Opioid therapy for chronic non-cancer pain: guidelines for Hong Kong.

Opioids are increasingly used to control chronic non-cancer pain globally. International opioid guidelines have been issued in many different countries but a similar document is not generally available in Hong Kong. Chronic opioid therapy has a role in multidisciplinary management of chronic non-cancer pain despite insufficient evidence for its effectiveness and safety for long-term use. This document reviews the current literature to inform Hong Kong practitioners about the rational use of chronic opioid therapy in chronic non-cancer pain. It also aims to provide useful recommendations for the appropriate, effective, and safe use of such therapy in the management of chronic non-cancer pain in adults. Physicians should conduct a comprehensive biopsychosocial evaluation of patients prior to the commencement of opioid therapy. When opioid use is deemed appropriate, the patient should provide informed consent within an agreement that specifies treatment goals and expectations. A trial of opioid can be commenced and, provided there is progress towards treatment goals, then chronic therapy can be considered at a dose that minimises harm. Monitoring of effectiveness, safety, and drug misuse should be continued. Treatment should be stopped when opioids become ineffective, intolerable, or misused. The driving principles for opioid prescription in chronic pain management should be: start with a low dose, titrate slowly, and maintain within the shortest possible time.

Highly efficient star formation in NGC 5253 possibly from stream-fed accretion.

Gas clouds in present-day galaxies are inefficient at forming stars. Low star-formation efficiency is a critical parameter in galaxy evolution: it is why stars are still forming nearly 14 billion years after the Big Bang and why star clusters generally do not survive their births, instead dispersing to form galactic disks or bulges. Yet the existence of ancient massive bound star clusters (globular clusters) in the Milky Way suggests that efficiencies were higher when they formed ten billion years ago. A local dwarf galaxy, NGC 5253, has a young star cluster that provides an example of highly efficient star formation. Here we report the detection of the J = 3→2 rotational transition of CO at the location of the massive cluster. The gas cloud is hot, dense, quiescent and extremely dusty. Its gas-to-dust ratio is lower than the Galactic value, which we attribute to dust enrichment by the embedded star cluster. Its star-formation efficiency exceeds 50 per cent, tenfold that of clouds in the Milky Way. We suggest that high efficiency results from the force-feeding of star formation by a streamer of gas falling into the galaxy.

Aperture-coupled MIM plasmonic ring resonators with sub-diffraction modal volumes.

We propose and investigate ultracompact aperture-coupled plasmonic ring resonators with submicron bending radii based on strongly-confined metal-insulator-metal plasmonic waveguides. Enhanced coupling can be obtained via diffraction by small apertures having typical widths between 50-100 nm in the metallic sidewall between the ring and bus waveguides. Both analytical model and rigorous FDTD simulations show that 500 nm-radius ring resonators can be obtained with low insertion loss, wide free spectral range and sub-diffraction cavity volume of less than 0.1(lambda(0)/n(eff))(3).

Photonic logic NOR gate based on two symmetric microring resonators.

We demonstrate an all-optical NOR logic gate based on symmetric GaAs-AlGaAs microring resonators whose resonances are closely matched. Two input pump data streams are tuned close to one resonance of the symmetric microrings to switch a probe beam tuned to another resonance by two-photon absorption. The switching energy of the gate is 20 pJ/pulse, and the switching window is 40 ps, limited by the carrier lifetime. The use of two rings provides for better cascading in photonic logic circuits because of the higher number of available ports.

Enhanced linear and nonlinear optical phase response of AlGaAs microring resonators.

We have constructed and characterized several optical microring resonators with scale sizes of the order of 10 microm. These devices are intended to serve as building blocks for engineerable linear and nonlinear photonic media. Light is guided vertically by an epitaxially grown structure and transversely by deeply etched air-clad sidewalls. We report on the spectral phase transfer characteristics of such resonators. We also report the observation of a pi-rad Kerr nonlinear phase shift accumulated in a single compact ring resonator evidenced by all-optical switching between output ports of a resonator-enhanced Mach-Zehnder interferometer.

All-optical time-division demultiplexing and spatial pulse routing with a GaAs/AlGaAs microring resonator.

