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Based on the ability to recruit lymphocytes and dendritic cells to lymphoid tissue and to promote inflammation, we hypothesized a role for dysregulated CCL19 and CCL21 levels in human immunodeficiency virus (HIV)-infected patients with advanced immunodeficiency, and in particular in those with accompanying Mycobacterium avium complex (MAC) infection. The hypothesis was explored by studies in HIV-infected patients with and without MAC infection, as well as in vitro, examining the ability of proteins from MAC to promote CCL19 and CCL21 responses in peripheral blood mononuclear cells (PBMC) during highly active anti-retroviral therapy (HAART). Our main findings were: (i) raised serum levels of CCL19 in HIV-infected patients with CD4(+) T cell count <50 cells/µl compared with HIV-infected patients with CD4(+) T cell count >500 cells/µl and healthy controls, with particularly high levels in those with MAC infection; (ii) elevated plasma levels of CCL19 predicted a higher mortality in acquired immune deficiency syndrome (AIDS)-patients, independent of ongoing MAC infection; and (iii) marked production of CCL19 in MAC-stimulated peripheral blood mononuclear cells (PBMC) and pronounced disturbances in MAC-induced CCL19 production in PBMC from HIV patients that was partly reversed during HAART. Our findings suggest the involvement of CCL19 in AIDS patients with advanced immunodeficiency, potentially mediating both adaptive and maladaptive responses.

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BACKGROUND: It is well documented that highly active antiretroviral therapy (HAART) restores systemic immunity to human immunodeficiency virus (HIV) but the effect of this treatment on the mucosal immune system is less clear. AIMS: Because future preventive or therapeutic vaccines against HIV may be administered by the mucosal route, we wished to evaluate the effect of HAART on the activation level and homeostasis of the intestinal B cell system. PATIENTS AND METHODS: Duodenal biopsy specimens were collected consecutively from infection prone HIV positive adults (n = 31), mostly with advanced AIDS. In situ two colour immunofluorescence staining was performed to quantify mucosal immunoglobulin (Ig) class and subclass producing immunocytes (plasmablasts and plasma cells). RESULTS: HIV positive patients had, on average, duodenal proportions of IgA (74.6%), IgM (19.5%), and IgG (3.4%) immunocytes similar to median values recorded in 11 HIV seronegative healthy controls but the total immunocyte number per mucosal section length unit (500 microm) was significantly increased in patients (median 175 v 120 cells/unit; p<0.008), mainly comprised of IgA (p<0.02) and IgG1 (median 81.8% of total IgG; p<0.02) isotypes. Patients receiving a successful HAART regimen tended to normalise their IgG1 proportion and showed significantly lower total duodenal IgA immunocyte number than those receiving no or insufficient antiretroviral treatment (p<0.005). CONCLUSION: Our study demonstrated that advanced AIDS patients hyperactivate their intestinal B cell system. HAART could significantly reverse this perturbation, suggesting restored ability of the mucosal immune system to control intestinal infections.

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Cytidine deaminase (CDD) catalyzes the hydrolytic deamination of cytidine, which thereby is converted to uridine. CDD is found in serum and different tissues, with particularly high concentrations in polymorphonuclear neutrophils (PMN). We measured the CDD levels in plasma from patients with systemic meningococcal disease. Thirty-seven patients had significantly higher plasma levels of CDD than did 29 healthy control subjects (P=.0001). CDD levels in plasma or serum increased from a median of 96 ng/mL in healthy control subjects to medians of 168 ng/mL in patients without persistent shock (n=23; P=.001) and 422 ng/mL in patients with fulminant meningococcal septicemia (n=14; P=.0001). In most patients with fulminant septicemia, CDD levels in plasma increased during the first 3-53 h after the initiation of therapy (P=.003). CDD alone had no immediate harmful effect when injected into mice during a 4-day period. CDD may modulate the stimulatory effect of colony-stimulating factors on PMN in patients.

