Interleukin-2 and natural killer activity in acute type B hepatitis

Natural killer (NK) cell activity against K562 cell line, and interleukin-2 (IL-2) activity in supernatants from lectin-activated PBMC cultures from 17 patients with acute hepatitis B in the early phase of illness were studied. These patients showed enhanced NK cytotoxicity and higher levels of IL2 activity as compared with control subjects. There was a positive correlation between cytotoxicity values and levels of IL2 activity. Furthermore, in the recovery phase of illness there was a tendency towards normalization in both parameters. When patients were divided in accordance with markers of HBV replication, HBV-DNA positive patients showed increased NK cell activity and IL2 levels as compared with the control group, whereas in HBV-DNA-negative patients no differences were found. However, no differences were found between patients with HBeAg and patients with anti-HBe. These results suggest that natural cytotoxicity is increased early in the course of acute hepatitis B, while NK cell activity returns to normal later, during convalescence. Enhanced NK cell activity appears to be secondary, at least in part, to increased production of IL2. Natural cytotoxicity may be one mechanism that controls the HBV infection before other cytotoxic mechanisms become fully operative.     

Resistance to reinfection in experimental murine schistosomiasis: role of porto-hepatic hemodynamics

Experiments were conducted to evaluate critically, and independently of the immune system, the possible role of hemodynamic mechanisms in resistance to schistosomal reinfection. The effects of a challenge schistosomal infection were compared in groups of mice which were either previously infected with schistosomiasis, vaccinated with irradiated cercariae, or underwent partial portal vein ligation for the induction of portal hypertension and porto-systemic shunting. Following infection with 60 cercariae, the appearance of portal hypertension preceded by approximately 2 weeks the development of porto-systemic shunting, which reached maximal values 11 weeks postinfection. Such a primary infection conferred on C3H mice an estimated 90% protection to a 2nd infection, measured by the reduction of worm burden. Worm burdens were also reduced in vaccinated and ligated animals as compared to normal controls. The protection amounted to 30% and 56%, respectively, in the C3H strain and 63% and 75-85%, respectively, in the C57Bl/6 strain. Reduction in worm burden in the ligated animals is believed to be due to the extrahepatic porto-systemic vascular shunts. Hemodynamic as well as immunological factors may account for the resistance to reinfection observed in chronic murine schistosomiasis.     

Fecal lactate and short bowel syndrome

In patients with short bowel syndrome (SBS), the carbohydrate overload to the colon may disturb the normal pattern of colonic fermentation with production ofd-lactic acid and subsequent development of a metabolicd-lactic acidosis. We measuredd-lactic acid in blood, urine, and feces, as well as the composition of fecal water and fecal reducing substances from 11 patients with SBS, comparing the results with those from normal subjects. The fecal water from patients with SBS was characterized by low pH, potassium, and volatile fatty acids, high osmotic gap, and high concentration ofl- andd-lactic acid. Five of 11 had abnormal amounts of fecal reducing substances. Fecald-lactic acid was increased in nine of 11 patients. However, none of these patients showedd-lactic acid in urine, and only one had a very low concentration in plasma. These results show thatd-lactic acid was overproduced in the colon of most of the patients with SBS. However, other factors such as absorption or impairedd-lactic acid metabolism may be necessary for a plasmatic increase ofd-lactic acid.Unidad de Terapia Nutricional, Hospital de Niños Sor Maria Ludovica, La Plata, Provincia de Buenos Aires, Argentina.Part of this work was presented at the International Symposium on Short Chain Fatty Acids, Strasbourg, France, September 1993.     

Cortisol Response to Stress in Adults with Attention Deficit Hyperactivity Disorder

Background:

Differences in the cortisol response have been reported between children exhibiting the inattentive and hyperactive/impulsive subtypes of attention deficit hyperactivity disorder. However, there is no such information about adults. The aim of the present study was to determine the possible differences between the combined and inattentive subtypes in the cortisol response to stress.

Methods:

Ninety-six adults with attention deficit hyperactivity disorder, 38 inattentive and 58 combined, without any medical or psychiatric comorbidities and 25 healthy controls were included. The Trier Social Stress Test was used to assess physiological stress responses. Clinical data and subjective stress levels, including the Perceived Stress Scale, were also recorded.

