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ObjectivesThe aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). MethodsAn open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naive patients with CD4 count 350 cells/L and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA ResultsFor the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA 400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. ConclusionsA single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

Contains fulltext : 47519.pdf (Publisher’s version ) (Closed access) BACKGROUND: To improve the dosing frequency and pill burden of antiretroviral therapy, we compared two once-daily dosed regimens to a twice-daily dosed regimen. METHOD: HIV-1-infected, antiretroviral drug-naive adults were randomized to either twice-daily nelfinavir and stavudine and once-daily didanosine (regimen A) or simplified once-daily dosed antiretroviral regimens consisting of nevirapine, didanosine, and lamivudine (regimen B) or saquinavir, ritonavir, didanosine, and lamivudine (regimen C). RESULTS: At 48 weeks of therapy, the proportion of patients with a blood plasma HIV-1 RNA concentration (pVL)

The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI).An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/μL and HIV-1 RNA30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/μL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59).For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm.A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

To the best of our knowledge, this is the first report of an HIV-infected patient successfully treated with chemotherapy for AML. We did not observed any effect of zidovudine alone on myeloid blast cells

Objective: To investigate the relationship between exposure to antiretroviral drugs and the initial decline of plasma HIV-1 RNA. Design: Open-label study in antiretroviral-naive HIV-1 infected patients using a quadruple drug regimen [nelfinavir (NFV), saquinavir (SQV), stavudine, and lamivudine]. Methods: The elimination rate constant (k) for HIV-1 clearance was calculated during the first 2 weeks of treatment in 29 patients. Exposure to NFV and SQV was quantified on each study visit. Observed NFV and SQV concentrations were related to those expected in a reference population and a concentration ratio was calculated. The median concentration ratios for NFV and SQV, the baseline CD4+ lymphocyte count and baseline log10 HIV-1 RNA were correlated with k. Results: A significant positive correlation was observed between k and the median NFV (P = 0.001) or SQV concentration ratio (P = 0.016) in univariate analysis. In multivariate analyses, the median NFV concentration ratio remained significantly correlated with k. Conclusions: The variation in the rate of decline of plasma HIV-1 RNA between patients after the initiation of a quadruple drug regimen could be explained by differences in exposure to NFV or SQV. Determination of k could be used to optimise further antiretroviral drug therapy and may be a first tool to assess antiretroviral activities of new or increasing doses of drugs administered in combination regimens. Furthermore, our data suggest that exposure to antiretroviral drugs should be incorporated in mathematical models to describe HIV-1 dynamics in more detail.

A 23-year-old black women with acute blurred vision of the right eye was referred for ophthalmological examination. Fundus examination and fluorescence angiography showed a non-ischaemic central retinal vein occlusion (papillophlebitis). The diagnosis of sarcoidosis, suggested by the presence of bilateral hilar and mediastinal lymphadenopathy, was confirmed by transbronchial biopsy of the lymphadenopathy demonstrating noncaseating granulomas. The eye problems were successfully treated with systemic corticosteroids. Central retinal vein occlusion is a rare complication of sarcoidosis.

Tako Tsubo cardiomyopathy is a serious condition that is caused by heart failure due to inordinate stress. We here present a case of a young woman with this disorder in association with anorexia nervosa. We postulate a pathophysiological relationship and discuss the management of Tako Tsubo cardiomyopathy.

Pepsinogen A (PGA) isozymogen patterns in urine and gastric mucosa can be visualised in non-denatured polyacrylamide gel electrophoresis by showing proteolytic activity after the conversion of pepsinogen into pepsin by acid. This method is not suitable for visualising PGA patterns in serum due to low PGA concentrations. To obtain a more sensitive visualisation method an immunoblotting technique was developed. PGA isozymogen patterns from urine and sonified gastric mucosa specimens obtained by immunoblotting were identical with those obtained by activity staining. The immunostaining method was at least 50 times more sensitive. PGA isozymogen patterns could be visualised in serum. Preliminary results suggest that the PGA patterns in serum and gastric mucosa are identical. As an association has been found between the genetically determined PGA isozymogen patterns in gastric mucosa and gastric malignancies in man, immunoblotting of PGA isozymogens in serum may provide a screening tool for subjects at risk of malignant gastric disease.