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Alterations in duodenal immunoglobulin (Ig-)producing cells after excessive physical stress (marathon running) were studied by immunohistochemistry in 11 well-trained male adults, both shortly after running (race time, approximately 3.00 h) and later on after a "resting period" of 8-12 weeks with normal training (7-20 h/week). The ratios of IgA-, IgM- and IgG-producing cells were similar in the two biopsy specimens and virtually identical to those in eight normal duodenal controls (medians 77.6% IgA, 18.6% IgM, and 2.5% IgG). However, in the first sample the total number of positive cells per intestinal length unit was increased in five for IgA and in seven for IgM, while it was decreased in eight for IgG compared with the second biopsy. Also, the IgA cell number tended to be slightly increased immediately after the race (median 128 cells/unit) compared with that in normal controls (median 111 cells/unit); the same tendency was found for all Ig classes considered together. This apparent change was not explained by a thickening of the mucosa. Our study showed that marathon runners seem to maintain or even enhance their intestinal IgA and IgM-production, in contrast to the IgA decrease reported for other compartments such as salivary secretions and peripheral blood. The tendency to slightly increased intestinal IgA and IgM immunocyte populations in some runners might reflect a stress-induced hormonal influence on the homing of primed B cells to the mucosa, or perhaps an immune response to elevated influx of stimulatory luminal antigens.

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Human immunodeficiency virus (HIV) is often combined with unexplainable diarrhoea and weight loss. This study was designed to see if changes in the intestinal mucosal structure could explain the malabsorption found in HIV-infected patients with diarrhoea. Twenty acquired immunodeficiency system (AIDS) patients, 19 men and 1 woman, CD4 < 0.01, with severe weight loss and with non-infectious chronic diarrhoea, were evaluated using a new intestinal function test (D-xylose breath test). Fifteen of the subjects were examined with an upper intestinal endoscopy with biopsy specimens taken from the duodenal mucosa. The function test showed that the D-xylose uptake was markedly decreased to the same extent as for patients with coeliac disease (breath index AIDS patients 9.4 (4.3-14.4), coeliac patients 15.6 (7.6-23.6), reference level 2.5 (2.4-2.9), urine excretion AIDS patients 20% (13-26), coeliac patients 22% (14-24), reference level 37% (32-42)). The severe malabsorption could not be explained by the slight mucosal changes occasionally seen by light microscopy with small mucosal inflammation and almost normal villi. However, electron microscopy showed enterocytes with signs of hypofunction and degeneration correlating better to the intestinal malabsorption found in patients with advanced HIV infection and chronic diarrhoea.

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Intravenous drug abuse is a well-known risk factor for acquiring hepatitis A infection. Among drug abusers most cases are sporadic, but epidemic outbreaks may occur occasionally. In this article we describe an epidemic outbreak including 144 serologically proved cases of hepatitis A among intravenous heroin and amphetamine abusers in Oslo. The outbreak lasted for 11 months. 59 (41%) of the patients were admitted to hospital. One of them died and seven developed severe but reversible acute hepatitis. We also registered 26 cases of hepatitis A among close contacts, 14 of whom were associated with a nosocomial outbreak that affected nurses, fellow patients and relatives. We do not know how the hepatitis A virus was introduced into the abuser population, but the further spread was probably dominated by a combination of faecal-oral transmission and parenteral transmission secondary to sharing needles. Although we were unable to detect hepatitis A virus in confiscated drug samples by means of polymerase chain reaction we cannot exclude that some abusers were infected by injection of contaminated amphetamine.

