Choices, challenges, and constraints: a pragmatic examination of the limits of mental age matching in empirical research.

The work of Ed Zigler spans decades of research all singularly dedicated to using science to improve the lives of children facing different challenges. The focus of this article is on one of Zigler's numerous lines of work: advocating for the practice of mental age (MA) matching in empirical research, wherein groups of individuals are matched on the basis of developmental level, rather than chronological age. While MA matching practices represented a paradigm shift that provided the seeds from which the developmental approach to developmental disability sprouted, it is not without its own limits. Here, we examine and test the underlying assumption of linearity inherent in MA matching using three commonly used IQ measures. Results provide practical constraints of using MA matching, a solution which we hope refines future clinical and empirical practices, furthering Zigler's legacy of continued commitment to compassionate, meaningful, and rigorous science in the service of children.

Phosrestin I undergoes the earliest light-induced phosphorylation by a calcium/calmodulin-dependent protein kinase in Drosophila photoreceptors.

Activation of PI-PLC initiates two independent branches of protein phosphorylation cascades catalyzed by either PKC or Ca2+/calmodulin-dependent protein kinase (CaMK). We find that phosrestin I (PRI), a Drosophila homolog of vertebrate photoreceptor arrestin, undergoes light-induced phosphorylation on a subsecond time scale which is faster than that of any other protein in vivo. We determine that a CaMK activity is responsible for in vitro PRI phosphorylation at Ser366 in the C-terminal tryptic segment, MetLysSer(P)IleGluGlnHisArg, in which Ser(P) represents phosphoserine366. We also demonstrate that Ser366 is the phosphorylation site of PRI in vivo by identifying the molecular species resulting from in-gel tryptic digestion of purified phospho-PRI using HPLC-electrospray ionization tandem quadrupole mass spectroscopy. From these data, we conclude that the CaMK pathway, not the PKC pathway, is responsible for the earliest protein phosphorylation event following activation of PI-PLC in living Drosophila photoreceptors.

Tumor of the heart diagnosed by magnetic resonance imaging.

A case of liposarcoma metastatic to the heart is presented. This is a very rare entity and only three prior case reports could be found. Magnetic resonance imaging was successfully used to visualize the tumor. These images compared favorably with a two-dimensional echocardiographic study and postmortem examination.

Topographic maps of brain electrical activity--pitfalls and precautions.

Topographic mapping of brain electrical activity is a popular, powerful, and potentially misleading technique. The map lies at the end of a long chain of physiological, technical, electronic, and mathematical processes and is vulnerable to artifact, error, and distortion at many points. Close attention must be paid to data collection parameters, subject cooperation, minimization of artifact, limitations of resolutions, selection, and transformation of parameters for display, and map generation strategy to yield an accurate, physiologically interpretable map. Review of the data at each step of analysis, from the paper electroencephalogram (EEG) to sets of maps on video display, may be necessary for optimum understanding. Development of more sophisticated qualitative and quantitative concepts of "normal" physiology is needed. These improvements in electrophysiological data analysis demand, rather than obviate, sophistication on the part of the user.

Spectral and topographic analysis of EEG in schizophrenic patients.

The authors performed spectral analysis of electroencephalograms (EEG), recorded awake, with eyes closed, in 13 patients with schizophrenia and 9 age-matched individuals without psychiatric diagnosis. We tested several possible parameterizations of the data, and two data-reduction strategies; these yielded similar results. Comparison of the two groups revealed a relative increase in alpha frequency activity in the frontal regions in the patient group. The authors believe that this finding is consistent with data from neuropsychologic tests, metabolic imaging studies, and evoked potential studies that suggest impaired activation of frontal brain areas in patients with schizophrenia.

Predominant presence of beta-arrestin-1 in small sensory neurons of rat dorsal root ganglia.