On two separate occasions, a total of eight subjects ate tuna fish. Three out of four persons in the first case (a father aged 54, a mother aged 51 and a daughter aged 24 years) and one out of four persons in the second case (a 28-year-old woman) experienced erythema, respiratory distress and diarrhoea shortly after eating the fish. These symptoms are indicative of scombrotoxic fish poisoning. Histamine is produced in the muscle tissue of scombroid fish, such as tuna or mackerel, if it is kept at a temperature which is too high. Since the concentration of histamine is not evenly distributed through the fish's flesh, not everyone who eats the same fish will become ill to the same extent, and some may not even become ill at all. Furthermore, since the complaints are often mild and of short duration, most patients do not seek medical help, and probably few cases are officially reported. Despite the fact that sometimes only one person from a group of people eating the same fish becomes ill, and that the clinical complaints resemble an IgE-mediated allergic reaction, the illness is a food-borne intoxication with exogenous histamine. Therefore, patients can safely eat the same type of fish again.

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OBJECTIVE: To study the relationship between toxicity and the exposure to nelfinavir and saquinavir as part of a quadruple drug regimen. DESIGN: The ADAM study is a randomized study to investigate the feasibility of induction-maintenance therapy in HIV-1 infection. METHODS: HIV-1-infected patients with no prior use of antiretroviral treatment started induction therapy consisting of stavudine + lamivudine + nelfinavir + saquinavir for a period of 26 weeks. Data regarding toxicity of the quadruple regimen and exposure to the protease inhibitors were collected. RESULTS: Seven of the 65 patients enrolled had to switch therapy for reasons of toxicity within the first 26 weeks. Diarrhoea was frequently reported (49 of 65, one discontinuation), but could be relieved by using antidiarrhoeal agents. Laboratory monitoring revealed elevated liver enzymes (leading to four discontinuations) and mild to moderate elevations of triglycerides and cholesterol (nine and 23 of 65, respectively). The exposure to saquinavir and nelfinavir was lower than expected. Abdominal pain was associated with a higher exposure to nelfinavir or saquinavir. The association of nausea and abdominal distension with drug exposure appeared to vary over time. CONCLUSIONS: The quadruple drug regimen was quite well tolerated. Diarrhoea was frequently reported but could be relieved by the use of antidiarrhoeal agents. In comparison with other protease inhibitor combinations, lipid abnormalities in plasma were infrequent and mild. With the exception of diarrhoea, all gastrointestinal complaints observed were found to be associated with the level of exposure to nelfinavir or saquinavir. The exposure to the protease inhibitors was relatively low, although the virologic efficacy of the regimen used was satisfactory

In human immunodeficiency virus (HIV)-1 infection, decrease of telomere length is mainly found in CD8(+) T cells and not in CD4(+) T cells. Telomerase, a ribonucleoprotein enzyme that can synthesize telomeric sequence onto chromosomal ends, can compensate for telomere loss. Here, we investigated if telomerase activity could explain differential telomere loss of CD4(+) and CD8(+) T cells in HIV-1 infection. Telomerase activity was higher in CD8(+) than in CD4(+) T cells from HIV-infected patients, but still in the same range as in healthy controls, and upregulation after stimulation was comparable to normal. Telomerase activity in lymph node CD4(+) and CD8(+) T cells from HIV-infected patients was in the same range as that in CD4(+) and CD8(+) T cells from peripheral blood (PB) and was normal in unseparated bone marrow cells. Thus, our study did not provide evidence for compartmentalized elongation of telomeres in HIV infection. In patients treated with reverse transcriptase inhibitors, telomerase activity was inhibited, but this did not lead to accelerated loss of telomere length in vivo. Thus, differential telomere loss in CD4(+) and CD8(+) T cells in HIV-1 infection cannot be explained by telomerase activity.

