Primary cardiomyopathy in identical twins

Seventeen year old identical twin brothers with no family history of cardiopathy began experiencing palpitations almost simultaneously. In both, examination revealed marked cardiomegaly and hypokinesia of the ventricular walls, and clinical and radiologic signs of progressive cardiac failure developed a few days later. Both boys died suddenly, 49 days and 5 months, respectively, after the initial examination. Electrocardiographic and vectorcardiographic studies revealed a severe intraventricular conduction disturbance that coincided with histologic changes in the myocardial tissue, including profuse interstitial fibrosis, hypertrophy and degeneration of the myocardial fibers, aberrant arrangement of the muscular fibers and considerable alteration of the structure of cardiac tissue. In the absence of hereditary and chromosomal factors, and excluding possible viral intervention during fetal life, it is believed that a teratogenic factor can produce the structural alterations of the tissue and derangement of the fibers observed in these hearts.The irregular contractions of the heart at the level of the net-like meshwork, disarrangement of myocardial fibers, and adaptative mechanisms of the heart inherent in the destruction of the contractile tissue contributed to the functional cardiac disorders that resulted in congestive heart failure and sudden death in these twins.     

Step‐down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis

Objective

To evaluate the feasibility and outcome of the step‐down approach using either cyclosporin A (CSA) or methotrexate (MTX) as maintenance therapy following 6 months treatment with these 2 agents in combination in early, nonerosive rheumatoid arthritis (RA).

Methods

Fifty‐seven patients younger than 65 years with early, nonerosive RA were first treated with CSA and MTX in combination for 6 months. They were then randomly stepped down to single‐agent maintenance treatment for another 18 months. Safety, clinical efficacy, survival on treatment, and radiographic progression were evaluated.

Results

When being treated with combination therapy, 7 of the 57 patients (12.3%) withdrew because of adverse events. Of the remaining 50 patients, 42 (84.0%) were American College of Rheumatology (ACR) 20% responders, 30 (60.0%) were ACR 50% responders, and 23 (46.0%) were ACR 70% responders. At month 6, 22 patients were randomized to CSA and 27 to MTX. During this trial period, the treatment was discontinued by 16 patients taking CSA (mainly because of loss of efficacy) and by 4 taking MTX. At month 24, the probability (± SEM) of survival on treatment was 0.273 ± 0.09 for CSA and 0.852 ± 0.07 for MTX. Of the 6 CSA patients who completed the trial, 4 (66.7%) were ACR 20% responders, and 3 (50%) were both ACR 50% and ACR 70% responders. Of the 23 completers in the MTX arm, 21 (91.3%) were ACR 20% responders, 18 (78.3%) were ACR 50%, and 10 (43.5%) were ACR 70% responders. The treatment was not responsible for severe adverse events. Radiography showed a slow progression in the damage score and number of eroded joints in both treatment groups.

Conclusion

Stepping down to single agent maintenance therapy following 6 months of combination treatment with CSA and MTX in early RA was only successful with MTX. Because this treatment did not prevent some radiographic progression, other approaches (e.g., step‐up approach) may be more appropriate in early RA.

     

Poor glycemic control is associated with increased diastolic blood pressure and heart rate in children with Type 1 diabetes

Although higher levels of hemoglobin A1c (HbA1c) and blood pressure precede the development of nephropathy in Type 1 diabetes (T1DM), the relationship between glycemic control and cardiovascular factors early in the course of diabetes is not clear. We conducted a retrospective study from clinic data for a 1-year period in 148 children with T1DM aged 12.5+/-4.4 years who had average diabetes duration of 4.5+/-3.3 years. The influence of HbA1c and reported insulin dose on blood pressure and heart rate were analyzed in multivariate linear regression models, statistically adjusted for the effect of race, sex, age, body mass index, and duration of diabetes. There was a significant positive correlation of mean HbA1c with mean diastolic blood pressure (P<.025) and mean heart rate (P<.0004). Higher diastolic blood pressure and heart rate were associated with higher HbA1c. Increased insulin doses were also associated with increased diastolic blood pressure (P<.009) and heart rate (P<.013). Insulin dose and HbA1c were also significantly correlated (P<.001). There was no correlation between mean HbA1c and mean systolic blood pressure. Increased levels of HbA1c and insulin dose are associated with increased diastolic blood pressure and heart rate. Although within the normal range, early increases of diastolic blood pressure and heart may indicate early cardiovascular changes in response to diabetes and potentially contribute to a greater proclivity for later development of nephropathy.     

The 'Open-Artery Hypothesis': new clinical and pathophysiologic insights

The open-artery hypothesis states that myocardial reperfusion, even if late for myocardial salvage, provides benefits and prevents adverse cardiac remodeling. While observational data in humans regarding the deleterious impact of a permanent infarct-related artery occlusion and the benefits of spontaneous reperfusion are quite consistent, the reports regarding late revascularization are inconclusive in order to prove such a hypothesis. The observational studies tend to have selection biases, while randomized trials to date are too small to be conclusive. Moreover, the pathophysiological mechanisms underlying presumed benefits of reperfusion are still unclear. However, although the open-artery hypothesis remains unproven, the current evidence suggesting benefits calls for additional studies. Limitations of ischemic left ventricular dilatation and myopathy could markedly reduce cardiovascular morbidity and mortality after acute myocardial infarction.     