We report what is to our knowledge the first demonstration of all-optical time-division demultiplexing and spatial pulse routing in a compact nonlinear GaAs/AlGaAs microring resonator operating at 1.55 microm . Switching is through the refractive-index change induced by two-photon absorption. The switching time of the device, limited by the ring-charging time and the recombination time of the induced carriers, is measured to be 30 ps. The switching on-off contrast, limited by the slight mismatch between the input and output coupling coefficients, exceeds 8 dB. The device can be used for time-division multiplexing as well.

Spherical episodic ejection of material from a young star.

The exact processes by which interstellar matter condenses to form young stars are of great interest, in part because they bear on the formation of planets like our own from the material that fails to become part of the star. Theoretical models suggest that ejection of gas during early phases of stellar evolution is a key mechanism for removing excess angular momentum, thereby allowing material to drift inwards towards the star through an accretion disk. Such ejections also limit the mass that can be accumulated by the stellar core. To date, these ejections have been observed to be bipolar and highly collimated, in agreement with theory. Here we report observations at very high angular resolution of the proper motions of an arc of water-vapour masers near a very young, massive star in Cepheus. We find that the arc of masers can be fitted to a circle with an accuracy of one part in a thousand, and that the structure is expanding. Only a sphere will always produce a circle in projection, so our observations strongly suggest that the perfectly spherical ejection of material from this star took place about 33 years earlier. The spherical symmetry of the ejecta and its episodic nature are very surprising in the light of present theories.

Vertically coupled GaInAsP--InP microring resonators.

Vertically coupled microring resonator channel-dropping filters are demonstrated in the GaInAsP-InP material system. These devices were fabricated without regrowth. In this method, low-loss single-mode waveguides are removed from the growth substrate and bonded to a GaAs transfer substrate with benzocyclobutene. This permits fabrication of vertically coupled waveguides on both sides of the epilayer. Optical quality facets are obtained by cleaving through the transfer substrate. Operation of single-mode, single-ring optical channel-dropping filters is demonstrated.

Wavelength conversion in GaAs micro-ring resonators.

Tightly confined, low-loss waveguides in highly nonlinear materials permit nonlinear optical interactions to occur over much shorter distances than do fibers. The nonlinear interactions are further enhanced in resonators. Both theory and experiment of enhanced four-wave mixing in micro-ring resonators are presented that can be used for many applications. A conversion efficiency of 14% achievable with only 10-mW peak pump power is predicted under realizable conditions. The experiment, the first one to the authors' knowledge in nonlinear optics performed in micro-rings, shows, even in a lossy GaAs/AlGaAs ring, a 26-dB improvement in the conversion efficiency compared with that of an equivalent straight waveguide, in agreement with theory.

Pervasive developmental delay in children presenting as possible hearing loss.

OBJECTIVE/HYPOTHESIS: Children who fail to develop adequate language skills and/or appropriate social skills by age 2 years often are referred to the department of otolaryngology for otolaryngologic examination and evaluation of possible hearing deficits. Discovering a gross disparity between hearing function and language ability often uncovers an underlying developmental disorder satisfying criteria for diagnosis on the spectrum of autism and pervasive developmental delay (PDD). The otolaryngologist has a unique opportunity to identify these autistic children and initiate their evaluation and management. STUDY DESIGN: Retrospective review. METHODS: Review of charts of children referred over the past 4 years to the Department of Otolaryngology for possible hearing loss identified 15 children who were later diagnosed with PDD. RESULTS: Fifteen children initially referred for hearing evaluation were subsequently identified with a diagnosis of PDD. Males outnumbered females 4 to 1, with the average age of referral being 2 years. One third of the patients displayed middle ear disease that improved with PE tube placement. One third of the patients showed brainstem conduction dysfunction on auditory brainstem evoked response testing. CONCLUSIONS: Children with developmental delays, especially higher functioning ones, may present with a myriad of language and communication deficits that are often mistakenly attributed to hearing loss. Otolaryngologists and audiologists can assist in their early identification and appropriate referral for therapy.

Cancer recurrences and secondary primary cancers after use of antihistamines or antidepressants.

