Spectral narrowing of Yb:YAG waveguide lasers through hybrid integration with ultrafast laser written Bragg gratings.

Laser written waveguides in crystalline materials can be used to make highly efficient, high gain lasers. The bi-directional emission from such lasers however is typically broadband with poor spectral control. Hybridizing a tapered, mode matched laser written Bragg grating with a broadband Yb:YAG crystalline waveguide laser, we demonstrate single longitudinal mode output from one end of the device. Careful control of the grating characteristics led to laser thresholds below 90 mW, slope efficiencies greater than 42% and output powers greater than 20 mW.

Competition of Faraday rotation and birefringence in femtosecond laser direct written waveguides in magneto-optical glass.

We consider the process of Faraday rotation in femtosecond laser direct-write waveguides. The birefringence commonly associated with such waveguides may be expected to impact the observable Faraday rotation. Here, we theoretically calculate and experimentally verify the competition between Faraday rotation and birefringence in two waveguides created by laser writing in a commercial magneto-optic glass. The magnetic field applied to induce Faraday rotation is nonuniform, and as a result, we find that the two effects can be clearly separated and used to accurately determine even weak birefringence. The birefringence in the waveguides was determined to be on the scale of Δn = 10(-6) to 10(-5). The reduction in Faraday rotation caused by birefringence of order Δn = 10(-6) was moderate and we obtained approximately 9° rotation in an 11 mm waveguide. In contrast, for birefringence of order 10(-5), a significant reduction in the polarization azimuth change was found and only 6° rotation was observed.

Annealing dynamics of waveguide Bragg gratings: evidence of femtosecond laser induced colour centres.

There is still significant speculation regarding the nature of femtosecond laser induced index change in bulk glasses with colour centre formation and densification the main candidates. In the work presented here, we fabricated waveguide Bragg gratings in doped and undoped phosphate glasses and use these as a diagnostic for monitoring subtle changes in the induced refractive index during photo- and thermal annealing experiments. Reductions in grating strengths during such experiments were attributed to the annihilation of colour centres.

High efficiency, multi-Watt CW yellow emission from an intracavity-doubled self-Raman laser using Nd:GdVO4.

Efficient multi-Watt continuous-wave (CW) yellow emission at 586.5 nm is demonstrated through intracavity frequency-doubling of a Nd:GdVO(4) self-Raman laser pumped at 880 nm. 2.51 W of CW yellow emission with an overall diode-to-yellow conversion efficiency of 12.2% is achieved through the use of a 20 mm long Nd:GdVO(4) self-Raman crystal and an intracavity mirror which facilitates collection of yellow emission generated within the resonator, and reduces thermal loading of the laser crystal.

Role of Epstein-Barr virus DNA measurement in plasma in the clinical management of nasopharyngeal carcinoma in a low risk area.

OBJECTIVE: To evaluate the role of quantitative measurement of Epstein-Barr virus (EBV) DNA in the clinical management of nasopharyngeal carcinoma (NPC) in a low tumour risk area (western Europe). METHODS: 22 consecutive Dutch NPC patients (11 europid) were studied. EBV DNA load in pretreatment and post-treatment plasma samples was determined. Three patients were also sampled at frequent intervals during treatment. RNA in situ hybridisation for the detection of EBV encoded RNAs (EBERs) was carried out on tumour biopsies of all cases. RESULTS: All patients with EBER positive NPC (20/22) showed a positive EBV DNA load in plasma at the time of diagnosis (median EBV DNA level, 4.1 log(10) copies/ml). Patients with EBER negative NPC had no detectable EBV DNA in plasma. After treatment, complete remission was achieved in all cases and concurrently EBV DNA in plasma became undetectable in all patients. In the three longitudinally evaluated cases, EBV DNA load gradually declined towards undetectable levels within three weeks after start of treatment. Two patients developed a distant metastasis with concomitant increases in EBV viral load. In addition, one EBER positive patient developed an EBER negative metastasis in the neck during follow up and in this case EBV DNA load remained undetectable at the time of recurrence. CONCLUSIONS: Plasma EBV DNA load measurement appears to be useful in a low tumour risk area. However, development of local recurrences may not always coincide with raised levels of EBV DNA.

A patient with dizziness, tachycardia and a DDDR pacemaker.

An 84-year-old female patient presented to the coronary care unit with dizziness. A DDD-R minute ventilation sensor pacemaker had been implanted eight years previously. The ECG showed an atrial and ventricular paced rhythm of 140 beats/min. After disconnecting the patient from the cardiac monitor the pacemaker rate dropped gradually to 90 beats/min. The cardiac rhythm monitoring system applies low-amplitude electrical pulses in order to measure respiration rate by transthoracic impedance (TTI) measurement. The minute ventilation pacemaker sensor is driven by the same TTI measurement for rate response. Inappropriate interference between these two systems caused a sensor-driven high pacemaker rate. The dizziness was not related to the sensor-driven high rate.

