Distinct physiological states of Plasmodium falciparum in malaria-infected patients.

Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children, ranging from mild flu-like symptoms to coma and death. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown. Studies of in vitro gene expression have found few transcriptional differences between different parasite strains. Here we present a large study of in vivo expression profiles of parasites derived directly from blood samples from infected patients. The in vivo expression profiles define three distinct transcriptional states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast Saccharomyces cerevisiae. The three states in vivo closely resemble, first, active growth based on glycolytic metabolism, second, a starvation response accompanied by metabolism of alternative carbon sources, and third, an environmental stress response. The glycolytic state is highly similar to the known profile of the ring stage in vitro, but the other states have not been observed in vitro. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular evidence for a functional mitochondrion in the asexual-stage parasite, and indicate in vivo and in vitro studies to determine how this variation may affect disease manifestations and treatment.

A self-adaptive hardware with resistive switching synapses for experience-based neurocomputing.

Neurobiological systems continually interact with the surrounding environment to refine their behaviour toward the best possible reward. Achieving such learning by experience is one of the main challenges of artificial intelligence, but currently it is hindered by the lack of hardware capable of plastic adaptation. Here, we propose a bio-inspired recurrent neural network, mastered by a digital system on chip with resistive-switching synaptic arrays of memory devices, which exploits homeostatic Hebbian learning for improved efficiency. All the results are discussed experimentally and theoretically, proposing a conceptual framework for benchmarking the main outcomes in terms of accuracy and resilience. To test the proposed architecture for reinforcement learning tasks, we study the autonomous exploration of continually evolving environments and verify the results for the Mars rover navigation. We also show that, compared to conventional deep learning techniques, our in-memory hardware has the potential to achieve a significant boost in speed and power-saving.

SM-Omics is an automated platform for high-throughput spatial multi-omics.

The spatial organization of cells and molecules plays a key role in tissue function in homeostasis and disease. Spatial transcriptomics has recently emerged as a key technique to capture and positionally barcode RNAs directly in tissues. Here, we advance the application of spatial transcriptomics at scale, by presenting Spatial Multi-Omics (SM-Omics) as a fully automated, high-throughput all-sequencing based platform for combined and spatially resolved transcriptomics and antibody-based protein measurements. SM-Omics uses DNA-barcoded antibodies, immunofluorescence or a combination thereof, to scale and combine spatial transcriptomics and spatial antibody-based multiplex protein detection. SM-Omics allows processing of up to 64 in situ spatial reactions or up to 96 sequencing-ready libraries, of high complexity, in a ~2 days process. We demonstrate SM-Omics in the mouse brain, spleen and colorectal cancer model, showing its broad utility as a high-throughput platform for spatial multi-omics.

Pathophysiology and fate of hepatocytes in a mouse model of mitochondrial hepatopathies.

BACKGROUND: Although oxidative phosphorylation defects can affect the liver, these conditions are poorly understood, partially because of the lack of animal models. AIMS: To create and characterise the pathophysiology of mitochondrial hepatopathies in a mouse model. METHODS: A mouse model of mitochondrial hepatopathies was created by the conditional liver knockout (KO) of the COX10 gene, which is required for cytochrome c oxidase (COX) function. The onset and progression of biochemical, molecular and clinical phenotypes were analysed in several groups of animals, mostly at postnatal days 23, 56, 78 and 155. RESULTS: Biochemical and histochemical analysis of liver samples from 23-56-day-old KO mice showed liver dysfunction, a severe COX deficiency, marked mitochondrial proliferation and lipid accumulation. Despite these defects, the COX-deficient hepatocytes were not immediately eliminated, and apoptosis followed by liver regeneration could be observed only at age 78 days. Hepatocytes from 56-78-day-old KO mice survived despite very low COX activity but showed a progressive depletion of glycogen stores. In most animals, hepatocytes that escaped COX10 ablation were able to proliferate and completely regenerate the liver between days 78 and 155. CONCLUSIONS: The results showed that when faced with a severe oxidative phosphorylation defect, hepatocytes in vivo can rely on glycolysis/glycogenolysis for their bioenergetic needs for relatively long periods. Ultimately, defective hepatocytes undergo apoptosis and are replaced by COX-positive cells first observed in the perivascular regions.

