Neuropsychological outcome of subjects participating in the PKU Adult Collaborative Study: A preliminary review

Adult subjects with classical phenylketonuria (PKU) who were diagnosed and treated neonatally participated in this long-term follow-up study. Twenty-four subjects received neuropsychological (NP) assessment and a subset received magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) to identify: (1) pattern of cognitive dysfunction; (2) effect of high blood phenylalanine (Phe) level at time of cognitive testing; and (3) treatment variables that may be associated with cognitive difficulties in adulthood. All subjects had average IQ except one subject in the borderline range. Diet was initiated by the 15th day of life. All subjects except one were on diet until age 6 years (mean years of treatment = 15). Blood Phe levels at cognitive testing ranged from 157 to 1713 micromol/L (mean = 1038); 11 subjects had levels < 1000 micromol/L and 13 subjects had levels >1000 micromol/L. Results suggest that adults with early-treated PKU demonstrate specific cognitive deficits, a number of which are associated with the frontal and temporal area of the brain. Deficits were noted in several domains including executive functioning, attention, verbal memory, expressive naming and verbal fluency. Self-report measures of depression and anxiety were generally in the normal/mild range. The group with a Phe level > 1000 micromol/L scored lower than the group with Phe level < 1000 micromol/L on measures of focused attention, verbal fluency, reaction time, verbal recognition memory, visual memory and naming. Tests of cognitive functioning were often correlated with measures of treatment during childhood rather than with Phe level at the time of cognitive testing. Subjects with abnormal MRI scored significantly lower on two cognitive tests (Trails A and CVLT Recognition Memory). We found no significant correlation between current brain Phe level obtained through MRS (n = 10) and neuropsychological functioning. Future longitudinal investigation with a larger sample size will assist in clarifying the aetiology of neuropsychological deficits and association with treatment history.     

Class II major histocompatibility complex molecules of murine dendritic cells: synthesis, sialylation of invariant chain, and antigen processing capacity are down-regulated upon culture.

Dendritic cells (DCs), such as Langerhans cells (LCs) of the epidermis and the DCs of lymphoid organs such as spleen, are potent antigen presenting cells. DCs express high levels of major histocompatibility complex (MHC) class II molecules, but, partly because of the low numbers of primary DCs in any tissue, there has been no detailed study of the biochemistry of their class II molecules. This information may be needed to help explain recent findings that DCs process native protein antigens when freshly isolated from epidermis and spleen. Processing ceases during culture, yet a strong accessory function for activating resting T cells develops. We studied immunoprecipitates of DC class II and invariant chain (Ii) molecules by two-dimensional gel electrophoresis. We found that (i) freshly isolated LCs synthesize large amounts of class II and Ii polypeptides; (ii) Ii molecules that are known to be involved in antigen processing display an unusually large number of sialic acids in fresh LCs; (iii) with culture, class II and Ii synthesis decreases dramatically and has virtually ceased at 3 days; and (iv) the turnover of class II in pulse/chase experiments is slow, being undetectable over a 12- to 32-hr culture period, whereas the turnover of Ii is rapid. We conclude that MHC class II molecules of DCs do not seem to be qualitatively unique. However, the regulation of class II and Ii expression is distinctive in that biosynthesis proceeds vigorously for a short period of time and the newly synthesized class II remains stably on the cell surface, whereas Ii turns over rapidly. This may enable DCs to process and retain antigens in the peripheral tissues such as skin and migrate to the lymphoid organs to activate T cells there.     

Circulating homocysteine levels in patients with type 2 diabetes mellitus

Background and aimPrevious studies have shown conflicting results regarding circulating homocysteine levels in patients with type 2 diabetes.Methods and resultsThis observational study included 2121 patients with angiographically proven coronary artery disease (507 patients with type 2 diabetes and 1614 patients without diabetes). Circulating homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism, renal function, presence of coronary artery disease (CAD) diagnosed by coronary angiography, and circulating folate and vitamin B₁₂ status were assessed. Plasma homocysteine levels [median (25th; 75th percentile)] were significantly higher in patients with diabetes than in those without [12.4 μmol/L (9.9 μmol/L; 15.9 μmol/L) versus 11.7 μmol/L (9.6 μmol/L; 14.5 μmol/L), P = 0.011]. Diabetes affected homocysteine levels only in patients with a glomerular filtration rate <90 mL/min [13.0 μmol/L (10.5 μmol/L; 16.7 μmol/L) in patients with diabetes versus 12.2 μmol/L (10.1 μmol/L; 15.2 μmol/L) in patients without diabetes, P = 0.006] but not in those with a glomerular filtration rate ≥90 mL/min [10.1 μmol/L (8.1 μmol/L; 12.4 μmol/L) versus 10.2 μmol/L (8.8 μmol/L; 12.3 μmol/L), P = 0.267]. Multivariable analysis did not show an independent association between diabetes and homocysteine level (P = 0.342).ConclusionCirculating homocysteine levels are increased in patients with type 2 diabetes compared with non-diabetic patients due to a more diabetes-associated adverse risk profile rather than to diabetes itself.     

