Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

The recent discovery of a novel family of precursor processing endoproteases has greatly accelerated progress in understanding the complex mechanisms underlying the maturation of prohormones, neuropeptides, and many other precursor-derived proteins. At least six members of this family have been found thus far in mammalian species, several having alternatively spliced isoforms, and related enzymes have been identified in many invertebrates, including molluscs, insects, nematodes, and coelenterates. The proprotein convertases are all dependent on calcium for activity and all possess highly conserved subtilisin-like domains with the characteristic catalytic triad of this serine protease (ordered Asp, His, and Ser along the polypeptide chain). Two members of this family, PC2(SPC2) and PC1/PC3(SPC3), appear to play a preeminent role in neuroendocrine precursor processing. Both convertases are expressed only in the brain and in the extended neuroendocrine system, while another important family member—furin/PACE (SPC1)—is expressed more ubiquitously, in almost all tissues, and at high levels in liver. SPC2 and SPC3 exhibit acidic pH optima and other properties which enhance their activity in the acidic, calcium-enriched environment of the dense-core secretory granules of the regulated pathway in neuroendocrine cells, while furin has a neutral pH optimum and is localized predominantly to the trans Golgi network where it is retained by a C-terminal transmembrane domain. Furin processes a wide variety of precursors in the constitutive pathway, such as those of growth factors, receptors, coagulation factors, and viral glycoproteins. Recent findings on the processing of proopiomelanocortin, proinsulin, proglucagon, and several other neuroendocrine precursors by SPC2 and SPC3 are discussed, along with information on the structure, properties, evolution, developmental expression, and regulation or the convertases. An inherited defect in the fat/fat mouse which affects the processing of proinsulin, and probably also many other prohormones, due to a point mutation in carboxypeptidase E has recently been identified and has begun to provide new insights into the functional integration of the individual processing steps.     

Impact of Ingested Liquids on 24-Hour Ambulatory pH Tests

A prospective investigation of the impact ofingested liquids on 24-hr pH test scores was conducted.Eighty-two patients contributed 142 samples. The liquidsused were coffee/tea (N = 35), water (N = 32), fruit juice (N = 29), cola (N = 34), and beer (N =12). The pH of cola, juice, and beer are approximately3.0. The parameters studied included: total test time,total drink time, total minutes of pH < 4.0 during drink, minutes of pH < 4.0 10 min beforedrink, and minutes of pH < 4.0 10 min followingdrink. Analysis was performed using one-way ANOVA andrepeated measures. Age of patients, total test time, and total time pH < 4.0 were notsignificantly different (P > 0.05). The total time toconsume the drink was significantly greater (P <0.05) for beer than all other liquids. The total time(7.7 ± 6.0 min) pH < 4.0 for cola wassignificantly different (P < 0.023) than beer (3.3± 3.7 min), tea/coffee (1.4 ± 6.5 min),and water (1.1 ± 2.5 min). The percentage oftotal time pH < 4.0 was not significantly different (P >0.05) among any of the liquids. The percentage of timepH < 4.0 during the drink was the highest for cola(63 ± 47%) and juice (51 ± 57%); water,coffee/tea, and beer were not significantly different (P> 0.05). Although the impact of cola and juice werethe greatest, none of these had an impact that exceeded0.5%. The lack of impact of beer appears to be due to the increased period of time it takes toconsume. We conclude that the impact of ingested fluidsis minimal and can probably be disregarded in mostpatient groups.     

Intra-abdominal desmoplastic small cell tumor presenting as an acute abdomen after trauma

The intraperitoneal mass most commonly encountered after blunt abdominal truama is a hematoma. However, one must also consider unusual bulky tumors that can have imaging characteristics similar to those of hematoma. The most typical of these neoplasms is lymphoma, but a desmoplastic small cell tumor also may be observed. The presentation and imaging findings of a desmoplastic small tumor are described.     

Biliary cystadenoma with mesenchymal stroma of the liver: Correlation between unusual MR appearance and pathologic findings

We reported a case of the biliary cystadenoma of the liver. The cystic mass had labulation and septation and showed marked hyperintensity on T1-weighted images and hypointensity on T2-weighted images; MR findings were very unusual for cystadenoma. The content of the cystic mass was jelly-like, thick mucinous fluid without intracystic hemorrhage. We concluded that these unusual signal intensities of the cyst were due to hyperproteinous mucinous fluid.     