Application of ventricular tachyarrhythmia definitions of the updated Lambeth Conventions provides incompatibility with earlier results, masks antifibrillatory activity and reduces inter-observer agreement.

The Lambeth Conventions (LC I), a landmark guidance document for arrhythmia research was updated and arrhythmia definitions were changed in the new Lambeth Conventions II (LC II). This study examined whether the arrhythmia definitions of LC I and LC II yield the same qualitative results and whether LC II improves inter-observer agreement. Two independent investigators performed blinded arrhythmia analysis of the electrocardiograms of isolated, Langendorff rat hearts subjected to regional ischemia and perfused with Class I antiarrhythmics with 3 or 5 mM K+ in the perfusate. Data obtained with arrhythmia definitions of LC I and LC II were compared within and between observers. Applying ventricular fibrillation (VF) definition of LC II significantly increased VF incidence and reduced VF onset time irrespective of treatment by detecting 'de novo' VF episodes not found by LC I. LC II reduced the number of ventricular tachycardia (VT) episodes and simultaneously increased the number of VF episodes as compared with the respective values obtained according to LC I. Using VF definition of LC II masked the significant antifibrillatory effects of flecainide and the high K+ concentration identified with the VF definition of LC I. When VF incidence was tested, a very strong inter-observer agreement was found according to LC I, whereas using VF definition of LC II reduced inter-observer agreement. It is concluded that LC II shifts some tachyarrhythmias from VT to VF class, and thus results obtained by arrhythmia definitions of LC I and LC II are not compatible; VF definition of LC II may change the conclusion of pharmacological, physiological and pathophysiological arrhythmia investigations and may reduce inter-observer agreement. Thus, VT and VF definitions of LC II should be amended in order to increase compatibility and inter-observer agreement.

Effect of pretransplant hepatitis C virus RNA status on posttransplant outcome.

Undetectable hepatitis C virus (HCV) RNA [RNA(-)] before liver transplantation (OLT) has been shown to decrease the rates of disease recurrence. We sought to determine whether RNA(-) subjects differ in post-OLT recurrence (virological/VR, histological/HR), graft failure (GF), or patient survival from RNA(+) patients using a retrospective review. From 1995 to 2004, a total of 49 patients were RNA(-) at OLT as a result of interferon-based therapy: 22 SVR and 27 with end-of-treatment response (ETR) transplanted when RNA(-) within 6 months of ET. Forty-eight RNA(+) patients were analyzed as controls. Virological recurrence (VR) was seen in 55% of RNA(-) subjects with no difference in HR between RNA(-) vs (+) groups, namely 36.7% versus 56.3% (P = .068), respectively. The RNA(+) subjects showed a lower time to HR (5.6 vs 11 months; P = .027). The SVR subjects displayed lower VR (36.4%) and histological recurrence (HR) (13.6%) compared to ETR (VR 70.4%, P = .023; HR 55.6%, P = .003) or RNA(+) (HR 56%, P = .0008). The SVR subjects, who were identified with a sensitive assay (SVR(S), lower limit <600 IU/mL) showed no VR, HR, or GF. The 1- and 5-year survivals were 87.8%/75.6% and 89.6%/77.8% for RNA(-) and (+) groups, respectively (P = .77). In conclusion, RNA(-)-transplanted patients displayed lower VR and longer time to HR. The SVR patients showed lower VR and HR compared to ETR and RNA(+) patients.

Very late recurrence of hepatocellular carcinoma after liver transplantation: case report and literature review.

