Tightly locked optical frequency comb from a semiconductor disk laser.

Ultrafast semiconductor disk lasers (SDLs) passively modelocked using semiconductor saturable absorbers mirrors (SESAMs) generate optical frequency combs (OFCs) with gigahertz line spacings - a regime where solid-state and fiber lasers struggle with geometrical and Q-switching limitations. We stabilized both the frequency comb spacing and the offset without any additional external optical amplification or pulse compression. The overall noise performance is competitive with other gigahertz OFCs. A SESAM-modelocked vertical external-cavity surface-emitting laser (VECSEL) at a center wavelength around 1 µm generates 122-fs pulses with 160 mW average output power and we only needed 17-pJ pulse energy coupled into a silicon nitride (Si3N4) waveguide for supercontinuum generation (SCG) and OFC offset stabilization.

Direct thermo-optical tuning of silicon microresonators for the mid-infrared.

We use light from a visible laser diode to directly tune silicon-on-chip microresonators by thermo-optical effect. We show that this direct tuning is local, non invasive and has a much smaller time constant than global temperature tuning methods. Such an approach could prove to be highly effective for Kerr comb generation in microresonators pumped by quantum cascade lasers, which cannot be easily tuned to achieve comb generation and soliton-mode locked states.

Frequency comb offset detection using supercontinuum generation in silicon nitride waveguides.

We present the first direct carrier-envelope-offset (CEO) frequency detection of a modelocked laser based on supercontinuum generation (SCG) in a CMOS-compatible silicon nitride (Si(3)N(4)) waveguide. With a coherent supercontinuum spanning more than 1.5 octaves from visible to beyond telecommunication wavelengths, we achieve self-referencing of SESAM modelocked diode-pumped Yb:CALGO lasers using standard f-to-2f interferometry. We directly obtain without amplification strong CEO beat signals for both a 100-MHz and 1-GHz pulse repetition rate laser. High signal-to-noise ratios (SNR) of > 25 dB and even > 30 dB have been generated with only 30 pJ and 36 pJ of coupled pulse energy from the megahertz and gigahertz laser respectively. We compare these results to self-referencing using a commercial photonic crystal fiber and find that the required peak power for CEO beat detection with a comparable SNR is lowered by more than an order of magnitude when using a Si(3)N(4) waveguide.

Ultrabroadband supercontinuum generation in a CMOS-compatible platform.

We demonstrate supercontinuum generation spanning 1.6 octaves in silicon nitride waveguides. Using a 4.3 cm-long waveguide, with an effective nonlinearity of γ=1.2 W(-1) m(-1), we generate a spectrum extending from 665 nm to 2025 nm (at -30 dB) with 160 pJ pulses. Our results offer potential for a robust, integrated, and low-cost supercontinuum source for applications including frequency metrology, optical coherence tomography, confocal microscopy, and optical communications.

Extended adjuvant temozolomide with cis-retinoic acid for adult glioblastoma.

OBJECTIVE: To determine the toxicity and effectiveness of 24 months of adjuvant temozolomide (tmz) with cis-retinoic acid (cra) for patients with glioblastoma. METHODS: This retrospective population-based review considered the charts of all patients diagnosed with glioblastoma in Manitoba and referred to a provincial cancer centre during 2002-2008. Consecutive patients came from a population-based referral centre and provincial cancer registry. All patients were treated according to the local standard of care with surgical resection followed by concurrent radiotherapy and tmz 75 mg/m(2) daily, followed by tmz 150-200 mg/m(2) for days 1-5, repeated every 28 days for up to 24 cycles, and cra 50 mg/m(2) twice daily for days 1-21, repeated every 28 days. The main outcome measures were safety, tolerability, and effectiveness of long-term tmz and cra. RESULTS: Of 247 patients diagnosed with glioblastoma in Manitoba during the study period, 116 started concurrent chemoradiotherapy, and 80 received adjuvant tmz. Of the patients who started concurrent chemoradiotherapy, 80 began adjuvant chemotherapy. Patients completed a median of 5.5 cycles of tmz and 3 cycles of cra. Grade 3 or 4 hematologic toxicity was noted in 16% of patients. Median overall survival was 15.1 months, and 26.7% of patients remained alive at 2 years. CONCLUSIONS: Extended adjuvant tmz and cra is well tolerated. However, the population-based effectiveness of this regimen is similar to the clinical trial efficacy of 6 months of adjuvant tmz. Future studies in glioblastoma should incorporate duration of adjuvant chemotherapy into the study design.

Maple syrup urine disease: further evidence that newborn screening may fail to identify variant forms.

Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has allowed for early detection and initiation of treatment in many patients with maple syrup urine disease (MSUD) (OMIM 248600), however, a recent report suggests that variants forms may be missed. Information on these patients is limited. We present clinical, biochemical and molecular information on patients with variant forms of MSUD not detected by the California Newborn Screening Program. Between July 2005 and July 2009, 2200,000 newborns were screened in California by MS/MS. Seventeen cases of MSUD were detected and three (two siblings) were missed. Additionally, the NBS cards of two siblings with late onset MSUD, who were born pre-expanded NBS, were retrospectively analyzed. None of the five patients met criteria to be considered presumptive positive for MSUD (leucine>200micromol/L and a ratio of leucine/alanine>or=1.5). Alloisoleucine (allo-ile) was subsequently analyzed in the NBS cards of all five patients, two of whom were found to have elevated levels. The proband in each family was diagnosed following symptoms triggered by an intercurrent illness or increased protein intake. At diagnosis, leucine levels ranged between 561 and >4528micromol/L, and allo-ile ranged from 137 to 239micromol/L. Two affected siblings had normal plasma amino acids when asymptomatic; however, their biochemical profiles were diagnostic of MSUD during intercurrent illnesses. The median age at diagnosis of all patients was one year (range 0.8-6.7). Heterozygous BCKDHB (E1beta) mutations (c.832G>A/c.970C>T) were identified in one family and a homozygous DBT (E2) sequence variant (c.1430 T>G) in another. The third family had one identifiable DBT mutation (c.827T>G), however, a second mutation was not detected. This report provides further evidence that NBS by MS/MS is unable to detect all cases of MSUD. Second-tier testing with allo-ile may improve sensitivity; however, some children with variant forms will invariably be missed.

Clinical and molecular features of mitochondrial DNA depletion due to mutations in deoxyguanosine kinase.

Published mutations in deoxyguanosine kinase (DGUOK) cause mitochondrial DNA depletion and a clinical phenotype that consists of neonatal liver failure, nystagmus and hypotonia. In this series, we have identified 15 different mutations in the DGUOK gene from 9 kindreds. Among them, 12 have not previously been reported. Nonsense, splice site, or frame-shift mutations that produce truncated proteins predominate over missense mutations. All patients who harbor null mutations had early onset liver failure and significant neurological disease. These patients have all died before 2-years of age. Conversely, two patients carrying missense mutations had isolated liver disease and are alive in their 4th year of life without liver transplant. Five subjects were detected by newborn screening, with elevated tyrosine or phenylalanine. Consequently, this disease should be considered if elevated tyrosine is identified by newborn screening. Mitochondrial DNA content was below 10% of controls in liver in all but one case and modestly reduced in blood cells. With this paper a total of 39 different mutations in DGUOK have been identified. The most frequent mutation, c.763_c.766dupGATT, occurs in 8 unrelated kindreds. 70% of mutations occur in only one kindred, suggesting full sequencing of this gene is required for diagnosis. The presentation of one case with apparent viral hepatitis, without neurological disease, suggests that this disease should be considered in patients with infantile liver failure regardless of the presence of neurological features or apparent infectious etiology.

A5814G mutation in mitochondrial DNA can cause mitochondrial myopathy and cardiomyopathy.

We describe a 5-year-old child with hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis. Mitochondrial DNA analysis showed a heteroplasmic A5814G point mutation in the tRNA(Cys) gene. The mutational load was extremely high (>95%) in muscle, fibroblasts, and blood. This report expands the clinical heterogeneity of the A5814G mutation, which should be considered in the differential diagnosis of hypertrophic cardiomyopathy in childhood.

Severe lactic acidosis caused by a novel frame-shift mutation in mitochondrial-encoded cytochrome c oxidase subunit II.

We report the first frame-shift truncation mutation in a mitochondrial DNA (mtDNA)-encoded subunit II of cytochrome c oxidase (COXII). The mutation was identified by temporal temperature gradient gel electrophoresis (TTGE) followed by direct DNA sequencing in an infant who died at 12 days of age following a course of apnea, bradycardia, and severe lactic acidosis. The patient had a twin brother who died at two days of age of similar course. The mutation, 8042delAT, produced a truncated protein that was 72 amino acids shorter than the wild type protein. The mutant protein, missing one third of the amino acid residues at the C-terminal essential for hydrophilic interaction with cytochrome c, ligand binding to CuA and Mg, and the formation of proton and water channels, apparently has devastating effects on mitochondrial respiratory function.

Novel approach for specific detection of herpes simplex virus type 1 and 2 antibodies and immunoglobulin G and M antibodies.