Pepsinogen A (PGA) isozymogens are low molecular weight proteins that are present in serum and urine. The differences in the molecular structure of PGA-isozymogens involve only 2-4 amino acid substitutions. In a previous study, performed in 13 subjects only, a remarkable difference between the fractional renal clearances of the main PGA-isozymogens (PGA-3, PGA-4 and PGA-5) has been demonstrated. The aim of the present study was to further investigate these differences in fractional clearance between PGA-isozymogens and to determine whether these differences are caused by differences in glomerular sieving. For this purpose the fractional clearances of PGA-isozymogens were measured in 57 subjects. In accordance with the previous study, the median fractional clearance of PGA-5 (13%) was lower than the median fractional clearance of PGA-4 (17%; p0.02) and the median fractional clearance of PGA-4 was lower than the median fractional clearance of PGA-3 (26%; p0.001). The glomerular sieving coefficients of PGA-isozymogens were measured in 11 subjects during an elective heart catheterization by means of the fractional renal extraction method. No significant difference between the glomerular sieving coefficients of PGA-isozymogens could be demonstrated, being 0.81 for PGA-3, 0.96 for PGA-4 and 0.84 for PGA-5. It is concluded that the differences in renal handling between PGA-isozymogens must be explained by differences in tubular reabsorption. These differences in tubular reabsorption between PGA-isozymogens support the hypothesis that positively charged amino acid residues of proteins are involved in the tubular protein reabsorption.

The kidney is responsible for a considerable part of the clearance of insulin and C-peptide. Two routes are thought to be involved in the renal extraction of insulin and C-peptide from the circulation: (1) glomerular filtration, and (2) uptake by tubular cells from peritubular capillaries. The aim of the present study was to investigate these processes in non-insulin-dependent diabetes mellitus (NIDDM). For this purpose we measured the renal extraction of inulin, insulin, and C-peptide in 12 NIDDM patients and 16 control subjects during elective heart catheterization. In addition, a 24-h urine sample was obtained from all subjects to assess the fractional clearance of the peptides. The total renal extraction of both insulin and C-peptide exceeded the amount that was extracted by filtration, confirming the supposition that both peptides are cleared by an additional mechanism, most probably peritubular uptake. The peritubular uptake of insulin in the NIDDM group was not significantly different from that in the control subjects, whereas the insulin extraction over the legs was significantly lower in NIDDM than in the controls. The peritubular uptake of C-peptide was significantly lower in NIDDM, while the fractional clearance of C-peptide was significantly higher. The latter indicates that the reabsorption of C-peptide from the luminal side of the tubular cell is impaired in diabetes mellitus. It is therefore concluded that urinary C-peptide excretion is not a reliable index for insulin production in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

The kidney is responsible for a considerable part of the clearance of insulin and C-peptide. Two routes are thought to be involved in the renal extraction of insulin and C-peptide from the circulation: (1) glomerular filtration, and (2) uptake by tubular cells from peritubular capillaries. The aim of the present study was to investigate these processes in non-insulin-dependent diabetes mellitus (NIDDM). For this purpose we measured the renal extraction of inulin, insulin, and C-peptide in 12 NIDDM patients and 16 control subjects during elective heart catheterization. In addition, a 24-h urine sample was obtained from all subjects to assess the fractional clearance of the peptides. The total renal extraction of both insulin and C-peptide exceeded the amount that was extracted by filtration, confirming the supposition that both peptides are cleared by an additional mechanism, most probably peritubular uptake. The peritubular uptake of insulin in the NIDDM group was not significantly different from that in the control subjects, whereas the insulin extraction over the legs was significantly lower in NIDDM than in the controls. The peritubular uptake of C-peptide was significantly lower in NIDDM, while the fractional clearance of C-peptide was significantly higher. The latter indicates that the reabsorption of C-peptide from the luminal side of the tubular cell is impaired in diabetes mellitus. It is therefore concluded that urinary C-peptide excretion is not a reliable index for insulin production in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Every dentist should accept the responsibility of treating HIV-infected and AIDS' patients in his own office. By taking the appropriate hygienic measures, the risk of HIV-transmission in the dental office can be almost completely eliminated.

In 8 healthy male volunteers, urinary excretion (UE) and fractional clearance (FC) of pepsinogen A (PGA), beta 2-microglobulin (beta 2-m) and albumin were measured after 6 days high protein diet (HPD; 2.0 g/kg/day) and compared to values obtained after 6 days low protein diet (LPD; 0.5 g/kg/day). In addition, the effect of an acute protein load (APL; 500 g beef) on these variables were measured. Both chronic and acute protein loading induced a rise in glomerular filtration rate (GFR) of about 10% together with a parallel rise in effective renal plasma flow. UE PGA and FC PGA increased both after HPD (UE PGA 1,707 +/- 1,106 ng/min; FC PGA 23 +/- 12%) as compared to LPD (UE PGA 1,200 +/- 987 ng/min, p less than 0.01; FC PGA 18 +/- 12%, p less than 0.05), and after APL (UE PGA 2,276 +/- 1,389 ng/min; FC PGA 26 +/- 16%) as compared to baseline (UE PGA 1,418 +/- 965 ng/min, p less than 0.02; FC PGA 21 +/- 12%, p less than 0.05). UE and FC of beta 2-m and albumin were not affected by protein loading. As PGA is nearly freely filtered, it is concluded that the increase in fractional PGA clearance reflects a decrease in fractional tubular PGA reabsorption. Our results suggest that an increase in fractional protein clearance after protein loading is not necessarily due to an impaired glomerular permselectivity but represents a decreased fractional tubular reabsorption as a result of a GFR-mediated increase in filtered load without a concomitant increase in tubular reabsorption.