Hepatocellular carcinoma (HCC) recurs in 10% to 60% of the patients after liver transplantation (OLT) and is associated with increased mortality. The average time to recurrence ranges from 1 to 2 years following OLT, and the median survival from the time of diagnosis is about 1 year. We report a case of a 69-year-old man who underwent OLT for hepatitis C virus-related cirrhosis with HCC, and was diagnosed with recurrent HCC 6.5 years after OLT. Biopsies from the initial and recurrent tumors showed a well-differentiated HCC with foci of clear cell pattern. The patient was still alive and asymptomatic 32 months after the diagnosis despite extensive tumor burden. He expired 9 years, 9 months after OLT and 3 years, 2 months after the detection of recurrence. In conclusion, HCC may recur more than 6 years after OLT and may exhibit an indolent course. This case illustrates the highly variable rate of tumor growth and progression post-OLT. The impact of this information on the need for long-term surveillance for recurrent HCC post-OLT remains to be determined.

The impact of nonalcoholic fatty liver disease and the metabolic syndrome on progression of fibrosis in patients with recurrent HCV after liver transplantation.

Nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MS) have been shown to play a role in disease progression and response to therapy in patients with chronic hepatitis C virus (HCV) infection. The primary objective of this study was to evaluate the impact of coexisting NAFLD and MS on the progression of fibrosis in patients with recurrent HCV treated with interferon (IFN)/ribavirin after orthotopic liver transplantation (OLT). From 1998 to 2004, a total of 418 patients underwent OLT in our center for HCV-related cirrhosis. Thirty-five patients with recurrent HCV on IFN/ribavirin treatment, who had at least 2 posttransplant liver biopsies at least 6 months apart, were included in the study. Patients who had MS at the time of their first posttransplant biopsy were identified. The first and last posttransplant biopsies were assessed for the presence and severity of NAFLD, grade of inflammation, and stage of fibrosis. The fibrosis progression rate (FPR) was calculated and expressed in fibrosis units per month (FU/mo). Among 35 patients, 34% were diagnosed with NAFLD in the first posttransplant biopsy. The mean FPR was 0.05+/-0.16 FU/mo in the presence of NAFLD compared to 0.07+/-0.10 FU/mo in its absence (P=.68) and 0.03+/-0.06 FU/mo in the presence of MS versus 0.10+/-0.15 FU/mo in its absence (P=.06). When FPR values were divided into two categories of <0.16 FU/mo or >or=0.16 FU/mo (below/above the 25% upper quartile) or <0.08 FU/mo or >or=0.08 FU/mo (below/above the 50% upper quartile), there was no correlation between FPR categories and the presence of NAFLD with or without MS, only MS, or the absence of both in the first liver transplant biopsy (P=.13). Coexisting NAFLD or MS had no significant effect on the progression of fibrosis after OLT in patients with treated hepatitis C after OLT.

Pharmacodynamic comparison of LY3023703, a novel microsomal prostaglandin e synthase 1 inhibitor, with celecoxib.

To assess the safety, tolerability, and pharmacology of LY3023703, a microsomal prostaglandin E synthase 1 (mPGES1) inhibitor, a multiple ascending dose study was conducted. Forty-eight subjects received LY3023703, celecoxib (400 mg), or placebo once daily for 28 days. Compared with placebo, LY3023703 inhibited ex vivo lipopolysaccharide-stimulated prostaglandin E2 (PGE2 ) synthesis 91% and 97% on days 1 and 28, respectively, after 30-mg dosing, comparable to celecoxib's effect (82% inhibition compared to placebo). Unlike celecoxib, which also inhibited prostacyclin synthesis by 44%, LY3023703 demonstrated a maximal increase in prostacyclin synthesis of 115%. Transient elevations of serum aminotransferase were observed in one subject after 30-mg LY3023703 dosing (10× upper limit of normal (ULN)), and one subject after 15-mg dosing (about 1.5× ULN). Results from this study suggest that mPGES1 inhibits inducible PGE synthesis without suppressing prostacyclin generation and presents a novel target for inflammatory pain.