Reverse transcription-polymerase chain reaction and western immunoblot analyses were performed to demonstrate the presence of beta-arrestin-1 in rat dorsal root ganglion. beta-Arrestin-1 existed as two alternatively spliced variants, although predominantly in its untruncated form. Several factors affected the visualization of the truncated version on a sodium dodecyl sulfate-polyacrylamide gel; however, the isoform was clearly detected on a two-dimensional gel. We further localized beta-arrestin-1 immunoreactivity in the sensory neurons of the 5th lumbar dorsal root ganglia. Beta-arrestin-1-immunoreactive neurons accounted for approximately 60% of the sensory neurons, and approximately 88% of the beta-Arrestin-1 immunoreactive neurons fell into a category of small neurons having a diameter of 10-30 microm. Members of the arrestin superfamily play crucial roles in the desensitization of G protein-coupled receptors. Our data demonstrating the presence of beta-arrestin-1 in the rat dorsal root ganglion at both messenger RNA and protein levels support the idea that beta-arrestin- participates in receptor desensitization in the sensory neurons. Furthermore, because small-size neurons of dorsal root ganglion are often implicated in nociception, the predominant presence of beta-arrestin-1 immunoreactivity in small-size sensory neurons suggests that beta-arrestin-1 may have a role modulating nociceptive signals.

Renal cell carcinoma in patients with tuberous sclerosis.

An adolescent with anemia and weight loss was found to have bilateral renal cell carcinoma (hypernephroma). Further investigation revealed an underlying tuberous sclerosis that had escaped previous clinical detection. Several reports of this association were subsequently found when the world's literature was reviewed. Physicians treating patients with tuberous sclerosis should be aware of the possible development of these renal malignancies in their patients.

Correlation between clinical diagnoses and autopsy findings in critically ill children.

STUDY OBJECTIVE: To examine the correlation between clinical diagnoses and autopsy findings in children who die in the pediatric intensive care unit (PICU). DESIGN: Retrospective chart review. SETTING: PICU of a university-affiliated hospital. PATIENTS: A consecutive sample of patients who died in the PICU and had autopsies performed. MEASUREMENTS AND MAIN RESULTS: Of 193 patients who died during the 7 1/2-year study period, 50 (26%) had autopsies performed. The mean age was 34.7 months (range 15 hours to 17 years), and the mean length of stay in the PICU was 12.2 days (range 2 hours to 60 days). Major admitting diagnoses included postoperative cardiac surgery (19), nonoperative cardiac disease (7), hematologic/malignant disorder (5), and acquired immunodeficiency syndrome (5). There were 5 cases (10%) where autopsy revealed a major finding that, if known prior to death, would have altered clinical management and might have resulted in cure or prolonged survival. In another 9 patients (18%) the autopsy revealed major findings that, if known prior to death, would not have altered management. Eight of these findings related to the cause of death and 2 of them involved the basic disease. There was no correlation between new findings and either patient age or length of stay in the PICU. CONCLUSIONS: Despite modern diagnostic techniques, the autopsy continues to reveal valuable and unsuspected information.

Female external genitalia and müllerian duct derivatives in a 46,XY infant with the smith-lemli-Opitz syndrome.

We report on a 46,XY newborn infant with Smith-Lemli-Opitz (SLO) syndrome with female external genitalia, intraabdominal testes with epididymides and deferent ducts and a normally shaped uterus and vagina. Polydactyly, cleft palate, and several internal organ malformations were also present, and the patient died shortly after birth. Data on six reported male infants with SLO syndrome and female external genitalia suggest a correlation between degree of genital involvement and overall degree of severity. Scoring systems to quantify overall degree of severity (SLO score) and degree of genital involvement in males (genital score) were devised and applied to 122 reported cases from the literature. Statistical analyses showed a unimodal distribution of the SLO severity scores, and positive correlations between the SLO score and the genital score in males, the presence of polydactyly, and the presence of cleft palate. In 19 multiplex families the affected sibs were generally similar in their SLO scores. The above analyses suggest that the wide phenotypic variability in the SLO syndrome is determined by variable expressivity of the same entity as opposed to genetic heterogeneity. The observed phenotypic correlations naturally determine that males with complete feminization are among the more severe patients and tend to have polydactyly and cleft palate.