Recently a few new herpes simplex virus (HSV) type-specific serological diagnostic tests have been introduced to the commercial market, but these tests have some limitations. Moreover, it is not yet clear which commercial test can be regarded as a "gold standard" for the serodiagnosis of HSV infections. In order to improve the clinical diagnostic value of serological tests for the detection of HSV infections, we developed novel, competition-based enzyme-linked immunosorbent assays for the specific determination of HSV type 2 antibodies (SeroHSV2) and HSV type 1 antibodies (SeroHSV1) and two complementary tests for the detection of HSV immunoglobulin M (IgM) and IgG antibodies (SeroHSV IgM and SeroHSV IgG). These four new kits were evaluated in comparison with some commercial kits for the detection of HSV antibodies that are commonly used at present in Israeli clinical laboratories. The results indicate that SeroHSV2 is highly sensitive (>92%) and highly specific (>94%). SeroHSV2 does not cross-react with other alphaherpesvirus antibodies. SeroHSV1 is highly sensitive (>94%) and specific (>91%) compared to four commercial available kits. SeroHSV IgM is highly specific (>92%) in comparison with other commercial HSV IgM tests. The sensitivity of SeroHSV IgM ranges between 50 and 70% compared to these tests. Further investigation of the discrepant results obtained by using in-house competition tests indicated that SeroHSV IgM is more sensitive. SeroHSV IgG was also found to be highly sensitive (>94%) and highly specific (>92%) compared to the other commercial HSV IgG tests.

Medical education about end-of-life care in the pediatric setting: principles, challenges, and opportunities.

OBJECTIVE: To identify the opportunities for and barriers to medical education about end-of-life (EOL) care in the pediatric setting. METHODS: A working group of pediatric specialists and ethicists was convened at the National Consensus Conference on Medical Education for Care Near the End-of-Life sponsored by the Open Society Institute's Project Death in America and the Robert Wood Johnson Foundation. The charge to the working group was to consider the unique aspects of death in childhood, identify critical educational issues and effective instructional strategies, and recommend institutional changes needed to facilitate teaching about EOL care for children. CONCLUSIONS: Although providing EOL care can be challenging, the cognitive and psychologic skills needed can be taught effectively through well-planned and focused learning experiences. The ultimate goals of such instruction are to provide more humane care to very sick children, enhance bereavement outcomes for their survivors, and develop more confident clinicians. Six specific principles regarding EOL care in the pediatric setting emerged as essential curricular elements that should be taught to all medical care providers to ensure competent patient-centered care. 1) Cognitively and developmentally appropriate communication is most effective. 2) Sharing information with patients helps avoid feelings of isolation and abandonment. 3) The needs of the patient are served when the ethical principles of self-determination and best interests are central to the decision-making process. 4) Minimization of physical and emotional pain and other symptoms requires prompt recognition, careful assessment, and comprehensive treatment. 5) Developing partnerships with families supports them in their caregiving efforts. 6) The personal and professional challenges faced by providers of EOL care deserve to be addressed. These principles actually transcend patient age and can be used to inform medical education about the care of any terminally ill patient. Similarly, these principles of effective communication, ethical decision-making, and attention to the quality of life of patients, families, and providers apply to the care of all children regardless of diagnosis and prognosis. With this in mind, teaching about EOL care does not require a new and separate curriculum, but rather taking better advantage of the many teachable moments provided by caring for a dying patient.

Multifocal osteosarcoma following retinoblastoma.

Three survivors of retinoblastoma, one with hereditary bilateral and two with nonhereditary (spontaneous) unilateral disease, developed multifocal osteosarcoma. For one patient, unilateral retinoblastoma was followed by primitive neuroepithelioma at age 13 years. Multifocal chondroblastic osteosarcoma represented the patient's third malignant neoplasm. The course of multifocal osteosarcoma in these three patients compares to that of multifocal osteosarcoma which presents de novo in other patients without prior retinoblastoma.

Prenatal diagnosis of rhizomelic chondrodysplasia punctata due to isolated alkyldihydroacetonephosphate acyltransferase synthase deficiency.

Current practices in prenatal diagnosis of rhizomelic chondrodysplasia punctata (RCDP) are reviewed. A case is presented with a family having one daughter affected with RCDP due to alkyldihydroacetonephosphate acyltransferase synthase (DHAPAT synthase) deficiency, and three subsequent pregnancies. Biochemical test values are presented for the pregnancies and daughter. Post-mortem tests of one fetus of a terminated pregnancy showed that radiologic examination could not make the diagnosis of RCDP. We conclude that biochemical or molecular testing is necessary to accurately diagnose this type of RCDP prenatally.

Modulation transfer function of a lens measured with a random target method.

We measured the modulation transfer function (MTF) of a lens in the visible region using a random test target generated on a computer screen. This is a simple method to determine the entire MTF curve in one measurement. The lens was obscured by several masks so that the measurements could be compared with the theoretically calculated MTF. Excellent agreement was obtained. Measurement noise was reduced by use of a large number of targets generated on the screen.

Thanatophoric dysplasia type I with syndactyly.

