip strength (-4.39 kg, -6.91 to -1.86), for amount of use in the MAL (-0.17, -0.38 to 0.04), or for how well the limb was used in the MAL (-0.14, -0.34 to 0.06). The additional changes were in the direction of increased therapeutic effect. For the strength components of the WMFT, p<0.0001. INTERPRETATION Patients who have mild to moderate impairments 3-9 months poststroke have substantial improvement in functional use of the paretic upper limb and quality of life 2 years after a 2-week CIMT intervention. Thus, this intervention has persistent benefits.

The EXCITE trial: attributes of the Wolf Motor Function Test in patients with subacute stroke.

The Wolf Motor Function Test (WMFT) has been used in rehabilitation studies of chronic stroke patients, but until now its psychometric properties have not been evaluated in patients with subacute stroke. Two hundred twenty-nine participants with subacute stroke (3-9 months postinjury) at 7 research sites met inclusion criteria for the EXCITE Trial and were randomized into immediate or delayed (by 1 year) constraint-induced movement therapy treatment. All evaluations were undertaken by assessors standardized in the administration of the WMFT and masked to treatment designation. Participants were also assessed using the Fugl Meyer Motor Assessment (FMA). Delayed group members had measurements repeated 2 weeks following baseline assessment to determine learning or exposure effects. The results demonstrate that the WMFT differentiated higher from lower functioning participants across sites; scores were uninfluenced by hand dominance or affected side. Women exhibited slower performance times than men. The Functional Ability scale (FAS) portion of the WMFT also revealed lower scores among lower functioning participants and women. Minimal changes were observed after repeating the WMFT among delayed group participants 2 weeks later. The FMA revealed similar results when the total group was divided into higher and lower functional levels at its midpoint score of 33. The WMFT discriminates higher from lower functioning participants tested across research sites. Comparable findings using the FMA support the criterion validity of the WMFT.

Magnetic Resonance Imaging Evaluation of Hepatic Cysts in Early Autosomal-Dominant Polycystic Kidney Disease: The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease Cohort

The objective of this study was to investigate the prevalence of hepatic cysts by age and gender in patients with early autosomal-dominant polycystic kidney disease (ADPKD) and to determine whether hepatic cyst volume is related to renal and renal cyst volumes by using magnetic resonance imaging (MRI). A total of 230 patients with ADPKD (94 men and 136 women) who were aged 15 to 46 yr and had relatively preserved renal function were studied. MRI images of the kidney and liver were obtained to measure renal, renal cyst, and hepatic cyst volumes. These volume measurements and hepatic cyst prevalence were compared in all patients and in subgroups on the basis of gender and age (15 to 24, 25 to 34, and 35 to 46 yr). The overall prevalence of hepatic cysts was 83%; the prevalence was 58, 85, and 94% in the sequential age groups and 85% in women and 79% in men. The prevalence was related directly to renal volume (chi2 = 4.30, P = 0.04) and to renal cyst volume (chi2 = 5.59, P = 0.02). The total hepatic cyst volume was significantly greater in women than in men (a logarithmic transformation mean of 5.27 versus 1.94 ml; P = 0.003). The average hepatic cyst volume was 0.25, 5.75, and 22.78 ml in sequential age groups. Hepatic cysts are evident in 94% of patients who are older than 35 yr and in 55% of individuals who are younger than 25 yr. Hepatic cysts are more prevalent and larger in total cyst volume in women than in men. Hepatic cyst prevalence and aggregate total hepatic cyst volume increased with age.

Cyst Number but Not the Rate of Cystic Growth Is Associated with the Mutated Gene in Autosomal Dominant Polycystic Kidney Disease

Data from serial renal magnetic resonance imaging of the Consortium of Radiologic Imaging Study of PKD (CRISP) autosomal dominant polycystic kidney disease (PKD) population showed that cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population, and that larger kidneys are associated with more rapid disease progression. The significance of gene type to disease progression is analyzed in this study of the CRISP cohort. Gene type was determined in 183 families (219 cases); 156 (85.2%) had PKD1, and 27 (14.8%) had PKD2. PKD1 kidneys were significantly larger, but the rate of cystic growth (PKD1 5.68%/yr; PKD2 4.82%/yr) was not different (P = 0.24). Cyst number increased with age, and more cysts were detected in PKD1 kidneys (P < 0.0001). PKD1 is more severe because more cysts develop earlier, not because they grow faster, implicating the disease gene in cyst initiation but not expansion. These insights will inform the development of targeted therapies in autosomal dominant PKD.

1H-magnetic resonance spectroscopy of the left temporal and frontal lobes in schizophrenia: Clinical, neurodevelopmental, and cognitive correlates ☆

Twenty eight schizophrenic patients and 20 normal volunteers underwent proton magnetic resonance spectroscopy (MRS) on the left temporal and frontal lobe regions. Male patients showed a significant reduction in frontal but not temporal n-acetylaspartate (an intraneuronally distributed metabolite) in comparison with either male controls or female patients; frontal choline was raised in male patients relative to these groups. Putative neurodevelopmental indices, including obstetric complications, family history of schizophrenia, and minor physical anomalies, proved unrelated to MRS resonances. However, multiple aspects of memory function in patients were related to temporal but not frontal creatine, a pattern that was not apparent among controls. These MRS findings complement some previous structural MRI studies and much clinical and epidemiological evidence of important gender differences in schizophrenia. The findings also suggest that memory dysfunction in patients with schizophrenia may be associated with a particular pattern of temporal lobe metabolism on MRS.

