Functioning human insulinomas

Sixty-seven insulinomas were investigated by immunohistochemistry using site-directed antibodies against insulin, proinsulin, chromogranin A, HISL-19, and four proteins directly or indirectly involved in the proteolytic processing of proinsulin: the prohormone convertases PC2 and PC3, carboxypeptidase H (CPH) and 7B2. Results were expressed in a six-grade score according to the frequency of immunoreactive tumour cells. Insulin was expressed by all tumours, appearing in either a diffuse or a polarized pattern and being detected in more than 30% of tumour cells in all cases but three. Proinsulin was also expressed in all tumours, with more than 50% of tumour cells immunoreactive in all cases but 5. It was consistently localized in the Golgi apparatus. In about half the cases, moreover, it also showed diffuse cytoplasmic staining, usually with a very sparse distribution. Trabecular and solid insulinomas did not present specific, homogeneous patterns of insulin immunostaining. However, insulin immunoreactivity was much more abundant in trabecular than in solid neoplasms, being present in virtually all tumour cells (score 6) in 50% and 8% of cases, respectively. Virtually all insulinomas expressed PC2, PC3, CPH and 7B2, usually in 30–100% of tumour cells, with a frequency significantly related to that of insulin. However, detection of PC2 and 7B2 was slightly less frequent than that of PC3 and CPH. In consecutive sections these proteins were found to be mostly co-localized with insulin and chromogranin A but not with proinsulin. They were heavily expressed in all 10 tumours with more than 10% of cells showing cytoplasmic proinsulin immunoreactivity, indicating that the leakage of proinsulin from the Golgi compartment is not associated with faulty expression of converting enzymes and possibly reflects a saturated processing capacity. HISL-19 immunoreactivity was found in both Golgi apparatus and insulin stores, indicating that the relevant antigen is different from all other proteins investigated. These results do not support a defect in expression or localization of proinsulin-processing enzymes in most insulinomas.     

Effectiveness of neonatal transport in New York city in neonates less than 2500 grams—A population study

In the past two decades, there has been a gradual trend to regionalization of perinatal care, categorization of hospitals and transport services for neonatal health care. The literature alludes to both beneficial and deleterious effects of neonatal transport (T) but no controls such as a matched nontransport (NT) population have been utilized to date.The major goal of this study was to evaluate the effect of neonatal transport from Level I and II high risk 2500 gm. neonates (born in NYC in one calendar year, 1979) compared to a cohort nontransported population matched for hospital of birth, weight, race, sex and risk. All transported 2500 gm. from Level I and II (n=328) were studied and a stratified random sample of the nontransported (NT) infants 2500 gm. from these same hospitals (n=2042) was used for comparison. The principle outcome variable was survival. The major conclusion of this study is that in Level I and II hospitals the transport group had a significantly increased survival in infants who were sick (Apgar <6) compared to cohorted nontransported controls. Interhospital differences in survival were noted among Level I and II but not seen in the subdivisions of (A) and (B) hospitals.Angelo Ferrara, M.D., Ph.D., is Professor, Pediatrics, NYU Medical Center, New York, N.Y.: Melvin Schwartz, M.D., was Research Professor, Environmental Medicine, NYU Medical Center, New York, N.Y.; Helen Page, R.N., M.P.A., is Quality Assurance Reviewer, Manhattan Eye, Ear, Throat Hospital, New York, N.Y.: Morton Israel, M.A., is Research Scientist, Health Resources Administration, City of N. Y., New York, N.Y.; Yucel Atakent, M.D., M.S., is Clinical Associate Professor, NYU Medical Center, New York, N.Y.; C.E. Smith, Ph.D., is President, Health Policy Analysis & Accountability Network, Inc. (HPAAN), Edgewood, New Mexico; Leon Landovitz, Ph.D., is Vice President, Management Information Systems, Healthways System Inc., Islin, N.J.Supported by NCHSR Grant #5-R018-HSO3832     

Effect of interferon-alpha therapy on epitope-specific cytotoxic T lymphocyte responses in hepatitis C virus-infected individuals.

The majority of hepatitis C virus (HCV)-infected individuals fail to resolve the infection and become chronically infected despite the presence of HCV-specific CTL responses directed to different HCV-derived peptide antigens. Only a minority of individuals is able to clear the virus by mounting efficient CTL responses early after acute infection, but at present it is not clear whether viral clearance is associated with CTL responses of defined specificity. To elucidate those responses associated with improvement of the disease, we analyzed CTL responses to 16 different HLA-A2-presented, HCV-derived epitopes in 12 chronically infected patients, 14 chronically infected patients treated with interferon-alpha, and in one patient with acute symptomatic disease. We show here that the majority of chronically infected individuals present CTL responses directed to an NS4-derived peptide antigen (amino acids 1789-1797). Treated patients presented stronger HCV-specific CTL responses and therapy-induced changes in CTL target choice. In particular, 13 out of 14 individuals responded to an NS3-derived epitope (amino acids 1073-1081). By longitudinal analysis we show that five individuals responding to IFN-alpha therapy with decreases in alanine aminotransferase levels presented a strong CTL activity directed to the NS3-derived epitope. One patient that spontaneously resolved the infection presented a generally strong CTL activity specific for HCV-derived epitopes with a dominant response to the NS3-derived peptide antigen. This suggests that CTL responses directed to this NS3-derived antigen may be beneficial for the control of HCV infection. Improvement of these responses may represent a therapeutic intervention in chronic HCV infection.     