Results:

No significant differences in the cortisol response to the Trier Social Stress Test were found between patients and controls. However, albeit there were no basal differences, lower cortisol levels at 15 (P=.015), 30 (P=.015), and 45 minutes (P=.045) were observed in the combined compared with the inattentive subtype after the stress induction; these differences disappeared 60 minutes after the stress. In contrast, the subjective stress responses showed significant differences between attention deficit hyperactivity disorder patients and controls (P<.001), but no differences were seen between attention deficit hyperactivity disorder subtypes. In turn, subjective stress measures, such as the Perceived Stress Scale, positively correlated with the whole cortisol stress response (P<.027).

Conclusions:

Both the combined and inattentive attention deficit hyperactivity disorder adults exhibited a normal cortisol response to stress when challenged. Nevertheless, the inattentive patients displayed a higher level of cortisol after stress compared with the combined patients. Despite the differences in the cortisol response, adults with attention deficit hyperactivity disorder reported high levels of subjective stress in their every-day life.     

Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity

Genetic diagnosis of steroid-resistant nephrotic syndrome (SRNS) using Sanger sequencing is complicated by the high genetic heterogeneity and phenotypic variability of this disease. We aimed to improve the genetic diagnosis of SRNS by simultaneously sequencing 26 glomerular genes using massive parallel sequencing and to study whether mutations in multiple genes increase disease severity. High-throughput mutation analysis was performed in 50 SRNS and/or focal segmental glomerulosclerosis (FSGS) patients, a validation cohort of 25 patients with known pathogenic mutations, and a discovery cohort of 25 uncharacterized patients with probable genetic etiology. In the validation cohort, we identified the 42 previously known pathogenic mutations across NPHS1, NPHS2, WT1, TRPC6, and INF2 genes. In the discovery cohort, disease-causing mutations in SRNS/FSGS genes were found in nine patients. We detected three patients with mutations in an SRNS/FSGS gene and COL4A3. Two of them were familial cases and presented a more severe phenotype than family members with mutation in only one gene. In conclusion, our results show that massive parallel sequencing is feasible and robust for genetic diagnosis of SRNS/FSGS. Our results indicate that patients carrying mutations in an SRNS/FSGS gene and also in COL4A3 gene have increased disease severity.     

A review of potential pharmacogenetic effects on catecholamine responses

Considerably, variability in the clinical response to inotropic agents is observed and could be explained partially by the genetic variants, such as single-nucleotide polymorphism (SNP) in genes encoding for enzymes implicated in catecholamines synthesis, metabolism, storage and release or in the signaling pathway. This review highlights the potential effect of pharmacogenetics studies in hemodynamic response and identified 11 SNPs that could be relevant to explain the high variability drug response for a same dose. Cardiovascular instability, such as hypotension, is one of the premature birth complications. The pharmacogenetics studies evaluating these SNP may be useful to better understand the clinical outcome, particularly in this population.     

Mitoxantrone, a topoisomerase II inhibitor, induces apoptosis of B-chronic lymphocytic leukaemia cells

B-chronic lymphocytic leukaemia (B-CLL) is characterized by the accumulation of long-lived CD5⁺ B lymphocytes. The effect of mitoxantrone, a topoisomerase II inhibitor, on B-CLL cells was studied. Treatment of B-CLL cells for 48 h with mitoxantrone (0.5 μg/ml) induced a decrease in cell viability as determined by MTT assay. The IC₅₀ calculated for the cells of three patients was 0.7 μg/ml for two of them and 1.4 μg/ml for the third. In all three patients the maximum effect was observed with 2 μg/ml. An additive cytotoxic effect was observed when mitoxantrone (0.5 μg/ml) was combined with fludarabine (5 μg/ml). Mitoxantrone induced DNA fragmentation and the proteolytic cleavage of poly(ADP-ribose) polymerase (PARP), a marker of the activation of caspases, in all the patients studied, demonstrating that the cytotoxic effect of mitoxantrone was due to induction of apoptosis. These results suggest that mitoxantrone, and possibly other topoisomerase II inhibitors, may be used in the chemotherapy of B-CLL, and that combination of mitoxantrone with fludarabine or other drugs could improve the effectiveness of the treatment.