Address: 1University Medical Center Groningen, Groningen, Netherlands, 2Medical Spectrum Twente, Enschede, Netherlands, 3Medical Center Haaglanden, The Hague, Netherlands, 4University Medical Center Utrecht, Utrecht, Netherlands, 5University Hospital Center, Charleroi, Belgium, 6Radboud University Nijmegen Medical Center, Nijmegen, Netherlands, 7Elisabeth Hospital, Tilburg, Netherlands, 8Catharina Hospital, Eindhoven, Netherlands, 9Kennemer Gasthuis, Haarlem, Netherlands, 10Isala Clinics, Zwolle, Netherlands and 11Rijnstate Hospital, Arnhem, Netherlands * Corresponding author

The presence of human papillomavirus (HPV) and Epstein-Barr virus (EBV) was analyzed in 21 oral biopsy specimens of HIV-infected patients using the polymerase chain reaction (PCR) method. Biopsies were categorized as hairy leukoplakia (HL) (n = 12), candidiasis (n = 3), oral warts (n = 2), and clinically normal epithelium (n = 4). For HPV detection a modified general primer-mediated PCR method (GP-PCR), which detects a broad spectrum of HPV genotypes at sub-picogram levels, was used. Human papillomavirus DNA was only found in two oral warts and was identified as HPV type 32. Epstein-Barr virus DNA was detected in 16 biopsy specimens, including the 12 HLs, 2 cases of candidiasis, and 2 samples of normal epithelium. Epstein-Barr virus positivity in HL could be confirmed by Southern blot analysis and DNA in situ hybridization using biotinylated DNA probes (bio-DISH). Epstein-Barr virus bio-DISH was also positive in one sample of normal epithelium from a patient with HL. The results indicate that HL is strongly associated with EBV and not with any of the common HPV types that react with general HPV primers in the PCR. However the detection of EBV in normal oral epithelium by PCR and bio-DISH suggests that the presence of this virus is not exclusively related to HL.

The occurrence of oral mucosal lesions was studied in 70 consecutive human immunodeficiency virus (HIV)-infected patients, including 35 patients with AIDS, who had been admitted to a Department of Internal Medicine. Lesions of the oral mucosa were observed in 52 patients (74 per cent). Oral candidiasis (50 per cent), hairy leukoplakia (14 per cent), periodontal disease (13 per cent), and oral Kaposi's sarcoma (4 per cent) were the most common lesions. Oral mucosal lesions suggestive of HIV infection were present in ten of 12 patients of unknown HIV status in whom Pneumocystis carinii pneumonia was suspected. Close cooperation between the medical and dental professions is recommended since accurate intraoral examination can make a valuable contribution towards the clinical management of HIV-infected patients and may influence the CDC classification of this disease.

Seventy patients infected with human immunodeficiency virus (HIV) have been included in this study to evaluate the impact of oral examination on the Centers for Disease Control (CDC), Atlanta, Ga, classification of HIV disease. Based on clinical data prior to oral examination, 22 patients were classified in the CDC group 2, 11 in CDC group 3, and 37 in CDC group 4. Twelve patients (55%) initially classified as CDC 2, and 4 patients (36%) initially classified as CDC 3 had to be reallocated to CDC group 4 due to the presence of oral candidiasis, hairy leukoplakia, or oral Kaposi's sarcoma. We conclude that oral examination has a large impact on the CDC classification of HIV-infected subjects. Since this classification system is used to select asymptomatic HIV-infected subjects (CDC groups 2 and 3) for clinical trials receiving antiretroviral therapy in early HIV disease, it is suggested that accurate oral examination is mandatory before inclusion of patients in such studies.