Small polydispersed circular DNA (spcDNA) in human cells: association with genomic instability.

Small Polydispersed Circular DNA (spcDNA) was suggested to be associated with genetically unstable cells. However, until now, qualitative and quantitative research has been limited due to the lack of efficient methods for detection and analysis. We developed a two-dimensional (2-D) neutral-neutral gel electrophoresis assay for the identification, characterisation and quantitation of spcDNA. Using this method, we established the relation of spcDNA to genetic and induced genomic instability in human cells, both in vitro and in vivo. Enhanced amounts of spcDNA were found in genetically unstable cells and tissues. spcDNA was detected in a tumor cell-line (HeLa) and in tumor tissue (colon carcinoma) as well as in fibroblasts derived from patients suffering from the genomic instability disease, Fanconi's Anemia. We failed to detect spcDNA in the genetically stable normal human fibroblasts. However, following treatment with the initiating carcinogen MNNG, an induction of spcDNA was observed. The level of spcDNA was quantified according to mitochondrial DNA (mtDNA) standards. In light of these findings, we discuss the possible role of spcDNA as a marker and an enhancer of genomic instability.

Telomeric repeats on small polydisperse circular DNA (spcDNA) and genomic instability.

Small polydisperse circular DNA (spcDNA) is a heterogeneous population of extrachromosomal circular molecules present in a large variety of eukaryotic cells. Elevated amounts of total spcDNA are related to endogenous and induced genomic instability in rodent and human cells. We suggested spcDNA as a novel marker for genomic instability, and speculated that spcDNA might serve as a mutator. In this study, we examine the presence of telomeric sequences on spcDNA. We report for the first time the appearance of telomeric repeats in spcDNA molecules (tel-spcDNA) in rodent and human cells. Restriction enzyme analysis indicates that tel-spcDNA molecules harbor mostly, if not exclusively, telomeric repeats. In rodent cells, tel-spcDNA levels are higher in transformed than in normal cells and are enhanced by treatment with carcinogen. Tel-spcDNA is also detected in some human tumors and cell lines, but not in others. We suggest, that its levels in human cells may be primarily related to the amount of the chromosomal telomeric sequences. Tel-spcDNA may serve as a unique mutator, through specific mechanisms related to the telomeric repeats, which distinguish it from the total heterogeneous spcDNA population. It may affect telomere dynamics and genomic instability by clastogenic events, alterations of telomere size and sequestration of telomeric proteins.

Inferring quantitative models of regulatory networks from expression data.

MOTIVATION: Genetic networks regulate key processes in living cells. Various methods have been suggested to reconstruct network architecture from gene expression data. However, most approaches are based on qualitative models that provide only rough approximations of the underlying events, and lack the quantitative aspects that are critical for understanding the proper function of biomolecular systems. RESULTS: We present fine-grained dynamical models of gene transcription and develop methods for reconstructing them from gene expression data within the framework of a generative probabilistic model. Unlike previous works, we employ quantitative transcription rates, and simultaneously estimate both the kinetic parameters that govern these rates, and the activity levels of unobserved regulators that control them. We apply our approach to expression datasets from yeast and show that we can learn the unknown regulator activity profiles, as well as the binding affinity parameters. We also introduce a novel structure learning algorithm, and demonstrate its power to accurately reconstruct the regulatory network from those datasets.

The impact of Campath 1H induction in adult liver allotransplantation.

