Recent developments and new applications of tandem mass spectrometry in newborn screening

PURPOSE OF REVIEW: To summarize recent developments in the field of newborn screening related to the use of tandem mass spectrometry as an analytic platform. RECENT FINDINGS: Novel inborn errors of metabolism with informative amino acid and/or acylcarnitine profiles have been characterized, increasing the complexity of the differential diagnosis of abnormal results. In addition, methods have been developed for the analysis in dried blood spots of steroids and lysosomal enzymes. Previously unrecognized genotype/phenotype correlations have been found among cohorts of patients whose conditions were diagnosed by screening rather than clinically. Several government entities and professional organizations have issued position statements on newborn screening, and worldwide outcome studies continue to underscore the clinical and financial benefits of expanded newborn screening. SUMMARY: Although it is done inconsistently, newborn screening in the United States is undergoing a rapid expansion driven by the introduction of tandem mass spectrometry in at least 34 state programs. This technology is also used to detect disease markers beyond acylcarnitines and amino acids, as both primary and second-tier tests. In addition to analytic improvements, there is a trend toward the development of joint programs not limited to contiguous geographic areas, often based upon public-private partnerships. This review will summarize several new developments in the field that have occurred since early 2003 and will mention others likely to occur in the near future.     

Spectroscopic time-resolved diffuse reflectance and transmittance measurements of the female breast at different interfiber distances

The first, to our knowledge, in-vivo broadband spectroscopic characterization of breast tissue using different interfiber distances as well as transmittance measurements is presented. Absorption and scattering properties are measured on six healthy subjects, using time-resolved diffuse spectroscopy and an inverse model based on the diffusion equation. Wavelength-tunable picosecond-pulse lasers and time-correlated single-photon counting detection are employed, enabling fully spectroscopic measurements in the range 610 to 1040 nm. Characterization of the absorption and reduced scattering coefficients of breast tissue is made with the aim of investigating individual variations, as well as variations due to different measurement geometries. Diffuse reflectance measurements at different interfiber distances (2, 3, and 4 cm) are performed, as well as measurements in transmittance mode, meaning that different sampling volumes are involved. The results show a large variation in the absorption and scattering properties depending on the subject, correlating mainly with the water versus lipid content of the breast. Intrasubject variations, due to different interfiber distances or transmittance modes, correlate with the known structures of the breast, but these variations are small compared to the subject-to-subject variation. The intrasubject variations are larger for the scattering data than the absorption data; this is consistent with different spatial localization of the measurements of these parameters, which is explained by the photon migration theory.     

Clinical trial of time-resolved scanning optical mammography at 4 wavelengths between 683 and 975 nm

The first time-resolved optical mammograph operating beyond 900 nm (683, 785, 913, and 975 nm) is presently being used in a clinical trial to test the diagnostic potential of the technique in detecting and characterizing breast lesions. Between November 2001 and October 2002, 101 patients with malignant and benign lesions were analyzed retrospectively. Scattering plots, as derived from a homogeneous model, and late gated intensity images, to monitor spatial changes in the absorption properties, are routinely used. The intensity images available at four wavelengths provide sensitivity to the main tissue constituents (oxy- and deoxyhemoglobin, water, and lipids), in agreement with expected tissue composition and physiology, while the scattering plots mirror structural changes. Briefly, tumors are usually identified due to the strong blood absorption at short wavelengths, cysts to the low scattering, and fibroadenomas to low absorption at 913 nm and high at 975 nm, even though the optical features of fibroadenomas seem not to be uniquely defined. The effectiveness of the technique in localizing and discriminating different lesion types is analyzed as a function of various parameters (lesion size, compressed breast thickness, and breast parenchymal pattern). .     

Renal replacement therapy in acute renal failure

Acute renal failure (ARF) is a common condition in hospitalized patients. The aetiology and physiological characteristics differ from those of chronic renal failure (CRF) and both conditions should be approached differently. At present, the approach to the management of ARF is very heterogeneous. Attempts have therefore been made to improve consensus and to standardize treatment in the Acute Dialysis Quality Initiative (ADQI). Technology for the treatment of ARF is expanding. Traditional intermittent haemodialysis (IHD) is still a major treatment modality but continuous renal replacement therapies (CRRT) and slow, low-efficiency daily dialysis (SLEDD) are commonly used alternatives. Each modality has advantages and disadvantages, but to date no evidence exists for the superiority of one over the other. On the other hand, the availability of multiple options allows us to provide tailor-made treatment: the best modality is chosen depending on local expertise and the individual clinical scenario. Practice guidelines based on the best available evidence and the author's opinion are suggested.     

Early DNA vaccination of puppies against canine distemper in the presence of maternally derived immunity

Canine distemper (CD) is a disease in carnivores caused by CD virus (CDV), a member of the morbillivirus genus. It still is a threat to the carnivore and ferret population. The currently used modified attenuated live vaccines have several drawbacks of which lack of appropriate protection from severe infection is the most outstanding one. In addition, puppies up to the age of 6-8 weeks cannot be immunized efficiently due to the presence of maternal antibodies. In this study, a DNA prime modified live vaccine boost strategy was investigated in puppies in order to determine if vaccinated neonatal dogs induce a neutralizing immune response which is supposed to protect animals from a CDV challenge. Furthermore, a single DNA vaccination of puppies, 14 days after birth and in the presence of high titers of CDV neutralizing maternal antibodies, induced a clear and significant priming effect observed as early as 3 days after the subsequent booster with a conventional CDV vaccine. It was shown that the priming effect develops faster and to higher titers in puppies preimmunized with DNA 14 days after birth than in those vaccinated 28 days after birth. Our results demonstrate that despite the presence of maternal antibodies puppies can be vaccinated using the CDV DNA vaccine, and that this vaccination has a clear priming effect leading to a solid immune response after a booster with a conventional CDV vaccine.     

Paragangliomas of the head and neck

Paragangliomas are neuroendocrine tumors derived from the extra-adrenal paraganglia of the autonomic nervous system. Within the head and neck, they are generally defined and named according to their site of origin, and may be found frequently neighboring vascular structures. Physiologic activity is rare in these neoplasms and they may exhibit patterns of inheritance which predispose their occurrence in families, often with multicentricity. These tumors generally exhibit a slow rate of growth, most often presenting asymptomatically as a space occupying mass lesion noted clinically or radiographically. The most common paraganglioma of the head and neck is the carotid body tumor followed by the jugulo-tympanic and vagal varieties. Other rare sites where this tumor may occur include; the larynx, sinonasal chambers and orbit. Diagnosis is generally made through a combination of clinical findings and radiographic studies. Magnetic resonance represents the most important imaging modality for the evaluation and characterization of suspected head and neck paraganglioma. Definitive management for these lesions should be carefully considered in relation to both tumor and patient-oriented factors, especially in regard to the potential morbidity of treatment. Surgery and radiation therapy represent the main treatment modalities for paraganglioma. The selection of treatment depends on the size, location, and biologic activity of the tumor as well as the overall fitness of the patient. Although radiotherapy may be effective in arresting growth of these tumors, rarely is the neoplasm eliminated without surgical resection. Surgery may be associated with significant morbidity, primarily as a consequence of incurring major cranial nerve injury. Patient selection (relative to age and medical condition) should be carefully considered prior to recommending aggressive surgery for paragangliomas of head and neck, especially in those patients at risk for disabling surgical morbidity.