Different patterns of 11q allelic losses in digestive endocrine tumors

Most foregut digestive endocrine neoplasms may be associated with the multiple endocrine type 1 (MEN-1) syndrome. In contrast, midgut/hindgut carcinoids never show such association. To investigate the pathogenetic involvement of the MEN-1 gene and of putative additional oncosuppressor gene(s) distal to it, a comparative analysis of loss of heterozygosity (LOH) at chromosome 11q13 to 11qter was performed in 27 foregut (pancreatic endocrine tumors [PETs]), 23 midgut (ileal and appendiceal), and 3 hindgut (rectal) endocrine tumors. LOH at the MEN-1 gene locus at 11q13 was observed in 52% of the 23 sporadic and in all 4 MEN-1-associated PETs and was found to consistently and continuously span to the most distal marker investigated at 11qter. In contrast, only occasional, discontinuous, and mostly interstitial LOH for 11q markers was observed in ileal (midgut) carcinoids, whereas no LOH was found in all appendiceal (midgut) and rectal (hindgut) carcinoids. The consistent extension of LOH from the MEN-1 region to 11qter in sporadic PETs suggests a mechanism of gene inactivation via chromosomal breakage and complete loss of chromosome 11q; furthermore, these results expand beyond the 11q13 region the search for additional oncosuppressor gene(s) potentially involved in the genesis of these neoplasms. The low frequency, limited extension, and discontinuous distribution of 11q deletions in midgut/hindgut carcinoids suggest that MEN-1 gene is not involved in the pathogenesis of these tumors.     

Aerobic exercise performance correlates with post-ischemic flow-mediated dilation of the brachial artery in young healthy men

In older healthy men, aerobic exercise capacity is related to postischemic flow-mediated dilation of the brachial artery (FMD), but corresponding data in a younger population is not available. In addition, whether submaximal aerobic exercise performance also correlates with this kind of vasomotor reactivity is not known. Therefore, in 15 nonsmoking young healthy men [age 27 (5) years; body mass index: 24 (2) kg/m²; mean (SD)] with different levels of ordinary physical activity, but not performing upper-extremity training, we measured FMD at 1 min after reactive hyperemia, and pulmonary oxygen uptake (O₂) at ventilatory anaerobic threshold (O₂AT) and at peak effort (peak O₂) during an incremental exercise on a treadmill. In our participants, FMD was 9.1 (3.4)%, O₂AT was 40.72 (5.92) ml/kg per min, and peak O₂ was 52.95 (8.13) ml/kg per min. Using bivariate Pearsons correlation, and in separate multivariate regression analyses, O₂AT and peak VO₂ showed a significant and reasonably good correlation with FMD (r=0.84, P<0.001 and r=0.77, P=0.001, respectively), independent of age, body mass index and serum total cholesterol (=0.77, P<0.001, R² of the overall model=0.79 and =0.70, P<0.005, R² of the overall model=0.69, respectively). Our data provide evidence suggesting that in young healthy men a higher submaximal and maximal aerobic exercise performance is associated with a greater FMD of peripheral conduit arteries.     

Outbreak of infection with hepatitis A virus (HAV) associated with a foodhandler and confirmed by sequence analysis reveals a new HAV genotype IB variant

An outbreak of infection with hepatitis A virus associated with a foodhandler and involving 26 subjects occurred in Southern Italy. Sequence analysis of the VP3-VP1 and VP1-P2A junctions confirmed that the outbreak was due to a point source and allowed the identification of a new genotype IB variant. This report confirms the usefulness of sequence-based molecular fingerprinting during outbreaks.     

Corticospinal excitability and sleep: a motor threshold assessment by transcranial magnetic stimulation after awakenings from REM and NREM sleep

Transcranial magnetic stimulation (TMS) is a recently established technique in the neurosciences that allows the non-invasive assessment, among other parameters, of the excitability of motor cortex. Up to now, its application to sleep research has been very scarce and because of technical problems it provided contrasting results. In fact delivering one single suprathreshold magnetic stimulus easily awakes subjects, or lightens their sleep. For this reason, in the present study we assessed motor thresholds (MTs) upon rapid eye movement (REM) and non-rapid eye movement (NREM) sleep awakenings, both in the first and in the last part of the night. Taking into account that a full re-establishment of wake regional brain activity patterns upon awakening from sleep needs up to 20-30 min, it is possible to make inferences about the neurophysiological characteristics of the different sleep stages by analyzing the variables of interest immediately after provoked awakenings. Ten female volunteers slept in the lab for four consecutive nights. During the first night the MTs were collected, following a standardized procedure: 5 min before lights off, upon stage 2 awakening (second NREM period), upon REM sleep awakening (second REM period), upon the final morning awakening (always from stage 2). Results showed that MTs increased linearly from presleep wakefulness to REM sleep awakenings, and from the latter to stage 2 awakenings. There was also a time-of-night effect on MTs upon awakening from stage 2, indicating that MTs decreased from the first to the second part of the night. The increase in corticospinal excitability across the night, which parallels the fulfillment of sleep need, is consistent with the linear decrease of auditory arousal thresholds during the night. The maximal reduction of corticospinal excitability during early NREM sleep can be related to the hyperpolarization of thalamocortical neurons, and is in line with the decreased metabolic activity of motor cortices during this sleep stage. On the contrary, the increase of MTs upon REM sleep awakenings should reflect peripheral factors. We conclude that our findings legitimate the introduction of the TMS technique as a new proper tool in sleep research.