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The proportion of T-cell receptor gamma/delta+ cells and the CD4/CD8 ratio relative to all CD3+ intraepithelial lymphocytes (IEL) were determined by immunofluorescence in duodenal mucosa of late-stage (mostly CDC IVC1/D) subjects (n = 21) infected with human immunodeficiency virus type 1 (HIV-1). The gamma/delta fraction (median, 14.2%; range, 1.7 to 59.8%) was increased (P < 0.03) compared with that in HIV- controls (n = 11; median 2.8%; range, 0.3 to 38%). Also, the number of gamma/delta+ IEL per mucosal unit was increased (P < 0.05) in the HIV+ subjects (median, 11.1/U) compared with the controls (3.2/U). Approximately 100% of the gamma/delta+ IEL were CD8-, and most expressed the Vdelta1vJdelta1-encoded epitope (median, 90.9%). The total number of CD3+ IEL tended to be lower than in the controls (67.4 versus 72.9/U). Both the epithelium and the lamina propria contained mainly CD8+ T cells, the median ratios of CD4+ T cells being 1 and 7.6%, respectively. This result accorded with the reduced CD4 cell number in blood (median, 18 X 10(6)/liter). The HIV+ subjects had increased serum levels of neopterin and beta2-microglobulin (both P < 0.0001), probably reflecting immunostimulation. Serum neopterin and beta2-microglobulin were inversely related to duodenal gamma/delta IEL, particularly in the premortal group (r = -0.97 and r = -0.58, respectively). The increased gamma/delta IEL might reflect enhanced intestinal protection in late-phase HIV infection. Short survival expectancy (<7 months) was associated not only with high levels of neopterin and beta2-microglobulin but also with a reduced number of duodenal gamma/delta+ cells (P < 0.03).

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Patients with HIV infection often suffer from opportunistic and bacterial infections of the digestive tract. The most common agents are Candida albicans, Herpes simplex and Cytomegalovirus, Mycobacterium avium intracellulare, Cryptosporidium parvum, and enteropathogenic bacteria such as Salmonella, Shigella and Campylobacter. The diagnosis is established by means of microbiological examination of blood and faeces, often supplemented by gastrointestinal endoscopy, with mucosal biopsies for culture and histology. Most patients respond well to specific treatment, but the infections tend to relapse after withdrawal of drugs.

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Somatostatin produced in the D-cells of the stomach and the pancreas plays an important role in the carbohydrate metabolism and has been suggested to be involved in the disturbed glucose homeostasis during starvation. We investigated two groups of subjects during severe caloric deficiency. Nine healthy subjects (mean age, 32 years) fasted for 4 days, and the plasma concentration of somatostatin increased greatly, from 11.0 +/- 1.3 pM to 21.7 +/- 2.3 pM (p = 0.001). Intravenous infusion of 50 g glucose after a 60-h fast and oral loading of 50 g glucose after an 80-h fast normalized temporarily the plasma concentration within 45 min and 60 min, respectively. In another group of 12 subjects (mean age, 34 years), who participated in a 90-km cross-country ski race lasting 4.45-6.50 h and who were suspected of being in severely catabolic metabolic state, the plasma concentration of somatostatin increased from 6.1 +/- 0.8 pM to 26.9 +/- 4.7 pM (p < 0.001). Post-race oral feeding of 100 g glucose in seven of the subjects normalized the plasma concentration within 30 min, but the concentration remained increased in the five subjects who had no post-race caloric supply. The results indicate a close relationship between somatostatin and glucose during caloric deficiency in man.

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Two groups of long-distance runners were investigated for the effect of marathon running on the gastrointestinal mucosa. In one group gastric erosions with bleeding were found in five of nine subjects, mostly localized to the corpus region. The relative gastric blood flow measured by endoscopic laser Doppler flowmetry was slightly decreased in the cardia region (from 7.0 to 5.8; p less than 0.05) but unchanged in the other parts of the stomach, including the erosive lesions. In another group (n = 8) all the subjects showed a substantial increase in the urinary excretion of 51Cr-labeled ethylenediaminetetraacetic acid after oral intake, which indicates an increase in the intestinal permeability. There is reason to suggest that long-distance running affects the integrity of the gastric and the intestinal mucosa.