Renal-hepatic-pancreatic dysplasia: a syndrome reconsidered.

Five infants, three dying neonatally and two later in the first year of life, had renal, hepatic, and pancreatic dysplasia, a combination of abnormalities first described by Ivemark et al [1959]. The renal malformation consisted of cystic dysplasia, with abnormally differentiated ducts, deficient nephron differentiation, and glomerular cysts. The hepatic abnormality consisted of enlarged portal areas containing numerous elongated biliary "profiles," with a tendency to perilobular fibrosis. Serial liver biopsies in one child with cholestasis from birth showed a progression from bile duct paucity at 1 1/2 wk to typical biliary "dysgenesis" at 7 mo. Four of the five children had intrahepatic ductal dilatation, diagnosed ante mortem in the two older children as Caroli disease. The pancreatic abnormality consisted of fibrosis and cysts, with a diminution of parenchymal tissue. The clinical and functional reflection of these abnormalities in the two children surviving the newborn period included renal insufficiency, chronic jaundice, and insulin-dependent diabetes mellitus. Similar renal, hepatic, and pancreatic abnormalities occur in other syndromes, including trisomy 9, Meckel syndrome, Jeune, Saldino-Noonan, and Elejalde types of chondrodysplasia, and glutaric aciduria II. After exclusion of identifiable syndromes, the remaining cases of renal-hepatic-pancreatic dysplasia do not necessarily constitute a homogeneous group.

Four sibs with arterial tortuosity: description and review of the literature.

We described four offspring of a consanguineous couple with arterial tortuosity "syndrome" (ATS). The affected children had extensive arterial involvement although the clinical presentations were quite variable. Clinical manifestations included cutis laxa or soft/thin skin, joint laxity or contractures, and arachnodactyly. Aortic tortuosity and pulmonary artery aneurysms with or without peripheral stenoses were demonstrated in all four sibs. All three males had inguinal hernias. Inconsistent facial anomalies were downslanting palpebral tissues, beaked nose, micrognathia, and high-arched palate. Results of collagen type I and type III biosynthesis studies were normal on skin fibroblasts. Histologic findings on autopsy of one affected child showed arterial changes with disruption of elastic fibers of the media and fragmentation of the internal elastic membrane as well as mucosal and transmural necrosis of the stomach, small bowel, colon, and extensive necrosis of the liver. Coronary artery involvement was also seen in this child as well as biventricular hypertrophy. We conclude that ATS is an autosomal recessive connective tissue condition associated with diffuse arterial changes and involvement of the skin, joints, and other organs.

Identical twin discordance for the Brachmann-de Lange syndrome revisited.

The only known twin pair evidently discordantly affected for the BDLS (Brachmann-de Lange syndrome) and who had been considered monozygotic (MZ) based on blood analysis remained a problem because biological zygosity determination needed further typing. In this report we review the clinical findings of this pair of twins at the age of 20. The use of DNA fingerprinting with three multilocus probes, F10, DNF24, and 33.6, allowed us to present evidence of monozygosity with a high degree of certainty. The significance of this confirmation of discordance in determining the cause of BDLS is discussed. Intensive comparative genomic studies of the discordant twin sisters may be useful to unravel the molecular genetics of this enigmatic pattern of malformation.

The emerging role of mass spectrometry in molecular biosciences: studies of protein phosphorylation in fly eyes as an example.

Modern mass spectrometry (MS) streamlined with two-dimensional gel electrophoresis, in-gel digestion and HPLC-interfaced electrospray ionization quadrupole MS or matrix-assisted laser desorption ionization time-of-flight MS enables us to analyse proteins at a minuscule scale. We present here two examples of MS applications in which (1) we identified the in vivo phosphorylation site of Drosophila arrestin, phosrestin I (PRI), and (2) we revealed the identity of an 80 kDa phosphoprotein (80K) in Drosophila eyes to be the InaD gene product, a member of the PDZ domain proteins. Available evidence suggests that PRI quenches the activation of rhodopsin and that the InaD protein adjusts photoreceptor responsiveness by assembling/disassembling components involved in photoreceptor transduction in flies. PRI undergoes a reversible phosphorylation at a single site, and 80K at multiple sites. The phosphorylation states of PRI and 80K depend on the intensity and/or duration of light stimuli. From these results we postulate that these proteins function as a molecular switch adjusting the signalling cascade through phosphorylation. The combination of two-dimensional gel electrophoresis with MS will be a powerful tool for detailed investigation of such complex switching processes. The techniques described here can be applied also to other complex signalling systems.

