Frequency domain photon migration in the delta- P1 approximation: analysis of ballistic, transport, and diffuse regimes.

The standard diffusion approximation (SDA) to the Boltzmann transport equation (BTE) is commonly used to describe radiative transport for biomedical applications of frequency-domain diffuse optical imaging and spectroscopy. Unfortunately, the SDA is unable to provide accurate radiative transport predictions on spatial scales comparable to the transport mean free path and for media in which optical scattering is not dominant over absorption. Here, we develop and demonstrate the use of the delta- P1 approximation to provide improved radiative transport estimates in the frequency domain via the addition of a Dirac delta function to both radiance and phase function approximations. Specifically, we consider photon density wave propagation resulting from the illumination of an infinite turbid medium with an embedded, intensity-modulated, spherical light source. We examine the accuracy of the standard diffusion and delta- P1 approximations relative to Monte Carlo simulations that provide exact solutions to the BTE. This comparison establishes the superior accuracy of the delta- P1 approximation relative to the SDA that is most notable at distances less than 3 transport mean free paths from the source. In addition, we demonstrate that the differences in photon density wave propagation in a highly forward scattering medium (g1=0.95) vs an isotropically scattering medium (g1=0) provides a basis to define three spatial regimes where the light field is dominated by (a) unscattered/ballistic light, (b) minimally scattered light, and (c) diffusely scattered light. We examine the impact of optical properties, source modulation frequency, and numerical aperture of detection on the spatial extent and location of these regimes.

Nonsense and frameshift mutations in ZFHX1B, encoding Smad-interacting protein 1, cause a complex developmental disorder with a great variety of clinical features.

Mutations in ZFHX1B, encoding Smad-interacting protein 1 (SIP1), have been recently reported to cause a form of Hirschsprung disease (HSCR). Patients with ZFHX1B deficiency typically show mental retardation, delayed motor development, epilepsy, microcephaly, distinct facial features, and/or congenital heart disease, in addition to the cardinal form of HSCR. To investigate the breadth of clinical variation, we studied DNA samples from six patients with clinical profiles quite similar to those described elsewhere for ZFHX1B deficiency, except that they did not have HSCR. The results showed the previously reported R695X mutation to be present in three cases, with three novel mutations-a 2-bp insertion (760insCA resulting in 254fs262X), a single-base deletion (270delG resulting in 91fs107X), and a 2-bp deletion (2178delTT resulting in 727fs754X)-newly identified in the other three. All mutations occurred in one allele and were de novo events. These results demonstrate that ZFHX1B deficiency is an autosomal dominant complex developmental disorder and that individuals with functional null mutations present with mental retardation, delayed motor development, epilepsy, and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels.

Molecular analysis of Japanese patients with Rett syndrome: Identification of five novel mutations and genotype-phenotype correlation.

Rett syndrome is an X-linked dominant neurodevelopmental disorder that affects females almost exclusively. The recent identification of mutations of the methyl-CpG-binding protein 2 gene (MECP2) in patients with RTT, encouraged us to analyze the gene in 37 Japanese patients divided into classical RTT (14 cases), variant RTT (13 cases), and mentally retarded patients with Rett-like features (10 cases). Mutations in MECP2 were identified from most of the patients with classical and variant RTT (25 of 27 cases). Six reported common mutations were detected in 17 cases, and rare single nucleotide substitutions were found in 3 patients. In addition, one insertion mutation (1189insA) and four deletion mutations including one double deletion mutant (451delG, 100del4, 1124del53 and 881del289 plus 1187del8) were newly identified. In the 10 mentally retarded patients with Rett-like features, however, no mutation was detected in the coding region of MECP2. The finding of MECP2 mutations in 92.5% of patients with RTT indicates that RTT fulfilling the diagnostic criteria are due to genetic alteration.

Perturbation Monte Carlo methods to solve inverse photon migration problems in heterogeneous tissues.

We introduce a novel and efficient method to provide solutions to inverse photon migration problems in heterogeneous turbid media. The method extracts derivative information from a single Monte Carlo simulation to permit the rapid determination of rates of change in the detected photon signal with respect to perturbations in background tissue optical properties. We then feed this derivative information to a nonlinear optimization algorithm to determine the optical properties of the tissue heterogeneity under examination. We demonstrate the use of this approach to solve rapidly a two-region inverse problem of photon migration in the transport regime, for which diffusion-approximation-based approaches are not applicable.