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Sphenoid sinusitis is an uncommon infection, but an early diagnosis and appropriate treatment is important because of its serious complications. We report 4 patients (28, 28, 37 and 28 years old) admitted to a department of infectious diseases with meningitis, sepsis and orbital cellulitis as complications of acute sphenoidal cavity infection. The cases illustrate the value of computed tomography (CT) scan of the sphenoid sinus in the evaluation of patients with clinical features suspicious of sphenoid sinusitis.

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To study the relationship between stress and the endoscopic diagnosis of erosive prepyloric changes (EPC), upper gastrointestinal endoscopy was performed twice in 19 cadets from the Military Academy, once in a 'non-stressed' situation and once after exposure to a standardized stress model. Five biopsy specimens per examination were obtained from the prepyloric mucosa, and the features of acute and chronic inflammation, erosion, and campylobacter-like structures (CLS) were evaluated. The endoscopy showed a significant (p less than 0.001) aggravation of EPC after stress. The histologic examination showed an increase of acute inflammation (p less than 0.05) and a higher density of CLS (p less than 0.01) after stress, as compared with the findings under non-stressed conditions. No association was observed between CLS and EPC. The study sheds new light on the pathogenesis of EPC, as it shows that EPC is aggravated during stress.

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Vasoactive intestinal polypeptide (VIP) and endotoxin (lipopolysaccharides, LPS) were measured in plasma samples from 11 patients with bacteriologically verified meningococcal disease. Five patients suffered fulminant septicaemia, developed severe septic shock, and 2 died due to circulatory collapse. Initially, all 5 had levels of VIP above 4 pM and plasma endotoxin above 200 ng/liter. Five patients were diagnosed as meningitis and 1 as having meningococcaemia, all with a normal circulatory state. None of these 6 patients had initially levels of VIP above 2.5 pM or endotoxin levels above 25 ng/liter (P less than 0.001). A correlation existed between plasma endotoxin and VIP levels (r = 0.735, P = 0.01). Sequentially collected samples from 3 patients showed rapidly declining VIP levels after initiation of antibiotic and fluid treatment. These results are in agreement with previous animal experiments, suggesting that endotoxin directly or indirectly stimulates the VIP-ergic nervous system in the initial phase of gram-negative septic shock in man.

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Eight healthy men were exposed to 5 days of continuous heavy exercise combined with caloric deficiency and sleep deprivation. Immediately after the stress period the fasting and postprandial intragastric bile acid concentration, pepsin concentration, and gastric juice acidity were measured. Compared with a control experiment performed 8 weeks later, the results from the stress period showed a sevenfold increase in the fasting concentration of intragastic bile acids (from 35 mumol/l to 256 mumol/l; p less than 0.02), there was a tendency towards an increase in the fasting intragastric pepsin concentration, and there was an increase (p less than 0.05) in the intragastric pH level throughout the 3rd postprandial hour. It appears that physical stress induces changes in the intragastric milieu that might dispose for mucosal lesions.

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The topography of cholinergic and substance P containing habenulo-interpeduncular projections has been studied in the rat. The research has been carried out by combining choline acetyltransferase and substance P immunohistochemistry to experimental lesions and biochemical assays in microdissected brain areas. In addition, computer-assisted image analysis has been performed in order to obtain quantification of immunohistochemical data. The results show that cholinergic and substance P containing neurons have a different localization in the medial habenula and project to essentially different areas of the interpeduncular nucleus. Cholinergic neurons are crowded in the ventral two-thirds of the medial habenula while substance P containing cells are exclusively localized in the dorsal part of the nucleus. In most parts of the interpeduncular nucleus, choline acetyltransferase and substance P containing fibres and terminals are similarly segregated and no overlapping is apparent except for the rostralmost and the caudalmost ends of the nucleus. Cholinergic activity is largely concentrated in the central core of the nucleus, while substance P is preferentially localized in the peripheral subnuclei of the interpeduncular nucleus. In addition, both substance P and choline acetyltransferase levels show peculiar regional variations along the rostrocaudal axis of the interpeduncular nucleus. The results of experimental lesions demonstrate that the substance P projection carried by each fasciculus retroflexus is prevailingly ipsilateral in the rostral part of the interpeduncular nucleus and becomes progressively bilateral as far as more caudal regions of the nucleus are reached. By contrast, the cholinergic projections carried by each fasciculus retroflexus intermingle more rapidly and only show a slight ipsilateral dominance in the interpeduncular nucleus. The results of the study are discussed with reference to previous anatomical and neurochemical data which, in several instances, had given rise to discrepant interpretations.