Pulverisation of calcified and non-calcified gall bladder stones: extracorporeal shock wave lithotripsy used alone.

Using a modified electromagnetic lithotripter (Siemens), extracorporeal shock wave lithotripsy (ESWL) was performed in 260 patients with gall bladder stones. Exclusion criteria for treatment were a non-functioning gall bladder, subcostal gall bladder location, and multiple stones occupying more than three quarters of the gall bladder volume. Stone pulverisation was the end point of ESWL. The number of shock wave discharges and sessions was not limited. Pulverisation was achieved in 250 patients (96.1%) after a median of three ESWL sessions (range 1-21). The number of sessions required depended upon stone composition and burden. More than three sessions were required in 60.2% of patients with calcified stones compared with 35.9% of patients with non-calcified stones (p < 0.001). 65.8% of patients with stones measuring more than 30 mm in total diameter required more than three sessions compared with 42.9% of patients with a stone burden less than 30 mm (p < 0.01). At 18-24 (8-12) months follow up, stone clearance was achieved in 94.3% (80.4%) of patients with non-calcified stones, compared with 89.5% (76.8%) in patients with calcified stones and in 75% (71.4%) of patients with a total stone diameter more than 30 mm compared with 95.7% (80.4%) for patients with a total stone diameter less than 30 mm (p < 0.05). ESWL related complications (gross haematuria) occurred in three patients. Thirty six (13.8%) patients experienced biliary colic; four had cholecystectomy, and five endoscopic papillotomy because of common bile duct obstruction. Stone recurrence was seen in 5.3% of patients over a follow up period of up to two years (median 16.6 months).     

The efficacy and safety of ciprofloxacin and ofloxacin in chronic Pseudomonas aeruginosa infection in cystic fibrosis

The clinical efficacy and safety of ciprofloxacin and ofloxacin were compared in a prospective, randomized double blind, placebo combined cross-over study in 26 adult cystic fibrosis patients with chronic broncho-pulmonary Pseudomonas aeruginosa infection. Active treatment consisted of ciprofloxacin 750 mg orally twice daily or ofloxacin 400 mg orally twice daily; both treatments were given for 14 days, with three months between treatment periods; 21 patients completed both treatment periods. Treatment with both ciprofloxacin and ofloxacin was associated with a good clinical response as judged by clinical score, lung function tests and inflammatory parameters; no difference between ciprofloxacin and ofloxacin was found. Adverse reactions were seen in nine of 24 patients who received ciprofloxacin and in six of 23 who received ofloxacin. The majority were dyspeptic reactions or photosensitivity. No serious adverse reactions occurred. Three cases of treatment failure were found, one of which was associated with development of resistant P. aeruginosa during ofloxacin treatment. The mean MIC of both drugs increased during treatment but returned to pretreatment values within three months. Ciprofloxacin and ofloxacin seem to be valuable agents for intermittent treatment of chronic P. aeruginosa lung infection in adult cystic fibrosis patients.     

Early lumen diameter loss after percutaneous transluminal coronary angioplasty is related to coronary plaque burden: a role for viscous plaque properties in early lumen diameter loss

Objectives: We tested the hypothesis that lumen diameter loss within 1 h after percutaneous transluminal coronary angioplasty is related to plaque volume parameters. Background: Early lumen diameter loss after coronary balloon angioplasty may predict restenosis and may paradoxically decrease late lumen diameter loss. Viscous properties of the vessel wall, as would be determined by tissue volume and composition, may be involved in early lumen diameter loss. Methods: Early lumen diameter loss was measured with quantitative coronary angiography as the loss in lesion lumen diameter (significant loss 0.4 mm) occurring between 5 min and a median of 40 min after successful coronary balloon angioplasty in 68 patients. Thirty-nine patients were evaluated with intravascular ultrasound at the narrowest lumen cross-section of the dilated lesion, 29 patients formed a control group without intravascular ultrasound imaging. We tested the relation between intravascular ultrasound parameters and early lumen diameter loss. Results: Early lumen diameter loss of 0.4 mm was present in eight patients (12%), decreasing lumen diameter from 2.26 ± 0.36 mm to 1.73 ± 0.43 mm. There was no difference in the frequency of early lumen diameter loss between the groups with or without intravascular ultrasound imaging. Univariate intravascular ultrasound determinants of early lumen diameter loss were media bounded area (p = 0.01), maximal plaque thickness (p = 0.02), eccentricity index (p = 0.03) and the presence of hard lesions (p = 0.02). Conclusion: Early lumen diameter loss in the first hour after successful coronary balloon angioplasty occurs in a small proportion of patients. It is related to hard lesion type, maximal plaque thickness and eccentricity index, favoring a role for viscous plaque properties in early lumen diameter loss.     