Difficulty in writing Japanese semantic characters in a 9-year-old boy with Williams syndrome.

A 9-year-old boy diagnosed as having Williams syndrome was evaluated using psychological test batteries in order to clarify his ability in language and visual cognition. The subject had difficulty in writing some of the Japanese semantic characters (called Kanji) which he could otherwise read and understand. Although he could write the small components of which the Kanji characters were composed, he could not locate these correctly. This phenomenon is considered to be very similar to the difficulty in copying a figure observed clinically. The Kaufmann Assessment Batteries for Children clearly revealed that the boy had difficulty with the sub-test of spatial memory compared to his average score for simultaneous processing. This result is considered to be closely related to the difficulty in copying figures or writing Kanji characters. On the Illinois Test of Psycholinguistic Abilities, the present authors found that the subject's vocabulary was relatively good, although semantic and pragmatic problems remained. Clarifying the strong and weak points of the abilities of such patients will help to determine the most appropriate mode of education for them.

Structural property and in vitro self-assembly of shark type I collagen.

The main structure of shark type I collagen is similar to that of land mammals, with a partial difference in amino acid sequence and post-translational modification. By static light scattering, the weight-average molecular weight of shark collagen (7.52 x 10(5)) suggests the presence of some aggregated molecules, oligomeric collagen. The self-assembly curve of shark collagen had a shorter lag phase and a longer growth phase than that of pig collagen. The optimum temperature and pH of shark collagen self-assembly is different from that of pig collagen.

Epilepsy in Angelman syndrome associated with chromosome 15q deletion.

We report eight sporadic cases of typical Angelman syndrome (AS) associated with chromosome 15q12 deletion. Age at first visit was 3-35 months (average 18 months), and follow-up period was 4-20 years (average 14.1 years). The characteristic features of epilepsy in AS are (a) seizure onset in early childhood (8 of 8); (b) evolution of seizure type with age (8 of 8); (c) EEG abnormality changes from high-voltage slow bursts (HVS) in infancy to diffuse spike and waves in middle childhood (4 of 5); (d) atypical absence seizures (8 of 8), often occurring as atypical absence status (4 of 8); and (e) diminution of seizure discharges and clinical seizures after puberty (7 of 7). We believe that AS may frequently exist in the intractable epilepsies of childhood with severe mental retardation. We stress the importance of AS as one of the main etiologic background diseases of the intractable epilepsies with infantile onset such as West syndrome, Lennox-Gastaut syndrome, and others.

Absence of erythrocyte arginase protein in Japanese patients with hyperargininemia.

In Japan, hyperargininemia has been reported in only 5 unrelated families and four patients are alive at present. In this study we examined arginase protein in erythrocytes of these Japanese patients using two analytical methods of immunoblotting and two-dimensional gel electrophoresis. Immunoblotting study with anti-E. coli-expressed human liver arginase rabbit IgG revealed lack of cross-reacting materials in the erythrocyte lysates from these patients. On two-dimensional gels, arginase protein was detected in any control subject, but it was completely absent in all the patients studied. These results suggest that either arginase protein in erythrocytes is not produced or it is structurally labile in these patients.

Nonketotic hyperglycinemia: treatment with NMDA antagonist and consideration of neuropathogenesis.

Patients with neonatal-onset nonketotic hyperglycinemia have high-glycine content in cerebrospinal fluid (CSF) which is believed to be a cause of intractable neurologic manifestations. The glycine receptor was believed to be inhibitory in the central nervous system; however, a newly discovered glycine receptor is of the excitatory N-methyl-D-aspartate (NMDA) receptor type, which cannot be antagonized by strychnine. The NMDA receptor antagonist, ketamine, was administered to a patient with nonketotic hyperglycinemia; he demonstrated some improvement in hyperirritability, voluntary movement, and electroencephalographic findings. Strychnine therapy had been administered before this trial of NMDA antagonist, but without improvement. The respiratory condition improved with the reduction of the CSF glycine level after withdrawal of sodium valproate. Our findings indicate that high-glycine content in CSF may affect the brain in different ways via NMDA and classic glycine receptors.