Analysis and interpretation of serial position data

The representation of serial position in sequences is an important topic in a variety of cognitive areas including the domains of language, memory, and motor control. In the neuropsychological literature, serial position data have often been normalized across different lengths, and an improved procedure for this has recently been reported by Machtynger and Shallice (2009) Machtynger, J. and Shallice, T. 2009. Normalizing serial position analyses: The Proportional Accountability algorithm. Cognitive Neuropsychology, 26: 217–222. [Taylor & Francis Online], [Web of Science ®] , [Google Scholar]. Effects of length and a U-shaped normalized serial position curve have been criteria for identifying working memory deficits. We present simulations and analyses to illustrate some of the issues that arise when relating serial position data to specific theories. We show that critical distinctions are often difficult to make based on normalized data. We suggest that curves for different lengths are best presented in their raw form and that binomial regression can be used to answer specific questions about the effects of length, position, and linear or nonlinear shape that are critical to making theoretical distinctions.     

Matrix detachment and proteasomal inhibitors diminish Sulf-2 expression in breast cancer cell lines and mouse xenografts

Sulfatase 2 (Sulf-2) has been previously shown to be upregulated in breast cancer. Sulf-2 removes sulfate moieties on heparan sulfate proteoglycans which in turn modulate heparin binding growth factor signaling. Here we report that matrix detachment resulted in decreased Sulf-2 expression in breast cancer cells and increased cleavage of poly ADP-ribose polymerase. Silencing of Sulf-2 promotes matrix detachment induced cell death in MCF10DCIS cells. In an attempt to identify Sulf-2 specific inhibitor, we found that proteasomal inhibitors such as MG132, Lactacystin and Bortezomib treatment abolished Sulf-2 expression in multiple breast cancer cell lines. Additionally, we show that Bortezomib treatment of MCF10DCIS cell xenografts in mouse mammary fat pads significantly reduced tumor size, caused massive apoptosis and more importantly reduced Sulf-2 levels in vivo. Finally, our immunohistochemistry analysis of Sulf-2 expression in cohort of patient derived breast tumors indicates that Sulf-2 is significantly upregulated in autologous metastatic lesions compared to primary tumors (p < 0.037, Pearson correlation, Chi-Square analysis). In all, our data suggest that Sulf-2 might play an important role in breast cancer progression from ductal carcinoma in situ into an invasive ductal carcinoma potentially by resisting cell death.     

What is the role of motor simulation in action and object recognition? Evidence from apraxia

An important issue in contemporary cognitive neuroscience concerns the role of motor production processes in perceptual and conceptual analysis. To address this issue, we studied the performance of a large group of unilateral stroke patients across a range of tasks using the same set of common manipulable objects. All patients (n = 37) were tested for their ability to demonstrate the use of the objects, recognize the objects, recognize the corresponding object-associated pantomimes, and imitate those same pantomimes. At the group level we observed reliable correlations between object use and pantomime recognition, object use and object recognition, and pantomime imitation and pantomime recognition. At the single-case level, we document that the ability to recognize actions and objects dissociates from the ability to use those same objects. These data are problematic for the hypothesis that motor processes are constitutively involved in the recognition of actions and objects and frame new questions about the inferences that are merited by recent findings in cognitive neuroscience.     

PERCEPTUA.ND LEXICA.ACTORS IN A CAS.F LETTER-BY-LETTER READING

We report the case of a letter-by-letter reader (MJ) who showed normal processing of single letters and who could normally access the orthographic input lexicon when presented with letter names for aural recognition, or when allow ed enough tim e to process a visually presented letter string. However, MJ showed severe difficulties in simultaneously processing multiple letters and other simple visual stimuli. Furthermore, she does not have normal access to lexical orthographic representations and their meanings when stimuli are presented for too brief a time to allow for serial processing of the letter string. We found no evidence of (partial) lexical or semantic access without corresponding recognition of the letters in a word: No signs of implicit reading were observed w hen the input stimuli were controlled for the relevant visual features; “implicit reading” was only obtained under conditions that allowed sophisticated guessing. This pattern of results is interpreted as indicating that LBL reading (at least in MJ) results from damage to prelexical processing mechanisms. In MJ's case, the deficit reflects the degraded transfer of information from a normal visual processing system in the right hemisphere to a normal language processing system in the left hemisphere.     

Neuroprotective and reparative effects of carotid body grafts in a chronic MPTP model of Parkinson's disease

Intrastriatal transplantation of dopaminergic carotid body (CB) cells ameliorates parkinsonism in animal models and, with less efficacy, in Parkinson's disease patients. CB-based cell therapy was initially proposed because of its high dopamine content. However, later studies suggested that its beneficial effect might be due to a trophic action exerted on nigrostriatal neurons. Compatible with this concept are the high levels of neurotrophic factors encountered in CB cells. To test experimentally this idea, unilateral striatal transplants were performed with a sham graft in the contralateral striatum, as a robust internal control. Thereafter, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6, -tetrahydropyridine was injected during 3 months. CB grafts protected from degeneration ipsilateral nigral dopaminergic neurons projecting to the transplant in a dose-dependent manner regarding size and glial cell line-derived neurotrophic factor expression. Grafts performed at different times after the onset of the neurotoxic treatment demonstrated with histological and behavioral methods protection and repair of the nigrostriatal pathway by CB transplants. This study provides a mechanistic explanation for the action of CB transplants on parkinsonian models. It should also help to improve cell therapy approaches to Parkinson's disease.