Psychopathological correlates of the entorhinal cortical shape in schizophrenia

Animal experiments have shown that early developmental lesions of the entorhinal cortex lead, after a prolonged interval, to an enhanced mesolimbic dopamine release and an increased locomotor activity in rats. Hence, disturbed shape of the entorhinal cortex might indicate maturational abnormalities relevant for psychotic symptoms in schizophrenia. We used an automated surface-based MRI method to perform a region of interest analysis of entorhinal cortical surface area, folding and thickness in 59 patients with schizophrenia and 59 healthy controls. We postulated the entorhinal cortical surface area, folding index, and thickness to be significantly smaller in patients with schizophrenia. Additionally, we expected the complexity of the entorhinal cortical shape to be associated with psychotic symptoms in schizophrenia. Our ROI analysis showed a significant thinner left entorhinal cortex. In addition, our data demonstrate a positive correlation between left entorhinal cortical surface area and folding index and severity of psychotic symptoms. In conclusion, we present new evidence for the involvement of the entorhinal cortex in the pathogenesis of schizophrenia. As cortical folding is a stable neuroanatomical parameter terminated in early neonatal stages, our data give reason to assume that the vulnerability to develop psychotic symptoms might be manifest at an early level of brain maturation.     

Alpha-fetoprotein and tumour size are associated with microvascular invasion in explanted livers of patients undergoing transplantation with hepatocellular carcinoma

Background:

To determine factors associated with outcomes and microvascular invasion (MVI) in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC).

Methods:

Between July 1996 and August 2008 at the Universities of Kentucky or Tennessee, LT recipients were retrospectively analysed.

Results:

One hundred and one patients had HCC in the explanted liver; one patient was excluded because of fibrolamellar histology. Seventy-nine (79%) were male and 81 (81%) were older than 50. HCC was incidental in 32 patients (32%). Median follow-up was 31 months. Ten patients (10%) developed recurrence, which was associated with poor survival (P= 0.006). Overall 1-, 3-, and 5-year survival rates were 87%, 69% and 62%, respectively. Excluding patients with lymph node metastasis (LNM) or MVI yielded 91%, 81% and 75% survival at the same time points. MVI was independently associated with recurrence (OR 28.40, 95% CI 1.77–456.48, P= 0.018) and decreased survival (OR 4.70, 95% CI 1.24–17.80, P= 0.023), and LNM with decreased survival (OR 6.05, 95% CI 1.23–29.71, P= 0.027). Tumour size (OR 4.1, 95% CI 1.2–13.5, P= 0.013) and alpha-fetoproptein (AFP) > 100 (OR 5.0, 95% CI 1.4–18.1, P= 0.006) were associated with MVI.

Conclusions:

MVI greatly increases the risk of recurrence and death after LT for HCC, and is strongly associated with tumour size and AFP > 100.     

Effects of perfluorohexane vapor in the treatment of experimental lung injury

RationaleWe investigated the effects of vaporized perfluorohexane (PFH) on pulmonary vascular tone, pulmonary vascular resistance and peak inspiratory pressure as well as lipid mediator formation in the treatment of calcium ionophore induced lung injury in a model of the isolated perfused and ventilated rabbit lungs.MethodsLung injury was induced in isolated perfused and ventilated rabbit lungs by calcium ionophore A23187. Lungs were treated with either 4.5 vol.% (4.5 vol.% PFH; n = 6) or 18 vol.% (18 vol.% PFH; n = 6) PFH. Six lungs remained untreated (Control). In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Mean pulmonary artery pressure (mPAP), peak inspiratory pressure (P_max), and lung weight (weight) were monitored for 120 min. Experiments were terminated before when the increase in lung weight exceeded 40 g. Perfusate samples were taken at regular intervals for analysis of TXB₂, 6-keto-PGF₁ and LTB₄.ResultsControls reached the study end point significantly earlier than both PFH groups. Significant differences were found for a weight gain of 10 g and 20 g between the control and the 4.5 vol.% PFH and the 18 vol.% PFH. Differences in mPAP were more pronounced in the 4.5 vol.% PFH. However increases in P_max were more marked in 4.5 vol.% PFH. TXA₂-, PGI₂-, and LTB₄-levels were significantly lower in PFH groups. Uninjured lungs remained unaffected by the presence of 18 vol.% PFH.ConclusionInflammatory lung injury was attenuated by the treatment with 4.5 vol.% PFH and 18 vol.% PFH vapor in the isolated perfused rabbit lung. Therapeutic effects were more pronounced with a concentration of 4.5 vol.% PFH.