Terminal acute myelogenous leukemia in a patient with congenital agranulocytosis

Congenital agranulocytosis terminating in acute myelogenous leukemia has been previously reported in only two cases of adolescent males. We describe the clinical and laboratory features of a 13-year-old male with congenital agranulocytosis, treated with G-CSF with initial good neutrophil response, who subsequently developed acute myeloid leukemia. This rare complication may define a preleukemic subset of patients for whom G-CSF therapy is ineffective. The diagnostic challenges of this case are presented.     

New evidence for a gating action of norepinephrine in central neuronal circuits of mammalian brain

Many previous studies have examined the effects of norepinephrine (NE) on neuronal responsiveness to synaptic inputs and putative transmitter substances and have described differential depressant actions of NE on stimulus evoked versus spontaneous discharge such that the "signal to noise" ratio of threshold responses was increased. In the present studies, similar experimental strategies employing a combination of microiontophoresis, single unit recording and afferent pathway stimulation in intact anesthetized and brain tissue slice preparations have revealed noradrenergic "gating" actions whereby weak or subthreshold synaptic stimuli can evoke threshold neuronal responses in the presence of iontophoretically applied NE or following electrical stimulation of the locus coeruleus. Overall, these results suggest that potentially threshold excitatory and inhibitory synaptic inputs may normally arrive at central neurons but appear weak or absent except during behavioral conditions favoring the synaptic release of NE. As such, these findings provide evidence that signal to noise ratio may not be the only potential modulatory action expressed by NE in noradrenergic target circuits of the mammalian brain.     

Correlation of manual dexterity and comprehension with oral hygiene and periodontal status in mentally handicapped adults

Although there is relatively little information concerning the oral health of handicapped adults there is increasing evidence to suggest that their oral condition, particularly periodontal health, is poor. The present investigation involved assessment of 382 handicapped patients attending four different Adult Training Centres in Birmingham. The caries status, oral hygiene, and periodontal conditions were evaluated and the Community Periodontal Index of Treatment Need (CPITN) was calculated. In order to assess the manual dexterity and the comprehension of the trainees a standard test was devised. This consisted of timing each participant in carrying out simple instructions to pick up and position certain common objects. The results indicated high levels of plaque, calculus, and bleeding with a mean CPITN of 7.43. The mean time taken for the manual dexterity and comprehension test was 23.9 seconds with a range from 10 to 80 seconds, S.E.+/- 1.33. This compares with results from 34 "normal" adults of a mean time of 8.2 seconds +/- 1.8 with a range of 6 to 12 seconds. There was no significant correlation between the Manual Dexterity and Comprehension scores and the periodontal indices in the handicapped adults.     

Electroconvulsive Therapy in the Medically Ill Elderly

Treatment with electroconvulsive therapy (ECT) of medically ill geriatric patients with affective disorders is described. Of 135 patients to whom ECT was administered in 6 years, 55% were over 60 years of age. One-third (45) exhibited cardiovascular (62%), central nervous system (15%), or other medical conditions (22%) increasing the risks of the treatment. Treatment strategies are described.     

The implementation of a knowledge-based pathology Hypertext under HyperCard

A knowledge-based Hypertext of Pathology integrating videodisc-based images and computer-generated graphics with the textual cognitive information of an undergraduate pathology curriculum has been developed. The system described in this paper was implemented under HyperCard⁰⁰ during 1988 and 1989. Three earlier versions of the system that were developed on different platforms are contrasted with the present system. Strengths, weaknesses, and future extensions of the system are enumerated. The conceptual basis and organizational principles of the knowledge base are also briefly discussed.     

Chlorinated hydrocarbon levels in human serum: Effects of fasting and feeding

Twenty healthy adult humans had serum samples drawn on four occasions within a 24-hr period: after a 12 hr overnight fast, 4–5 hr after a high fat breakfast, at midafternoon, and the next morning after another 12 hr fast. Nonfasting samples had 22% to 29% higher mean concentrations (p < 0.05) than did fasting samples for polychlorinated biphenyls (PCBs, 4.81 vs 3.74 ng/g serum wt), hexachlorobenzene (HCB, 0.163 vs 0.134 ng/g serum wt), andp,p-dichlorodiphenyldichloroethylene (p,p-DDE, 6.74 vs 5.37 ng/g serum wt) measured by electron capture gas liquid chromatography. Total serum lipids were estimated from measurements of total cholesterol, free cholesterol, triglycerides, and phospholipids and were 20% higher in nonfasting samples than in fasting samples (7.05 g/L vs 5.86 g/L). When PCBs, HCB, andp,p-DDE concentrations were corrected by total serum lipids, results from fasting and nonfasting samples were not statistically different. Because of the differences in these chlorinated hydrocarbon concentrations observed with different sample collection regimens, meaningful comparison of analytical results requires standardizing collection procedures or correcting by total serum lipid levels.