Pseudopolyps of the small intestine in Crohn's disease.

The morphologic features of two types of pseudopolyps of the terminal ileum in a patient with Crohn's disease are described. One form of pseudopolyp is indistinguishable from that observed in the large intestine in Crohn's colitis, while the second, nodular lymphangiectasia, seems to be unique to the small bowel.

Metastatic malignant mesothelioma presenting as colonic polyps.

A 66-year-old male engineer diagnosed with malignant pleural mesothelioma 4 years previously had thoracotomy, radiotherapy, and chemotherapy. He was followed regularly with chest computed tomography (CT) scan and had been asymptomatic. During one of his physical examinations, routine sigmoidoscopy showed incidental colonic polyps which were biopsied. Subsequently, recurrence of pleural mesothelioma and peritoneal involvement by mesothelioma was documented. Two of the polyps showed metastatic malignant mesothelioma in the lamina propia which strongly resembled adenocarcinoma histologically causing difficulty in making definitive diagnosis. Review of the literature disclosed no previously documented similar occurrence. This case shows the importance of clinical history and ancillary laboratory procedures such as immunohistochemistry and electron microscopy to avoid diagnostic pitfalls.

Pancreatic disorders in pediatric acquired immune deficiency syndrome.

Acute pancreatitis, reported in 17% of pediatric patients with acquired immune deficiency syndrome (AIDS), is said to have a poor prognosis. We describe the pancreatic changes observed at autopsy from 71 children with human immunodeficiency virus (HIV) infection and document their nature, extent, and clinical relevance. The median age at autopsy of the children was 17 months (range, 2 months to 19 years); 38 were boys and 33 were girls. Parental intravenous drug use was the most frequent risk factor for AIDS, followed by blood transfusions. Respiratory failure and sepsis constituted the predominant causes of death. Nonspecific changes, such as edema, inflammation, fibrosis, inspissated material in acini and ducts, and enlarged Langerhans' islet predominated. Acute and chronic pancreatitis were mild except in one instance of a fatal acute probably dideoxyinosine-associated pancreatitis. Pancreatic involvement by opportunistic infections, such as cytomegalovirus (CMV), Mycobacterium avium intracellulare (MAI), and Candida, was focal and rare despite the high prevalence of these infections at autopsy. Focal lymphoplasmacytic infiltration and vascular calcifications were also observed. We conclude that pancreatic changes were frequently noted at autopsy in children with AIDS. They were usually mild, reflected systemic disease states, and were usually not life threatening. The incidence of opportunistic infections of the pancreas was low.

Hepatic pathology in pediatric acquired immunodeficiency syndrome.

In a retrospective study we assessed the hepatic changes in children with the acquired immunodeficiency syndrome by reviewing 12 biopsy specimens and 48 autopsy specimens from 54 children. Hepatopathology differed in biopsy and autopsy material. In biopsy specimens, chronic active hepatitis with predominantly T8 lymphocytes by tissue immunochemistry was common (five of 12 specimens). Fatty degeneration and hepatocellular necrosis were either absent, mild, or patchy. On the other hand, at autopsy, chronic active hepatitis was not observed. The most prominent changes were extensive fatty degeneration, nonspecific portal mononuclear infiltration, portal fibrosis, and confluent (ischemic) necrosis. Opportunistic infections such as Mycobacterium avium-intracellulare (MAI) were noted only at autopsy. In addition, three unusual morphologic characteristics were noted: nodular lymphoplasmacytic portal infiltrate, a pseudosarcomatous variant of Mycobacterium avium-intracellulare infection, and multinucleated giant cells (foreign both type and giant cell transformation of hepatocytes).