We report on a case of thanatophoric dysplasia type 1 (TD1) due to a Tyr373Cys mutation in the fibroblast growth factor receptor 3 (FGFR3) gene with soft tissue syndactyly of the fingers and toes. Syndactyly has not been previously described in TD or other conditions with FGFR3 mutations, but occurs in several craniosynostosis syndromes due to mutations in FGFR2. We conclude that mutations in FGFR3 may also be associated with developmental abnormalities due to interference with programmed cell death.

Differential expression of fibroblast growth factor receptors 1 to 4 and ligand genes in late fetal and early postnatal rat lung.

To characterize fibroblast growth factor (FGF) gene expression in the late fetal (days E18 to E22) and early postnatal lung (days P0 to P28), when the alveolar region undergoes extensive growth and reorganization, we analyzed the expression of four FGF receptors and six ligands. FGF receptor 1 (FGFR1) RNA levels were first low (E18) before rising late in the postnatal period (P28). FGFR2 RNA levels were detected early (at E18) and then increased (E20-P0) before falling (P2) to below later postnatal levels (P6 to P28). FGFR3 RNA levels were low at first (E18) and then increased, with peak levels in the days after birth (P2 to P10). FGFR4 RNA levels, barely detected in fetal lung (E18 to E22), increased at birth (P0) and remained high postnatally (P2 to P28). In fetal lung, FGF2 (basic FGF) RNA expression levels were low and FGF1 (acidic FGF) RNA levels were not detected: low RNA levels of each ligand were detected postnatally (P7 to P28). FGF3 to 5 and FGF7 RNA were not detected in fetal or postnatal lung. With in situ hybridization, predominantly the smooth muscle cells of large vessels expressed FGFR1 and 4 mRNA; the epithelial cells of large airways expressed FGFR1, 2, and 4; and alveolar cells expressed FGFR2, 3, and 4. Analysis of protein expression first identified FGF2 localized to the basement membrane of large airways and branching epithelial buds, to mesenchymal cells associated with buds, to the putative smooth muscle cells of large airways and vessels, and to pleural- and mesenchymal-associated cells (E18). Immediately before birth, this pattern of expression persisted (E20 to E22), with FGF2 also being expressed by putative smooth muscle cells of smaller airways and vessels (E22). After birth (P0 to P28), FGF2 expression remained relatively high in the smooth muscle cells of large and small vessels and in pleural cells; in airway smooth muscle cells and in most cells in the alveolar region, however, although FGF2 expression persisted in some cells, its intensity decreased with time.

Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations.

Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST, FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269-270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition-such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes-support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.

Diverse mutations in the gene for cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple epiphyseal dysplasia disease spectrum.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are autosomal dominant osteochondrodysplasias that result in mild to severe short-limb dwarfism and early-onset osteoarthrosis. PSACH and some forms of MED result from mutations in the gene for cartilage oligomeric matrix protein (COMP; OMIM 600310 [http://www3.ncbi.nlm. nih.gov:80/htbin-post/Omim/dispmim?600310]). We report the identification of COMP mutations in an additional 14 families with PSACH or MED phenotypes. Mutations predicted to result in single-amino acid deletions or substitutions, all in the region of the COMP gene encoding the calmodulin-like repeat elements, were identified in patients with moderate to severe PSACH. We also identified within this domain a missense mutation that produced MED Fairbank. In two families, one with mild PSACH and the second with a form of MED, we identified different substitutions for a residue in the carboxyl-terminal globular region of COMP. Both the clinical presentations of these two families and the identification of COMP-gene mutations provide evidence of phenotypic overlap between PSACH and MED. These data also reveal a role for the carboxyl-terminal domain in the structure and/or function of COMP.

[How to reveal to children that they are infected with the HIV virus]. / Como revelarle a los ninos que estan infectados con el VIH.

AIDS: Revealing to a child his or her positive HIV status is not only a clinical dilemma, it is also an ethical dilemma. Parents question when to tell the child, when the child is mature enough to understand, who should tell the child, and whether not telling would protect the child. A number of situations must be considered, including the child's role in the family, trust and support, and the possibility of death. Patients' stories dealing with these various situations are provided.^ieng

Six patients with oral-facial-digital syndrome IV: the case for heterogeneity.

The oral-facial-digital syndromes (OFDS) have in common minor facial and oral anomalies (including tongue lobulation and/ or hamartomas, accessory frenula, and alveolar anomalies) and variable digital defects such as polydactyly. The classification based on the presence of additional findings [Toriello, 1988, 1993] is not perfect, as many reported examples of a particular OFDS have some other condition. Here we describe six children, all diagnosed as having OFDS IV (OFDS with tibial defects), whose manifestations illustrate the apparent genetic heterogeneity.