To investigate the effect of pentagastrin on serum and urinary pepsinogens and gastric pepsin, eight healthy male volunteers were studied twice during continuous intragastric perfusion with either NaCl 0.9% or 0.1 M HCl in random order. To the perfusate 3 mg/ml phenol red was added as inert recovery marker. Gastric content was aspirated in 15-minute samples, 4 basally and subsequently 6 during continuous i.v. infusion of pentagastrin 1.5 micrograms/kg/h. Furthermore, serum and urine samples were collected immediately before and after each test. Gastric pepsin output increased after pentagastrin. There were no differences in basal or stimulated pepsin output during saline or HCl perfusion despite marked differences in intra-gastric acidity and acid delivery to the duodenum. In addition, no significant changes in serum pepsinogen levels or urinary pepsinogen excretion were observed after pentagastrin infusion. It is concluded that pentagastrin stimulates gastric pepsin secretion directly, but does not stimulate the release of pepsinogens into the systemic circulation.

Pepsinogen A (PGA) and Pepsinogen C (PGC) are circulating low-molecular-weight proteins. Both have been shown to be almost freely filtered through the glomerular basement membrane. In man, only PGA is present in significant amounts in the urine. This prompted us to investigate the tubular reabsorption of PGA and PGC in man. Fifty-eight 24-hour urine specimens and a serum samples were obtained from 21 healthy subjects. Eight serum and urine samples were obtained after raising the serum PGA and PGC levels by oral administration of omeprazole. Filtered loads of PGA and PGC and tubular reabsorptions were calculated. PGA was already present in the urine at filtered loads below the tubular reabsorption maximum (10.6 +/- 3.5 mg/24 h; mean +/- SD) that was reached at serum PGA levels above 66 micrograms/l. Furthermore, intraindividual variation in tubular reabsorption of PGA was observed. Urinary excretion of PGC remained very low and the tubular reabsorption maximum for PGC was not reached. These data show that the presence of large amounts of PGA in the urine of healthy volunteers is due to a low affinity of the tubules for PGA. Tubular affinity of PGA changes in time and factors responsible for these changes require further investigation. The absence of PGC from the urine is due to a high affinity of the tubules for PGC and a high capacity compared to normal filtered loads. The similarity between PGA and PGC molecules suggests that minor differences in molecular structure can be responsible for large differences in tubular reabsorption.

To investigate the effect of omeprazole on serum and urinary pepsinogens and on gastric pepsin, 8 healthy male volunteers were studied before and after 9 days of treatment with omeprazole 60 mg/day p.o. Fasting serum samples and 24 h urine specimens were obtained, and gastric contents were aspirated at 15-min intervals, 4 prior to and 6 during pentagastrin 1.5 micrograms.kg-1.h-1 i.v. during intra-gastric perfusion with NaCl 0.9% and phenol red 3 mg.ml-1 as an inert recovery marker. Basal and pentagastrin-stimulated volume and acid secretion were significantly decreased. The basal and pentagastrin stimulated pepsin output remained unchanged but pepsin concentration in gastric secretion was increased. Administration of omeprazole resulted in a significant increase in the serum PGA and PGC levels. The 24-h urinary excretion of PGA increased, but that of PGC remained unchanged, and so did the renal clearances of creatinine and pepsinogen A. The renal clearance of pepsinogen C decreased. It was concluded that omeprazole did not affect gastric pepsin output, but, due to the decreased volume output, the concentration of pepsin in the gastric secretion was increased. Omeprazole increased the serum levels of pepsinogen A and C because more pepsinogen was released into the systemic circulation. This might be due to greater back-diffusion of pepsinogen from the gastric mucosa into the systemic circulation as a result of the higher pepsinogen concentration in gastric secretion.

Diurnal variations in serum levels, urinary excretion and renal clearances of pepsinogen A and pepsinogen C were investigated in eight healthy volunteers during a consecutive 63-h observation period. Both serum pepsinogen A and pepsinogen C levels proved to be stable and unaffected by meals. Urinary excretion of pepsinogen A, and thus pepsinogen A clearance by the kidney, increased during the day. These changes might be related to food intake. Pepsinogen C and creatinine excretion were constant throughout the day as were the renal clearances of these substances. It is concluded that the kidney plays an important role in maintaining stable serum pepsinogen A levels despite changes in release of pepsinogen A into the circulation during the day. Changes in urinary excretion of pepsinogen A might reflect more accurately short-term changes in gastric secretory activity than do serum levels. The handling of pepsinogen C by the kidney needs further investigation.