Impact of azithromycin on oropharyngeal carriage of group A Streptococcus and nasopharyngeal carriage of macrolide-resistant Streptococcus pneumoniae.

BACKGROUND: Invasive group A streptococcal (GAS) infections are a cause of serious morbidity and high mortality. There is a need for a simple, effective antimicrobial regimen that could be used to prevent invasive GAS disease in high risk situations. To assess azithromycin as a chemoprophylactic agent, we evaluated its efficacy for eradication of oropharyngeal (OP) GAS and its impact on the nasopharyngeal (NP) colonization rate of macrolide-resistant Streptococcus pneumoniae. METHODS: We obtained OP and NP swabs for GAS and pneumococcus culture, respectively, from 300 schoolmates of a child with an invasive GAS infection. GAS culture-positive students were treated with daily azithromycin (12 mg/kg/day) for 5 days. We obtained follow-up OP and NP swabs at 9 (Day 17) and 24 (Day 32) days post-treatment from those students identified as GAS carriers on Day 0 and determined macrolide susceptibility of GAS and pneumococcal isolates. RESULTS: Of the 300 students swabbed 152 (50%) carried GAS in their oropharynx. On Day 17, efficacy of azithromycin for GAS eradication was 95% (140 of 147) for all students. NP colonization rates for pneumococci decreased from 46% (67 of 146) to 12% (17 of 144; P < 0.001) by Day 17 and to 20% (27 of 137; P < 0.001) by Day 32. The prevalence of erythromycin-resistant pneumococcal isolates increased from 2% (3 of 146) to 4% (6 of 144) by Day 17 and to 8% (11 of 137; P = 0.04) by Day 32. CONCLUSIONS: Azithromycin is an effective short course regimen for eradication of oropharyngeal GAS. However, azithromycin selected for macrolide-resistant strains of pneumococci. These findings highlight the importance of determining the appropriate circumstances for antimicrobial prophylaxis to prevent invasive GAS infections.

Secondary ion mass spectrometry (SIMS) microscopy: a new tool for pharmacological studies in humans.

The secondary ion mass spectrometry (SIMS) microscope has opened new fields in biological investigation because of its ability to map chemical elements that are either naturally present in tissue or introduced for diagnostic or therapeutic purposes. In this review, we will describe our attempts to localise and quantify antitumor drugs in histological sections to better evaluate successful early cancer treatment. Detection is dependent on the presence of chemical elements in the drug structure, for example halogens (F, Br, I, At) which are imaged and quantified within the nuclei. Our methodological approach combines the results obtained with ionic and photonic microscopes on serial sections. Thus, the different structures in tumor tissue (blood vessels and cells) can be identified and drug localisation visualized. Using embedded samples, we demonstrate that both fluorine (19F) in 5-Fluorouracil and iodine (127I) in 4'-iododeoxyrubicin can be mapped in human biopsy material obtained after in vivo chemotherapy.

Islet cell hyperplasia: an unusual cause of hypoglycemia in an adult.

This is a case presentation of a 32-year-old man with a one year history of symptomatic hypoglycemia and documented elevations of his fasting plasma insulin to glucose ratio, caused by islet cell hyperplasia. Islet cell hyperplasia is a common cause of hypoglycemia in the pediatric population, but is very rare in adults. As in the pediatric group, adults should be treated with subtotal (75-85%) resection of the pancreas and with diazoxide for symptomatic recurrence of hypoglycemia. We suggest that the term islet cell hyperplasia is preferred to designate a diffuse proliferation of endocrine cells that may express itself with different morphologic patterns, varying from case to case. Islet cell hyperplasia, therefore, comprises nesidioblastosis, endocrine cell budding from ductal structures, as well as islet and islet cell hypertrophy, septal islets, islet dysplasia, and adenomatosis. Immunohistochemistry is a valuable method for the demonstration of the polymorphic hormonal content of the proliferated islet cells. We propose that the term nesidioblastosis, previously used to describe some similar cases, should be avoided because of confusion about its definition.