Increased prevalence of catecholamine excess and phaeochromocytomas in a well-defined Dutch population with SDHD-linked head and neck paragangliomas.

OBJECTIVE: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas. METHODS: We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a proven SDHD gene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done. RESULTS: Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catecholamine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by 123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-type SDHD allele in all cases. CONCLUSIONS: The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.

SDHD mutations in head and neck paragangliomas result in destabilization of complex II in the mitochondrial respiratory chain with loss of enzymatic activity and abnormal mitochondrial morphology.

Hereditary head and neck paragangliomas are tumours associated with the autonomic nervous system. Recently, mutations in genes coding for subunits of mitochondrial complex II, succinate-ubiquinone-oxidoreductase (SDHB, SDHC, and SDHD), have been identified in the majority of hereditary tumours and a number of isolated cases. In addition, a fourth locus, PGL2, has been mapped to chromosome 11q13 in an isolated family. In order to characterize phenotypic effects of these mutations, the present study investigated the immunohistochemical expression of the catalytic subunits of complex II (flavoprotein and iron protein), SDH enzyme activity, and mitochondrial morphology in a series of 22 head and neck paragangliomas. These included 11 SDHD-, one SDHB-, two PGL2-linked tumours, and eight sporadic tumours. In the majority of the tumours (approximately 90%), the enzyme-histochemical SDH reaction was negative and immunohistochemistry of catalytic subunits of complex II showed reduced expression of iron protein and enhanced expression of flavoprotein. Ultrastructural examination revealed elevated numbers of tightly packed mitochondria with abnormal morphology in SDHD-linked and sporadic tumours. Immuno-electron microscopy showed localization of the flavoprotein on the remnants of the mitochondrial inner membranes, whereas virtually no signal for the iron protein was detected. These results indicate that the function of mitochondrial complex II is compromised in the majority of head and neck paragangliomas.

Myringoplasty: is it worth performing in children?

OBJECTIVE: To evaluate the results of myringoplasty in children 4 to 14 years old at the time of surgery. DESIGN: Retrospective analysis of case notes for 100 consecutive children who had myringoplasty in a teaching hospital serving as a primary care and referral center. METHODS: Between March 1994 and March 1999, patients 14 years or younger at the time of surgery were identified by the computer database. There were 118 procedures performed in 100 patients (18 had a second procedure performed in the contralateral ear at a later date). Twenty-three patients were excluded because they underwent concurrent mastoid exploration, and 6 others because of inadequate follow-up, leaving 89 cases for analysis. Data from revision procedures were not included. MAIN OUTCOME MEASURES: Graft success was defined as an intact eardrum at 12 months postoperatively and middle ear effusion signaled graft failure. Success in terms of hearing was defined as an improvement in perception of pure-tone thresholds of 10 dB or greater over 2 consecutive frequencies compared with the results of the preoperative audiogram. RESULTS: Closure of perforation was achieved in 90% (80) of patients, but dropped to 88% (78) as 2 patients developed glue ear. Hearing improved in 64 patients (72%), deteriorated in 7 (8%), and remained unchanged in 18 (20%). There was no case of profound hearing loss. CONCLUSIONS: The success rate of myringoplasty in children is comparable to that reported for adults. The incidence of middle ear effusion in grafted ears is not higher than that reported for nongrafted ears, and children who have had myringoplasty can be treated as safely with ventilation tubes as any other children.

Passive mode locking of a self-frequency-doubling Yb:YAl(3) (BO(3))(4) laser.

We report passive mode-locking experiments with a novel self-doubling laser crystal Yb:YAl(3)(BO(3))(4) (Yb:YAB). The diode-pumped laser was mode locked by an ion-implanted semiconductor saturable absorber mirror. Far off phase matching, soliton mode locking produced pulse widths of 198 fs to 1.4 ps, with up to 660-mW output and optical efficiency of 24% at 1040 nm. The shortest pulses had a peak power of 28 kW with 440-mW average power and 16% efficiency. A few degrees off phase matching, a total of 60 mW of green femtosecond pulses was generated simultaneously. Close to phase matching, the laser produced picosecond pulses and, without infrared output, a total of 270 mW of green output, corresponding to 10% conversion efficiency (absorbed pump to green output).

Physical interaction between Wilms tumor 1 and p73 proteins modulates their functions.