Seventy-five consecutive HIV-infected patients, including 33 AIDS cases were examined. One or more oral mucosal lesions were observed in 57 (76%); candidiasis was the most common finding (52%). Others included hairy leukoplakia (16%), periodontal disease (16%) and Kaposi's sarcoma (4%). Diversity of study design and methods allowed no reliable comparison with other reports.

Mortality from diabetic coma in district general hospitals is reported to be high, and the present prospective study was undertaken to investigate the outcome of treatment with a ‘low-dose’ insulin regimen in this situation. In a three-year period, 46 consecutive admissions to a general medical ward with diabetic coma were included. The overall mortality was 26%, due exclusively to the high mortality (42.8%) of elderly patients with non-ketotic coma. It is concluded that the high mortality of diabetic coma in a district general hospital reflects the poor prognosis of patients with non-ketotic coma, due to severe associated conditions. Mortality cannot be expected therefore to be influenced by the use of ‘low-dose’ insulin regimens.

Pepsinogen A (PGA) and pepsinogen C (PGC) are almost identical low molecular weight proteins with marked differences in renal handling. PGA is present in large amounts while PGC is almost absent in the urine of healthy subjects. Whether the amount of PGA in the urine represents the total amount of PGA that is extracted, is unknown. We, therefore, assessed the renal metabolism of PGA and PGC by measuring PGA, PGC and creatinine concentrations in the aorta and the right renal vein, and in the urine from patients undergoing elective heart catheterization. The renal extractions of PGA and PGC were not significantly different from the extraction of creatinine: 22%, 18% and 24%, respectively. Sixty-eight percent of PGA and 98% of PGC extracted from the circulation were metabolized by the kidney, and fractional metabolism was closely related to the fractional reabsorption of PGA and PGC from the glomerular filtrate. It is concluded that the kidney metabolizes PGA and PGC. The fractional metabolism of PGA and PGC can be calculated from the fractional reabsorption. Further studies on the renal handling of pepsinogens are warranted as they may provide information on factors affecting renal metabolism of low molecular weight proteins.

Pepsinogen A (PGA) and pepsinogen C (PGC) are negatively charged, low molecular weight (LMW) proteins with a striking difference in renal handling: PGA (molecular weight 43,500 daltons) shows a high fractional excretion while the fractional excretion of PGC (molecular weight 40,500 daltons) is low, presumably due to tubular reabsorption. As these data suggest a high glomerular sieving of pepsinogens, we assessed the glomerular sieving coefficient (GSC) of PGA, PGC and several other proteins from their renal extractions. For this purpose blood samples were obtained simultaneously from the aorta (A) and right renal vein (V) in nine patients undergoing an elective heart catheterization. After correction of A-V differences for diuresis with the A-V difference of transferrin, GSCs (+/- SEM) for PGA and PGC were 0.90 +/- 0.14 and 0.85 +/- 0.17, respectively, GSC of beta 2-microglobulin being 0.90 +/- 0.12. For albumin and IgG, known to have a low GSC, low values were found. It is concluded that the GSC of a LMW protein in man can be calculated from both its A-V difference over the kidney and the A-V difference of an inert marker with a GSC of 1, provided they are corrected by the A-V difference of an inert marker with a GSC of 0. Our results demonstrate that PGA and PGC are almost freely filtered through the glomerular basement membrane despite their size and negative net molecular charge.

Pepsinogen A (PGA) and pepsinogen C (PGC) are low-molecular-weight proteins synthesized by the gastric mucosa. Data in man suggest that both pepsinogens are almost freely filtered through the glomerular basement membrane despite a molecular weight of about 43,000 dalton and a strongly negative charge. This promoted us to investigate the glomerular sieving of PGA and PGC in the isolated rat kidney model by measuring their fractional excretions before and after inhibition of tubular function with sodium iodoacetate. During the control episode fractional excretion of PGA was 40 ± 0.04% and of PGC 42 ± 0.04% (mean ± SEM from 9 experiments). After complete inhibition of tubular function a large increase in fractional excretion was found for both pepsinogens: 87 ± 0.04% for PGA and 95 ± 0.09% for PGC. It is concluded that tubular secretion does not contribute to the high fractional excretion of pepsinogens and that both PGA and PGC are almost freely filtered through the glomerular basement membrane.