OBJECTIVES: Reports in the scientific literature have described accelerated tumor growth in association with antidepressant and antihistamine exposure in experimental rodent cancer models. This study was designed to determine whether exposure to prescription antidepressants or antihistamines is associated with tumor growth in humans. METHODS: Two nested case-control studies were conducted with a cohort of 1467 patients with breast cancer, colon cancer, or melanoma diagnosed between 1988 and 1994. Eligible patients included 95 with a cancer recurrence and 78 with a second primary lesion diagnosed during the follow-up period. Five control subjects were matched to each case patient according to cancer site, stage, and follow-up time. Conditional logistic regression was used to compare risk for tumor recurrence or occurrence of a second primary tumor among patients using antidepressants or antihistamines with risk among unexposed patients. RESULTS: For a cohort of patients who were predominantly female (78%), with breast cancer (57%) and with a tumor in situ or with localized disease (79%), the average age was 62 years at cancer diagnosis and average duration of follow-up period was 2.2 years. Use of antidepressants or antihistamines was unrelated to risk for tumor recurrence (odds ratio, 0.97; 95% confidence interval, 0.52 to 1.78) or second primary tumors (odds ratio, 0.94; 95% confidence interval, 0.50 to 1.77). CONCLUSION: Typical use of antidepressant or antihistamine drugs did not increase risk for recurrent or second primary tumors among patients with cancer.

Antisense oligonucleotides as therapeutics for malignant diseases.

The continued progress in our understanding of the biology of neoplasia and in the identification, cloning, and sequencing of genes critical to tumor cell function permits the exploitation of this information to develop specific agents that may directly modulate the function of these genes or their protein products. Antisense oligonucleotides are being investigated as a potential therapeutic modality that takes direct advantage of molecular sequencing. The antisense approach uses short oligonucleotides designed to hybridize to a target mRNA transcript through Watson-Crick base pairing. The formation of this oligonucleotide: RNA heteroduplex results in mRNA inactivation and consequent inhibition of synthesis of the protein product. A fundamental attraction of the antisense approach is that this method potentially may be applied to any gene product, in theory, for the treatment of malignant and non-malignant diseases. However, this simple and attractive model has proven to be much more complex in practice. A number of important challenges in the preclinical development of antisense oligonucleotides have been identified, including stability, sequence length, cellular uptake, target sequence selection, appropriate negative controls, oligonucleotide: protein interactions, and cost of manufacture. Although the biological activity of an oligonucleotide against its molecular target is theoretically sequence-dependent, the animal pharmacokinetics and toxicology of phosphorothioate analogues directed against vastly disparate gene products appear relatively non-sequence-specific. In oncology, a number of clinical trials have been initiated with antisense oligonucleotides directed against molecular targets including: p53; bcl-2; raf kinase; protein kinase C-alpha; c-myb. The experience gained from these early clinical trials will be applicable to the next generation of antisense agents in development. These may include molecules with novel backbones or other structural modifications, chimeric oligonucleotides, or peptide nucleic acids. Continued progress in this arena will require that many of the preclinical challenges confronting antisense development are satisfactory resolved.

Promising new agents under development by the Division of Cancer Treatment, Diagnosis, and Centers of the National Cancer Institute.

The Division of Cancer Treatment, Diagnosis and Centers of the National Cancer Institute (NCI) has a large program in clinical cancer therapeutics development. It currently holds investigational new drug applications for nearly 200 agents with which it sponsors clinical trials. In addition, it has a major preclinical development program. With the tremendous advances in our understanding of molecular and tumor biology during the past decade, the NCI's portfolio of agents has expanded beyond classical cytotoxic agents to include a wide variety of new molecular and therapeutic targets. In addition to agents with more conventional mechanisms of action, the NCI has targeted therapeutics programs that focus on tumor vasculature, cell cycle control and cell signaling, mechanisms of apoptosis, invasion and metastasis, and immunological recognition and response. Each of these focused areas includes agents of different classes and modes of action that are all directed at the target of interest. The scope of the NCI's program allows it to respond to incorporate promising new agents or targets as they arise and to prioritize them for use of preclinical and clinical resources. Agents in development through the NCI are derived from a number of diverse sources including its own screening efforts, academia, and numerous collaborations with the pharmaceutical and biotechnology industries. NCI works closely with collaborators to ensure complementary, non-duplicative clinical development and attempts to ensure that the full potential of promising agents is explored. A number of compounds in early clinical development or about to enter the clinic are discussed briefly in this manuscript.

Pediatric drug development: a perspective from the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI).