Homocitrullinuria and homoargininuria in hyperargininaemia.

A four-year-old boy with hyperargininaemia had increased urinary excretion of homocitrulline and homoarginine. A single oral lysine load created a marked increase in these amino acids in plasma. A daily oral lysine supplementation resulted in a remarkable urinary leakage of homocitrulline and homoarginine. These findings suggest that the patient had an enhanced synthesis of these amino acids.

Guanidino compounds in hyperargininemia.

Plasma and cerebrospinal fluid (CSF) concentrations and urinary excretion of guanidino compounds were investigated in a patient with hyperargininemia during the treatment with low-protein diet, oral administration of an essential amino acid mixture and sodium benzoate, or enzyme replacement therapy such as exchange transfusion or erythrocyte transfusion. In the patient, alpha-keto-delta-guanidinovaleric acid (GVA), N-alpha-acetylarginine (NAA), argininic acid (ArgA) and homoarginine concentrations in plasma were elevated as well as arginine. Urinary excretion of GVA, ArgA, NAA and gamma-guanidinobutyric acid (GBA) were also increased. CSF concentrations of ArgA, homoarginine and arginine were also elevated. On the other hand, guanidinosuccinic acid (GSA), which is usually detected in all samples, was not detected in plasma, CSF and urine of the patient. The present results suggest that in patients with hyperargininemia other factors such as arginine and its metabolites including GVA, GAA, ArgA and homoarginine may cause the neurological symptoms. Furthermore, it is suggested that in patients with hyperargininemia, arginine may be catabolized via other pathways and nitrogen may be excreted partially in urine in the form of some of guanidino compounds.

Enzyme replacement therapy in a patient with hyperargininemia.

In a patient with hyperargininemia, enzyme replacement therapy such as whole blood exchange transfusion or erythrocyte transfusion was performed, and its effect was confirmed in vitro as well as in vivo. The patient has been treated with the restriction of protein intake, oral administration of an essential amino acid mixture, and sodium benzoate or phenylacetic acid. With these treatments, his plasma ammonia levels were controlled. On the other hand, plasma and CSF concentrations of arginine were not so well controlled. With whole blood exchange transfusion and erythrocyte transfusion, plasma arginine concentrations and plasma ammonia levels were controlled. These effects have continued for about 3 months. Furthermore, the effect of exchanged erythrocytes on the blood arginine levels was also confirmed by in vitro experimentation that mixes arginine with erythrocytes in the medium RPMI 1640. Arginine concentration of the medium did not decrease when arginine was mixed with erythrocytes of the patient, but when arginine was mixed with erythrocytes of mother or normal controls, it decreased rapidly. In calculation, 10(7) of erythrocytes of the mother or normal controls was presumed to metabolize 4-5 nmole of arginine per day. From these results, the erythrocyte exchange transfusion is considered to be effective for the control of clinical and biochemical abnormalities in this disorder.

Increased urinary excretion of putrescine in hyperargininaemia.

A 4-year-old boy with hyperargininaemia had an increased urinary excretion of putrescine which was exaggerated with oral ornithine supplementation. It seems unlikely that putrescine was overproduced within the gut, because a loading with a single oral dose of ornithine showed that the intestinal ornithine absorption in the patient was normal. An acceleration of extramitochondrial ornithine metabolism due to impaired mitochondrial ornithine uptake may have caused the hyperexcretion of putrescine.

Selective binding behavior of zinc(II) and copper(II) ions to their native sites of apo-bovine superoxide dismutase.

The four binding constants of zinc(II) ions to apo-bovine superoxide dismutase were measured by the method of equilibrium dialysis. The binding constants (10(11.1)-10(10.9) M-1) of zinc ions to the native zinc sites were much larger than those to the native copper sites (10(7.8)-10(6.5) M-1) at pH 6.25. The competitive reaction between copper(II) and zinc(II) ions for the native copper sites of copper free bovine superoxide dismutase was also investigated. The native copper sites of bovine superoxide dismutase selectively react with copper ions, because the binding constants of copper ions for the native copper sites were much larger (10(6) times) than those of zinc ions.