BACKGROUND: We report our experience with Campath 1H in adult liver allotransplantation. METHODS: Between December 2001 and February 2004, 77 patients underwent liver transplantation using Campath 1H induction and low-dose maintenance tacrolimus immunosuppression. The control group consisted of 50 patients with similar baseline characteristics and the same eligibility criteria, transplanted under our standard Tacrolimus/steroids regimen. Hepatitis C patients were excluded from the study. RESULTS: Patient and graft survival were similar for both groups. The incidence of rejection was significantly lower in the Campath vs the control group (51% vs 65% at 12 months, P = .009). Tacrolimus trough levels and conversion from Tacrolimus or the addition of other immunosuppressive drugs due to nephrotoxicity were also significantly lower in the Campath 1H group. CONCLUSION: Campath 1H induction with low-dose Tacrolimus maintenance immunosuppression is an effective regimen in reducing acute rejection in adult liver transplantation, while maintaining lower tacrolimus levels and less nephrotoxicity than our conventional immunosuppressive regimen.

Viral hepatitis A, B, and C.

Mankind probably has known viral hepatitis for many centuries; however, the major and most dramatic developments in our knowledge of these diseases have taken place during the second half of the 20th century. During this relatively short period of time, the infectious nature of hepatitis A, B, and C has been proven, leading to their identification and description. The advent of serologic markers has provided the means for establishing the diagnosis. Epidemiologic studies have provided important information that led to exciting achievements in detection and prevention of transmission. Molecular biology studies and cell culture techniques have established our knowledge of the viral genomes, and led to the development of specific vaccines for hepatitis A and B. Anti-viral therapy has been developed and aggressive combination therapy has emerged as a promising strategy for chronic hepatitis B and C. This article reviews some of the main fields of progress and achievement related to viral hepatitis A, B, and C in the 20th century.

Digestion of delta-endotoxin by gut proteases may explain reduced sensitivity of advanced instar larvae of Spodoptera littoralis to CryIC.

The present study describes the correlation between gut protease activity of lepidopteran larvae of different instars, the inactivation of Bacillus thuringiensis delta-endotoxins in crystalline and noncrystalline forms, and the reduced susceptibility of advanced larval instars of Spodoptera littoralis to the toxin. The original assembly of delta-endotoxins in a crystal structure is essential for causing efficient larval mortality. Denaturation and renaturation (D/R) of delta-endotoxin crystals increased the vulnerability of the toxin molecules to proteolysis, reduced their capability to kill neonate larvae of S. littoralis, but sustained most of their larval growth-inhibition activity. E. coli-produced CryIC delta-endotoxin applied as a fraction of inclusion bodies exerted a growth inhibition effect, similar to the molecules released from the crystals by denaturation and subsequent renaturation. Incubation of CryIC with gut juice of 1st or 2nd instar larvae, left part of the CryIC toxin intact, while the toxin was completely degraded when incubated with gut juice of 5th instar larvae. The degradation rate was consistent with the increase of protease specific activity of the gut juice during larval development. This increase in toxin degradation may account for the loss of sensitivity of 5th instar larvae to CryIC. Specific protease inhibitors such as PMSF and Leupeptin were shown to inhibit gut proteases activity in all instar larvae, while, 1,10 phenanthroline, TLCK and TPCK were effective only in young instar larvae. The differential effect of protease inhibitors on proteases obtained from different larval instars indicated that gut juice protease profiles change with larval age. The observed quantitative and qualitative differences in degradation of delta-endotoxin by larval gut proteases that occur during larval maturation may account for the difference in susceptibility to the delta-endotoxin. This finding should be taken into consideration when designing strategies for the development of transgenic crops expressing delta-endotoxins as potent insecticidal proteins.

Intermittent administration of furosemide vs continuous infusion preceded by a loading dose for congestive heart failure.