The WT1 gene, which is heterozygously mutated or deleted in congenital anomaly syndromes and homozygously mutated in about 15% of all Wilms tumors, encodes tissue-specific developmental regulators. Through alternative mRNA splicing, four main WT1 protein isoforms are synthesized. All isoforms can bind to DNA via their zinc fingers, albeit with different affinities and specificities, and thereby modulate the transcriptional activity of their target genes. Several proteins bind to and alter the transcription regulatory properties of the WT1 proteins, including the product of the tumor suppressor gene p53. Interaction between WT1 and p53 was shown to modulate their ability to regulate the transcription of their respective target genes. Here, we report that all four isoforms of WT1 bind to p73, a recently cloned homologue of p53. p73 binds to the zinc finger region of WT1 and thereby inhibits DNA binding and transcription activation by WT1. Similarly, WT1 inhibits p73-induced transcription activation in reporter assays and counteracts p73-induced expression of endogenous Mdm2. This, taken together with our finding that WT1 also interacts with p63/KET, another p53 homologue, suggests that association between WT1 and the members of the p53 family of proteins may be an important determinant of their functions in cell growth and differentiation.

[Ocular hemoglobinometry--physiological variations]. / Die unblutige Hämoglobinmessung am Auge--ihre physiologische Variation.

BACKGROUND: To explore the relationship between ocular (fundus) hemoglobin and that sampled and measured conventionally. To look for differences in hemoglobin density determined by both methods when the body hemoglobin is acutely (blood donation) or pathologically e.g. anemia altered. PATIENTS AND METHODS: Conventional (capillary and antecubital) and ocular fundus (papillary and choroidal) determinations of hemoglobin density in 14 females and 23 males, aged 25 to 30 years were compared. Application of the ocular method before and after blood donation in 21 females and 12 males, aged 20 to 68 years was performed. All these subjects were ophthalmologically and systemically healthy. Five male and 5 female anemia patients, aged 27 to 90 years, were also measured as above. RESULTS: Good correlation between fundus hemoglobin density and capillary (r = 0.81) and venous (r = 0.61) hemoglobin was observed in healthy persons. Differences in hemoglobin density according to gender were obvious at all fundus sites measured. Following blood donation, papillary hemoglobin density in males moreover increased, while that in females decreased (F = 7.53), suggesting a gender-specific difference in the ocular blood regulation, an effect also noted in the anemia patients. CONCLUSIONS: Comparison of conventional and ocular determination of hemoglobin reveals good correlation in healthy people. However, in acute or chronic blood loss the papillary hemoglobin level differs from that measured peripherally. A gender-related regulatory capacity of the ocular tissues under low-level conditions can be shown: Male persons maintain ocular hemoglobin at a normal level even when peripheral hemoglobin falls to low values, whereas female persons show a decrease in ocular hemoglobin parallel to the venous levels. Hence, under such extreme conditions,--and only in males--the ocular method yields values other than those from the conventional method, because ocular regulatory mechanisms, otherwise undetected, are exquisitely revealed.

Efficient continuous-wave self-frequency-doubling green diode-pumped Yb:YAl(3)(BO(3))(4) lasers.

Efficient cw self-frequency-doubled green laser output of 160 mW has been obtained from Yb:YAl(3)(BO(3))(4) crystal pumped by 1.4-W incident power from a fiber-coupled 976-nm laser diode. The incident-pump-power-green-output-power conversion efficiency is greater than 11.3%, and the electrical-input-green conversion efficiency is 3.9%. Tunable green output from 513.0 to 545.8 nm is also demonstrated with a quartz birefringent filter.

Sutureless microvascular anastomoses by a biodegradable laser-activated solid protein solder.

A new sutureless technique to successfully anastomose the abdominal aorta of rats (1.3 mm in diameter) by using a fully biodegradable, laser-activated protein solder is presented. A total of 90 rats were divided into two groups randomly. In group one, the anastomoses were performed by using conventional microsuturing technique, whereas in group two, the anastomoses were performed by using a new laser welding technique. In addition, each of the two groups were divided into five subgroups and evaluated at different follow-up periods (10 minutes, 1 hour, 1 day, 1 week, and 6 weeks). At these intervals, the anastomoses were evaluated for patency and tensile strength. Three anastomoses in each subgroup were processed for light and electron microscopy. All anastomoses were found to be patent. The mean clamp time of the anastomoses performed with conventional suturing was 20.6 minutes compared with 7.2 minutes for the laser-activated welded anastomoses (p < 0.001). The strain measurements showed a stronger mechanical bond of the sutured anastomoses in the initial phase. However, at 6 weeks the tensile strength of the laser-welded anastomoses was higher compared with the conventional suture technique. Histologic evaluations revealed a near complete resorption of the solder after 6 weeks. The junction site of the vessel ends cannot be determined on the luminal side of the artery. In conclusion, a resorbable protein used as a solder, activated by a diode laser, can provide a reliable, safe, and rapid arterial anastomosis, which could be performed by any microsurgeon faster than conventional suturing after a short learning curve.

Tom22 is a multifunctional organizer of the mitochondrial preprotein translocase.

