INTELLECTUAL FUNCTIONS OF PATIENTS WITH CHILDHOOD-ONSET EPILEPSY

The intellectual functions of 64 epileptic patients who had had an initial evaluation between five and 16 years of age, including the WISC, were re-evaluated after a period of at least five years. In general the seizure states had improved, and 50 per cent were in remission for between two and eight years. All but four were still taking at least one anticonvulsant drug. WISC IQ estimates showed a slight decrease. Verbal and performance areas could be differentially affected, and a gain in one could be offset by a loss in the other, so the Full-scale IQ might not be a reliable measure of day-to-day performance. Those whose seizures remained uncontrolled had a statistically significant decrease in performance IQ, whereas in general it was stable or increased for patients in remission. There was evidence that decreased IQ indicated slower mental growth rather than loss of previously acquired function. Phenobarbital but not phenytoin levels were inversely correlated with IQ, suggesting that the upper limit of the 'therapeutic range' of phenobarbital may already be toxic with regard to learning abilities. To optimize an epileptic child's functioning in school and to prevent long-term intellectual problems, it is advisable that IQ testing should be part of the routine initial evaluation, and that drug levels should be checked at regular intervals.     

Assessment and Comparison of Three Dimensional Exoscopes for Near-Infrared Fluorescence-Guided Surgery Using Second-Window Indocyanine-Green

ObjectiveCompared to microscopes, exoscopes have advantages in field-depth, ergonomics, and educational value. Exoscopes are especially well-poised for adaptation into fluorescence-guided surgery (FGS) due to their excitation source, light path, and image processing capabilities. We evaluated the feasibility of near-infrared FGS using a 3-dimensional (3D), 4 K exoscope with near-infrared fluorescence imaging capability. We then compared it to the most sensitive, commercially-available near-infrared exoscope system (3D and 960 p). In-vitro and intraoperative comparisons were performed. MethodsSerial dilutions of indocyanine-green (1–2000 μg/mL) were imaged with the 3D, 4 K Olympus Orbeye (system 1) and the 3D, 960 p VisionSense Iridium (system 2). Near-infrared sensitivity was calculated using signal-to-background ratios (SBRs). In addition, three patients with brain tumors were administered indocyanine-green and imaged with system 1, with two also imaged with system 2 for comparison. ResultsSystems 1 and 2 detected near-infrared fluorescence from indocyanine green concentrations of >250 μg/L and >31.3 μg/L, respectively. Intraoperatively, system 1 visualized strong near-infrared fluorescence from two, strongly gadolinium-enhancing meningiomas (SBR=2.4, 1.7). The high-resolution, bright images were sufficient for the surgeon to appreciate the underlying anatomy in the near-infrared mode. However, system 1 was not able to visualize fluorescence from a weakly-enhancing intraparenchymal metastasis. In contrast, system 2 successfully visualized both the meningioma and the metastasis but lacked high resolution stereopsis. ConclusionThree-dimensional exoscope systems provide an alternative visualization platform for both standard microsurgery and near-infrared fluorescent guided surgery. However, when tumor fluorescence is weak (i.e., low fluorophore uptake, deep tumors), highly sensitive near-infrared visualization systems may be required.     

Respiratory health and indoor air pollution at high elevation

In this research, the authors sought to provide experimental data on indoor air quality, and the resulting respiratory impact, for a high-elevation (4550 m), rural community in Ladakh, India. This community is of interest because the primarily nomadic residents burn biomass inside the home for heating and cooking. The concentrations of particulate matter (PM), endotoxin, and carbon monoxide were determined for 6 homes. Lung function data and induced sputum samples were collected for 9 female test-home subjects. In addition, lung function data were collected for 84 additional Ladakhi highlanders at this location. Sputum from 3 visiting scientists (sojourners) was collected and analyzed as well. The average PM concentration ranged from 2 mg/m3 to 7 mg/m3, with 85% of the sampled PM sized as respirable. The average endotoxin concentration ranged from 2.4 ng/m3 to 19 ng/m3, and average carbon monoxide levels ranged from 50 ppm to 120 ppm. Lung function values for the highlander population and the test-home subjects were equal to or greater than predicted, despite the highlanders' significant exposure to indoor pollutants. An induced sputum analysis revealed a significantly greater total inflammatory cell count (M +/- SD, 10(5) cell/mg) in the Ladakhi natives than in the sojourners (107.5 +/- 75.2 vs 7.1 +/- 8.1, p < .01). Although the high levels of indoor pollutants did not correlate with significant decrements in lung function, the induced sputum analysis revealed marked airway inflammation dominated by macrophages and neutrophils. It appears that augmented lung mechanics of this high-altitude population are adaptive to reduce the work of breathing; thus, decrements in lung function go undetected because the true predicted values are greater than expected.     

Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States.

Tuberous sclerosis complex is an autosomal dominant neurocutaneous disorder marked by hamartoma growth in multiple organ systems. We performed mutational analyses on 325 individuals with definite tuberous sclerosis complex diagnostic status. We identified mutations in 72% (199/257) of de novo and 77% (53/68) of familial cases, with 17% of mutations in the TSC1 gene and 50% in the TSC2 gene. There were 4% unclassified variants and 29% with no mutation identified. Genotype/phenotype analyses of all observed tuberous sclerosis complex findings in probands were performed, including several clinical features not analyzed in two previous large studies. We showed that patients with TSC2 mutations have significantly more hypomelanotic macules and learning disability in contrast to those with TSC1 mutations, findings not noted in previous studies. We also observed results consistent with two similar studies suggesting that individuals with mutations in TSC2 have more severe symptoms. On performing meta-analyses of our data and the other two largest studies in the literature, we found significant correlations for several features that individual studies did not have sufficient power to conclude. Male patients showed more frequent neurologic and eye symptoms, renal cysts, and ungual fibromas. Correlating genotypes with phenotypes should facilitate the disease management of tuberous sclerosis complex.     

An invasion-independent pathway of blood-borne metastasis: a new murine mammary tumor model

It is generally believed that active invasion by cancer cells is essential to the metastatic process. In this report, we describe a murine mammary tumor (MCH66) model of metastasis that does not require invasion into the vascular wall of both the primary tumor and the target organ, in this case, the lung. The process involves intravasation of tumor nests surrounded by sinusoidal blood vessels, followed by intravascular tumor growth in the lung, without penetration of the vascular wall during the process. Comparative studies using a nonmetastatic MCH66 clone (MCH66C8) and another highly invasive metastatic cell line (MCH416) suggested that high angiogenic activity and sinusoidal remodeling of tumor blood vessels were prerequisites for MCH66 metastasis. Differential cDNA analysis identified several genes that were overexpressed by MCH66, including genes for the angiogenesis factor pleiotrophin, and extracellular matrix-associated molecules that may modulate the microenvironment toward neovascularization. Our analyses suggest that tumor angiogenesis plays a role in the induction of invasion-independent metastasis. This model should prove useful in screening and development of new therapeutic agents for cancer metastasis.     

Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb

Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.     

Interaction of Dr adhesin with collagen type IV is a critical step in Escherichia coli renal persistence

The pathogenic mechanism of recurrent or chronic urinary tract infection is poorly understood. Escherichia coli cells bearing Dr fimbriae display unique tropism to the basement membrane (BM)-renal interstitium that enables the bacteria to cause chronic pyelonephritis in experimental mice. The renal receptors for Dr-fimbriated E. coli are type IV collagen and decay-accelerating factor (DAF). We hypothesized that type IV collagen receptor-mediated BM-interstitial tropism is essential for E. coli to cause chronic pyelonephritis. To test the role of the type IV collagen tropism of Dr-fimbriated E. coli in renal persistence, we constructed an isogenic mutant in the DraE adhesin subunit that was unable to bind type IV collagen but retained binding to DAF and examined its virulence in the mouse model. The collagen-binding mutant DrI113T was eliminated from the mouse renal tissues in 6 to 8 weeks, while the parent strain caused persistent renal infection that lasted at least 14 weeks (P < or = 0.02). Transcomplementation with the intact Dr operon restored collagen-binding activity, BM-interstitial tropism, and the ability to cause persistent renal infection. We conclude that type IV collagen binding mediated by DraE adhesin is a critical step for the development of persistent renal infection in a murine model of E. coli pyelonephritis.