Well-designed and carefully conducted pediatric phase 1 trials are critical to the process of evaluating new agents for potential benefit in children with cancer, and the National Cancer Institute (NCI) has for a number of years sponsored pediatric phase I trials. The development of new agents for children with cancer differs in important ways from drug development for adults with cancer, primarily necessitated by the smaller number of children eligible for phase I trials in comparison to adults. Pediatric drug development is characterized by a greater need to prioritize new agents for evaluation, since many more agents can be evaluated in adults than can be evaluated in children. Pediatric phase I trials are also commonly conducted as multi-institutional collaborations, since most single institutions do not have enough eligible patients to complete phase I trials within a reasonable time. In addition, pediatric phase I trials begin at doses close to the adult maximum tolerated dose, thereby minimizing the number of patients required to complete pediatric phase I trials. While pediatric phase I trials have traditionally evaluated conventional cytotoxic agents, new classes of agents with distinctive mechanisms of action are entering clinical evaluation. These agents target specific cellular proteins (e.g., protein tyrosine kinases, protein kinase C isoforms, enzymes involved in controlling progression through the cell cycle). Determining whether these agents with specificity for critical cellular proteins will be effective anti-cancer agents will be an important objective of pediatric clinical investigations in the coming years.

A prospective evaluation of ifosfamide-related nephrotoxicity in children and young adults.

BACKGROUND: Ifosfamide has been associated with proximal renal tubular dysfunction resembling Fanconi-like syndrome and leading to rickets in young children. The characteristic manifestations of this nephrotoxicity include phosphaturia and hypophosphatemia, glycosuria, aminoaciduria, renal tubular acidosis, and urinary loss of low molecular weight serum proteins. However, the relationship between acute ifosfamide nephrotoxicity, which is frequently subclinical, and long term renal damage is unclear. In this prospective study, the laboratory features of ifosfamide-induced acute nephrotoxicity were characterized further and correlated with the development of chronic nephropathy. METHODS: The renal function of newly diagnosed children and young adults with high risk sarcomas was followed during therapy with a high dose ifosfamide-containing regimen. Serum and urine were collected regularly immediately before and after 5-day cycles of ifosfamide throughout treatment for determination of the fractional excretion of electrolytes (sodium, potassium, phosphate, magnesium, calcium) and glucose and urinary excretion of amino acids and beta 2-microglobulin. RESULTS: Significant changes in the renal threshold of phosphate excretion, the fractional excretion of calcium and glucose, and the urinary excretion of beta 2-microglobulin were observed when comparing pretreatment values with those at the end of a 5-day treatment cycle. The median renal threshold of phosphate excretion decreased from 1.22 to 0.82 mmol/L (P < 0.0001). The median fractional excretions of calcium and glucose increased from 1.05% to 1.68% (P < 0.0001) and 0.05% to 0.08% (P = 0.0006), respectively. Beta 2-microglobulin excretion increased by 70-fold from 0.02 to 1.42 mg/mmol (P < 0.0001). Except for glucose and beta 2-microglobulin excretion, renal parameters returned to baseline before the next ifosfamide treatment cycle. Acute aminoaciduria was observed in 21 of 23 patients. Chronic nephrotoxicity, as defined by the development of a Fanconi-like syndrome or chronic tubular electrolyte loss requiring oral supplementation, developed in the three patients with the highest urinary excretion of beta 2-microglobulin after ifosfamide therapy. CONCLUSIONS: Prospectively, high dose ifosfamide was associated with a 4% incidence of Fanconi-like syndrome; however, evidence of acute reversible subclinical nephrotoxicity was observed for all patients. Severe beta 2-microglobulinuria appeared to be a prognostic laboratory indicator for the development of chronic nephrotoxicity.

A high-resolution image of atomic hydrogen in the M81 group of galaxies.

It has long been recognized that interactions between galaxies are important in determining their evolution. The distribution of gas--out of which new stars are formed--is strongly affected; in particular, gas may be concentrated near the nucleus, leading to a burst of star formation. Here we present a map of atomic hydrogen (H I) in the nearest interacting group of galaxies (that dominated by M81), obtained by combining 12 separate fields observed with the Very Large Array. The H I that surrounds M81, M82 and NGC3077 (the most prominent galaxies in the group) is dominated by filamentary structures, clearly demonstrating the violent disruption of this system by tidal interactions. These observations should have detected all H I complexes more massive than 10(6) solar masses, meaning that our map contains all structures that might evolve into new dwarf galaxies.