Mitochondrial preproteins are imported by a multisubunit translocase of the outer membrane (TOM), including receptor proteins and a general import pore. The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40 (refs 11-13). Here we report the unexpected observation that a yeast strain can survive without Tom22, although it is strongly reduced in growth and the import of mitochondrial proteins. Tom22 is a multifunctional protein that is required for the higher-level organization of the TOM machinery. In the absence of Tom22, the translocase dissociates into core complexes, representing the basic import units, but lacks a tight control of channel gating. The single membrane anchor of Tom22 is required for a stable interaction between the core complexes, whereas its cytosolic domain serves as docking point for the peripheral receptors Tom20 and Tom70. Thus a preprotein translocase can combine receptor functions with distinct organizing roles in a multidomain protein.

Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties.

The Wilms' tumor 1 gene, WT1, is homozygously mutated in a subset of Wilms' tumors. Heterozygous mutations in WT1 give rise to congenital anomalies. During embryogenesis, WT1 is expressed mainly in the kidneys, uterus, and testes. Alternative splicing of the WT1 mRNA results in synthesis of four main WT1 protein isoforms with molecular masses of 52-54 kDa. In addition, translation initiation at a CUG upstream of the initiator AUG generates four larger WT1 proteins of 60-62 kDa. We describe here the existence of novel WT1 isoforms and demonstrate that they are derived from translation initiation at the second in-frame AUG of the WT1 mRNA. These N-terminally truncated WT1 proteins of 36-38 kDa can be detected in several cell lines, mouse testes, and Wilms' tumor specimens. They can bind to DNA and direct transcription from reporter constructs. The shorter WT1 protein lacking the two splice inserts has a greater transcription activation potential than the corresponding main WT1 protein isoform but shows no transcription repression potential. Overexpression of full-length or N-terminally truncated WT1 efficiently induces apoptosis. These data show that additional WT1 isoforms with distinct transcription-regulatory properties exist, which further increases the complexity of WT1 expression and activity.

The preprotein translocase of the mitochondrial inner membrane: function and evolution.

Growing mitochondria acquire most of their proteins by the uptake of mitochondrial preproteins from the cytosol. To mediate this protein import, both mitochondrial membranes contain independent protein transport systems: the Tom machinery in the outer membrane and the Tim machinery in the inner membrane. Transport of proteins across the inner membrane and sorting to the different inner mitochondrial compartments is mediated by several protein complexes which have been identified in the past years. A complex containing the integral membrane proteins Tim17 and Tim23 constitutes the import channel for preproteins containing amino-terminal hydrophilic presequences. This complex is associated with Tim44 which serves as an adaptor protein for the binding of mtHsp70 to the membrane. mtHsp70, a 70 kDa heat shock protein of the mitochondrial matrix, drives the ATP-dependent import reaction of the processed preprotein after cleavage of the presequence. Preproteins containing internal targeting information are imported by a separate import machinery, which consists of the intermembrane-space proteins Tim9, Tim10, and Tim12, and the inner membrane proteins Tim22 and Tim54. The proteins Tim17, Tim22, and Tim23 have in common a similar topology in the membrane and a homologous amino acid sequence. Moreover, they show a sequence similarity to OEP16, a channel-forming amino acid transporter in the outer envelope of chloroplasts, and to LivH, a component of a prokaryotic amino acid permease, defining a new PRAT-family of preprotein and amino acid transporters.

Preprotein translocase of the outer mitochondrial membrane: molecular dissection and assembly of the general import pore complex.

The preprotein translocase of the outer mitochondrial membrane (Tom) is a multisubunit machinery containing receptors and a general import pore (GIP). We have analyzed the molecular architecture of the Tom machinery. The receptor Tom22 stably associates with Tom40, the main component of the GIP, in a complex with a molecular weight of approximately 400,000 ( approximately 400K), while the other receptors, Tom20 and Tom70, are more loosely associated with this GIP complex and can be found in distinct subcomplexes. A yeast mutant lacking both Tom20 and Tom70 can still form the GIP complex when sufficient amounts of Tom22 are synthesized. Besides the essential proteins Tom22 and Tom40, the GIP complex contains three small subunits, Tom5, Tom6, and Tom7. In mutant mitochondria lacking Tom6, the interaction between Tom22 and Tom40 is destabilized, leading to the dissociation of Tom22 and the generation of a subcomplex of approximately 100K containing Tom40, Tom7, and Tom5. Tom6 is required to promote but not to maintain a stable association between Tom22 and Tom40. The following conclusions are suggested. (i) The GIP complex, containing Tom40, Tom22, and three small Tom proteins, forms the central unit of the outer membrane import machinery. (ii) Tom20 and Tom70 are not essential for the generation of the GIP complex. (iii) Tom6 functions as an assembly factor for Tom22, promoting its stable association with Tom40.