Several reports have suggested that continuous intravenous administration of loop diuretics may be superior to intermittent administration. We performed a prospective randomized crossover study comparing intermittent intravenous administration (IA) of furosemide with continuous infusion following a single loading dose (LDCI) in nine patients with severe congestive heart failure. At the time of hospital admission, patients were randomly assigned to one of two treatment groups. One group (four patients) received an IV bolus injection of furosemide followed immediately by a continuous infusion for 48 h. The second group (five patients) was treated with three IV bolus injections a day for 48 h. Total doses of furosemide were equivalent in the two groups. After 48 h, each patient was crossed over to the other method and treated for an additional 48 h. LDCI produced significantly greater diuresis and natriuresis than IA (total urine output increased by 12 to 26 percent, total sodium excretion increased by 11 to 33 percent) (p less than 0.01). There were no significant differences in side effects between the two methods. These results indicate that LDCI may be a preferred method for administration of furosemide in patients with congestive heart failure.

Large cystic lesions of the liver in adults: a 15-year experience in a tertiary center.

BACKGROUND: Cystic lesions of the liver consist of a heterogeneous group of disorders and may present a diagnostic and therapeutic challenge. Large hepatic cysts tend to be symptomatic and can cause complications more often than smaller ones. STUDY DESIGN: We performed a retrospective review of adults diagnosed with large (> or = 4 cm) hepatic cystic lesions at our center, over a period of 15 years. Polycystic disease and abscesses were not included. RESULTS: Seventy-eight patients were identified. In 57 the lesions were simple cysts, in 8 echinococcal cysts, in 8 hepatobiliary cystadenomas, and in 1 hepatobiliary cystadenocarcinoma. In four patients, the precise diagnosis could not be ascertained. Mean size was 12.1 cm (range, 4 to 30 cm). Most simple cysts were found in women (F:M, 49:8). Bleeding into a cyst (two patients) and infection (one patient) were rare manifestations. Percutaneous aspiration of 28 simple cysts resulted in recurrence in 100% of the cases within 3 weeks to 9 months (mean 4(1/2) months). Forty-eight patients were treated surgically by wide unroofing or resection (laparoscopically in 18), which resulted in low recurrence rates (11% for laparoscopy and 13% for open unroofing). Four of the eight patients with echinococcal cysts were symptomatic. All were treated by open resection after irrigation of the cavity with hypertonic saline. There was no recurrence during a followup period of 2 to 14 years. Hepatobiliary cystadenomas occurred more commonly in women (F:M, 7:1) and in the left hepatic lobe (left:right, 8:0). Seven were multiloculated. All were treated by open resection, with no recurrence, and none had malignant changes. Cystadenocarcinoma was diagnosed in a 77-year-old man, and was treated by left hepatic lobectomy. CONCLUSIONS: Large symptomatic simple cysts invariably recur after percutaneous aspiration. Laparoscopic unroofing can be successfully undertaken, with a low recurrence rate. Open resection after irrigation with hypertonic saline is a safe and effective treatment for echinococcal cysts. Hepatobiliary cystadenomas have predilection for women and for the left hepatic lobe. Malignant transformation is an uncommon but real risk. Open resection is a safe and effective treatment for hepatobiliary cystadenoma, and is associated with a low recurrence rate.

Is greater than normal nocturnal heart rate in children with renal scars a predictor of reflux nephropathy?