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Substance P (SP) has been determined by radioimmunoassay in the sciatic nerve and its fibular, tibial and sural branches; and in a red, slow-twitch and a white, fast-twitch muscle supplied by the sciatic nerve. The mixed sciatic nerve contained 25 ng SP per g tissue wet wt., while the sural branch, which is supplying mainly skin, and thus is rich in sensory fibres, had a significantly higher content (49 ng/g). The mixed fibular and tibial branches contained approximately the same amount as the sciatic nerve proper. SP was also found in the skeletal muscles. The red m. soleus had a significantly higher content (0.61 ng/g) than the white m. extensor digitorum longus (0.22 ng/g). A dorsal root lesion which leads to degeneration of sensory fibres, reduced the SP level more than 90% both in nerves and muscles. Ventral root section, which leads to degeneration of somato-motor fibres and terminals, had, on the other hand, no effect. We conclude that sensory neurons are the only source of importance for SP in the sciatic nerve and in skeletal muscles. Based on the above findings, the possibility that SP may function as a mediator of an axon reflex in skeletal muscle is discussed.

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Plasma renin activity (PRA), serum aldosterone and the serum and urinary levels of sodium and potassium have been investigated in 24 young men participating in a 5-day military training course with heavy continuous physical exercise, energy and sleep deprivation. The subjects were divided into three groups. Group 1 did not get any extra sleep or food, group 2 were compensated for the energy deficiency, and group 3 slept 3 h each night. The basic diet given to all the subjects was about 5,000 kJ and 2 g NaCl X 24 h-1 X cadet-1. The high calorie diet contained approximately 25,000-35,000 kJ and 20 g of NaCl X 24 h-1 X cadet-1. The study showed that serum aldosterone and PRA were extremely activated during such prolonged physical strain combined with lack of food and salt, whereas sleep deprivation did not seem to have any large influence. Only small variations were found in the serum levels of sodium and potassium and the urinary level of potassium during the course, whereas a decrease was seen in urinary sodium concentration. The fairly good correlations between the decrease in urinary sodium levels and the increase in PRA (r = 0.7) and further between PRA and serum aldosterone (r = 0.8) during the course indicate that there is a causal connection between the decrease in urinary sodium excretion and the increase in PRA and serum aldosterone.(ABSTRACT TRUNCATED AT 250 WORDS)

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Twelve healthy subjects were exposed to a 4-day period of hard physical exercise, calorie supply deficiency, and severe sleep deprivation. The basal acid output (BAO), the sham-feeding-induced acid output (MAOsh), and the pentagastrin-stimulated acid output (MAOpg) were measured immediately after this stress period and in a control experiment performed several weeks later. The stress induced a threefold increase in the median BAO and an increase (p less than 0.05) in the MAOsh, which, however, was not significantly elevated when basal-subtracted. MAOpg was unchanged. In contrast to acid, pepsin output was not influenced by stress. The human pancreatic polypeptide (hPP) level in serum increased twofold after the stress. The integrated hPP response induced by modified sham feeding was higher (p = 0.02) after the stress than in the control experiment. The results show that physical stress has separate influence on the gastric secretion of acid and pepsin.

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