Case-control study of endophthalmitis after cataract surgery comparing scleral tunnel and clear corneal wounds.

PURPOSE To study the possible association between clear corneal incision with or without placement of a suture during cataract extraction and postoperative endophthalmitis. DESIGN Retrospective, comparative, case-controlled study. METHODS Thirty-eight patients treated for culture-positive, acute post-cataract surgery endophthalmitis, and 371 randomly selected control patients who underwent uncomplicated cataract surgery in the referring community were studied. Incision type and use of suture during cataract surgery of endophthalmitis patients were compared with the controls. The data were analyzed using logistic regression methods. RESULTS Of the 38 patients with endophthalmitis, 17 patients (45%) had clear corneal incisions and 21 patients (55%) had a scleral tunnel incision. In 371 controls, 76 patients (20%) had clear corneal incisions and 295 patients (80%) had scleral tunnel incisions. Clear corneal incision was associated with a threefold greater risk of endophthalmitis than was scleral tunnel incision (Odds Ratio, 3.36, 95% Confidence Interval = 1.67 to 6.78). The type of incision was significant (chi(2) = 11.53, P =.0007); a clear corneal incision was more frequently associated with endophthalmitis. A subgroup analysis revealed that the presence or absence of a suture was not significant (chi(2) = 1.31, P =.2524). CONCLUSIONS In this retrospective, case-controlled study, clear corneal incisions were found to be a statistically significant risk factor for acute post-cataract surgery endophthalmitis when compared with scleral tunnel incisions.

Serotonin Receptors in Suicide Victims with Major Depression

Serotonin1A (5-HT1A) and serotonin2A (5-HT2A) receptors in the brain have been implicated in the pathophysiology of suicide. Brain samples were collected at autopsy from suicide victims with a current episode of major depression and matched comparison subjects who died of natural or accidental causes. Retrospective psychiatric assessments were collected from knowledgeable informants for all suicide victims and most of the comparison subjects. Psychiatric diagnoses were determined according to DSM-III-R criteria. Any subjects with current psychoactive substance use disorders were excluded. Quantitative receptor autoradiography was used in serial sections of the right prefrontal cortex (area 10) and hippocampus to measure the binding of [3H]8-hydroxy-2-(di-n-propyl)-aminotetralin ([3H]8-OH-DPAT) to 5-HT1A receptors and [3H]ketanserin to 5-HT2A receptors. Analysis of covariance was used to compare control subjects and suicide victims with major depression. The age of subjects, the time from death to freezing the tissue (postmortem interval), and the storage time of tissues in the freezer were used as covariates in the analyses. There were no significant differences between suicide victims with major depression and comparison subjects in 5-HT1A or 5-HT2A receptors in area 10 of the right prefrontal cortex or the hippocampus. The current results suggest that the number of 5-HT1A and 5-HT2A receptors in the right prefrontal cortex (area 10) or hippocampus are not different in suicide victims with major depression.

Neuropsychologic deficits in schizophrenia: Relation to social function and effect of antipsychotic drug treatment

Cognitive impairment is present in the majority of schizophrenic patients, even at the onset of psychosis. It is a relatively stable characteristic in most patients, usually with little progression over the course of illness, but sometimes progresses to severe dementia. The results of studies of the effects of typical neuroleptic drugs on cognitive functioning in schizophrenia are conflicting. Clozapine, which has superior antipsychotic effects compared to typical neuroleptic drugs, has been reported to improve executive function, verbal fluency, attention, and recall memory in two of three studies. Cognitive measures predict work function and overall outcome on clozapine as assessed by the Global Assessment Scale and Quality-of-Life Scale in neuroleptic—resistant schizophrenia. Improvement in cognitive function by clozapine may be a major reason for expanding its currently limited utilization.

Magnetic Resonance Measurements of Renal Blood Flow and Disease Progression in Autosomal Dominant Polycystic Kidney Disease

Whether changes in renal blood flow (RBF) are associated with and possibly contribute to cystic disease progression in autosomal dominant polycystic kidney disease (ADPKD) has not been ascertained. The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) was created to develop imaging techniques and analyses to evaluate progression. A total of 131 participants with early ADPKD had measurements of RBF and total kidney (TKV) and cyst (TCV) volumes by magnetic resonance and of GFR by iothalamate clearance at baseline and 1, 2, and 3 yr. The effects of age, gender, body mass index, hypertension status, mean arterial pressure (MAP), TKV, TCV, RBF, renal vascular resistance (RVR), GFR, serum uric acid, HDL and LDL cholesterol, 24-h urine volume, sodium (UNaE) and albumin (UAE) excretions, and estimated protein intake were examined at baseline on TKV, TCV, and GFR slopes. TKV and TCV increased, RBF decreased, and GFR remained stable. TKV, TCV, RVR, serum uric acid, UAE, UNaE, age, body mass index, MAP, and estimated protein intake were positively and RBF and GFR negatively correlated with TKV and TCV slopes. TKV, RBF, UNaE, and UAE were independent predictors of TKV and TCV slopes (structural disease progression). TKV, TCV, RVR, and MAP were negatively and RBF positively correlated with GFR slopes. Regression to the mean confounded the analysis of GFR slopes. TKV and RBF were independent predictors of GFR decline (functional disease progression). In ADPKD, RBF reduction (1) parallels TKV increase, (2) precedes GFR decline, and (3) predicts structural and functional disease progression.