BACKGROUND: The existence of renal scars constitutes the major etiologic factor for the development of hypertension during childhood. Elevated blood pressure in this setting can be considered a secondary form of hypertension. Certain forms of secondary hypertension have been associated with a lower than normal nocturnal fall in blood pressure. Resting heart rate per se has recently been reported to be an independent predictor of risk for cardiovascular mortality irrespective of age and the presence or lack of hypertension. OBJECTIVE: To ascertain the responses of heart rate and blood pressure in normotensive children with renal scars without, however, proteinuria and renal failure. METHODS: Ten children with renal scars documented by a 99Tc dimercaptosuccinic acid (DMSA) scan were subjected to ambulatory blood pressure monitoring. Ten age-matched and sex-matched healthy children served as the control group. Serum urea and creatinine levels, calculated rate of clearance of creatinine, microalbuminuria, plasma renin activity, and levels of aldosterone and catecholamines were determined for each subject. RESULTS: Average daytime and night-time systolic and diastolic blood pressures for the two groups did not differ. Subjects in both groups demonstrated the physiologic decrease in blood pressure during sleep (normal 'dipper' response), which was of equal magnitude for these two groups. Mean daytime heart rates were 92+/- 13 beats/min in children with renal scars versus 80+/-11 beats/min in controls (NS). Mean and minimal heart rates during night-time in children with renal scars were found to be significantly greater [79+/-6 versus 65+/-5 beats/min (mean) and 61+/-10 versus 56+/-7 beats/min (minimal), P < 0.01]. Parameters of renal function, plasma renin activity, and levels of aldosterone and catecholamines were similar for these two groups. CONCLUSION: Despite their having an equivalent physiologic dip in blood pressure during night-time, normotensive children with renal scars have a significantly greater nocturnal heart rate than do control subjects.

Abolition of pentagastrin-stimulated alkaline tide using the carbonic anhydrase inhibitor acetazolamide.

BACKGROUND: Alkaline tide is the transient increase in blood and urine pH following stimulation of gastric acid secretion. It is attributed to HCO3- release from parietal cells in parallel with H+ secretion. The enzyme carbonic anhydrase is thought to be responsible for HCO3- production from CO2 and OH- in the parietal cell. OBJECTIVE: To examine the effect of pretreatment with the carbonic anhydrase inhibitor, acetazolamide, on the alkaline tide phenomenon. METHODS: Ten patients with dyspepsia and demonstrable alkaline tide were tested on three separate days. The pH and base excess were determined in arterialized venous blood before and 45 minutes after an intramuscular injection of pentagastrin. The pH of the urine was measured before and 120 min after pentagastrin injection. Measurements were performed after pentagastrin alone on day 1, following pretreatment with acetazolamide 60 min before pentagastrin on day 2, and after the administration of acetazolamide alone on day 3. RESULTS: Following the administration of pentagastrin alone, the blood base excess increased by 1.61 +/- 0.2 mEq/L (mean +/- standard deviation) and the calculated alkaline tide at 45 min was 33.99 +/- 4.49 mEq. On day 2 with prior administration of acetazolamide, base excess decreased by 0.21 +/- 0.39 mEq/L, and the calculated alkaline tide was -3.28 +/- 7.57 mEq, which was significantly lower than on day 1 (P = 0.0001). On day 3, following acetazolamide alone, the base excess values decreased by 0.53 +/- 0.2 mEq/L and the alkaline tide was -10.05 +/- 3.33 mEq; there was no significant difference compared with day 2 (P = 0.44). CONCLUSION: Pretreatment with acetazolamide abolished the alkaline tide induced by pentagastrin. This finding supports the view that carbonic anhydrase has a major role in the alkaline tide phenomenon.

[Disappointing response of chronic C hepatitis to interferon].

From February 1990 to August 1995 we treated 58 patients with chronic hepatitis C alfa-interferon, 3 million units 3 times weekly for 6 months. Of the 48 patients with adequate follow-up, 34 did not respond to treatment at all. 10 patients responded, but within a few months hepatic enzymes again increased. These 2 groups can be considered failures of interferon treatment. In 4 patients enzymes remained normal for the duration of follow-up, (10-34 months). Even in this small group, 1 patient had a positive test for HCV RNA after completion of treatment. A partial explanation of our disappointing results may be the high prevalence of a subtype of C hepatitis-subtype 1b, which has recently been reported in Israel. This strain is particularly resistant to interferon. The means to define subtypes were not, and as far as we know are not yet available in Israel. Various groups have attempted to improve the outcome of treatment of hepatitis C, which in other hands too was still far from satisfactory. Thus, regimens of interferon utilizing higher doses and longer periods of treatment are being evaluated, as well as the addition of Ribavirin, which hopefully will improve results.