Hepatic scintigraphy in management of infants and children with liver disease

Scintiscans of liver and spleen using technetium 99m sulphur colloid in 15 infants with extrahepatic biliary atresia and 11 infants with severe obstructive jaundice (7 with genetic deficiency of alpha 1-antitrypsin) showed similar hepatic size, pattern of isotope uptake, and splenic abnormality with no distinguishing features. In 37 older children with a variety of liver disorders, the scan was invaluable in showing filling defects in five instances. Selenomethionine was taken up not only by the two filling defects due to hepatoblastoma but also in a haemangioendothelioma. In the remaining patiens liver scanning confirmed hepatic abnormality and the necessity for more specific invasive diagnostic investigations.     

Oral contraceptives and the risk of death from breast cancer

OBJECTIVE: To examine the relationship between the use of oral contraceptives and the risk of death from breast cancer. METHODS: We used interview data from the Cancer and Steroid Hormone Study, linked to cancer registry data from the Surveillance, Epidemiology, and End Results Program, to examine the 15-year survival and prior use of oral contraceptives among 4,292 women aged 20 to 54 years when diagnosed with breast cancer from December 1, 1980, to December 31, 1982. Cox proportional hazard models were used to estimate the relative rate of death from breast cancer by oral contraceptive use. RESULTS: Duration of oral contraceptive use, time since first use, age at first use, and use of specific pill formulations were not associated with survival. For time since last use, the risk of death from breast cancer decreased significantly with increasing time since last use of oral contraceptives, but a consistent gradient effect was not observed. Adjusted hazard ratios ranged from 0.86 to 1.41 and were 1.00 or less for all recency categories except during 13 to 24 months before diagnosis; none was statistically significant. Women who were currently using oral contraceptives had an adjusted hazard ratio of 0.90 (0.68, 1.19). CONCLUSION: Overall, oral contraceptive use had neither a harmful nor a beneficial effect on breast cancer mortality. The differences between pill users and nonusers were slight, and the risk estimates were usually reduced with confidence limits that nearly always included 1.0.     

Active proton secretion and potassium absorption in the rabbit outer medullary collecting duct. Functional evidence for proton-potassium-activated adenosine triphosphatase.

We examined the hypothesis that proton-potassium-activated adenosine triphosphatase (H-K-ATPase) mediates K absorption and acidification in the inner stripe of the outer medullary collecting duct (OMCDi). Rabbits were fed a low-K diet (0.55% K) for 7-14 d because we have demonstrated previously that this low-K diet stimulates K-absorptive flux by the OMCDi. Proton secretion was measured as net total CO2 flux (JTCO2) by microcalorimetry. After basal collections, either vehicle or an inhibitor of gastric H-K-ATPase, omeprazole (0.1 mM), was added to the perfusate during the second period. Addition of vehicle to the perfusate changed neither the transepithelial voltage (VT, in millivolts) nor the JTCO2. In contrast, the addition of omeprazole (0.1 mM) to the perfusate abolished JTCO2 (from 14.5 +/- 5.6 to -0.1 +/- 3.1 pmol.mm-1.min-1) without significantly affecting VT. In additional experiments, in 16 tubules there was significant net K absorption (JK) of 5.0 +/- 1.0 pmol.mm-1.min-1 during the basal period, which exceeded the rate of K absorption that could be attributed to a paracellular voltage-mediated pathway (JKP = 1.0 +/- 0.4 pmol.mm-1.min-1, P less than 0.01). Administration of vehicle did not significantly affect either VT or JK. However, omeprazole abolished JK (from 5.1 +/- 1.0 to 0.1 +/- 2.5 pmol.mm-1.min-1) without affecting VT or JNa. The present results demonstrate that the OMCDi possesses an active, omeprazole-sensitive acidification and K-absorptive mechanism. These findings are consistent with the presence of H-K-ATPase activity in this nephron segment.     

Monoclonal antibody to human high-molecular-weight kininogen recognizes its prekallikrein binding site and inhibits its coagulant activity

We developed a mouse monoclonal antibody (MoAb 115-21) to human high- molecular-weight kininogen (HK) that recognizes its prekallikrein binding site (residues 565 through 595 of HK). The corresponding synthesized 31-amino acid peptide (peptide IV) was recently shown to retain native HK's prekallikrein binding property. The same peptide bound factor XI also, although less avidly. Our MoAb recognizes purified HK, peptide IV, and the light chain moiety of HK (where the peptide IV resides), as shown by enzyme-linked immunosorbent assay (ELISA) and Western blotting experiments. The apparent dissociation constant for the HK and MoAb 115-21 interaction was 2.2 nmol/L. It does not recognize low-molecular-weight kininogen (LK) with which HK shares its heavy chain moiety or any antigens in human plasma congenitally deficient in kininogens. The binding of MoAb 115-21 to purified light chain of HK was competitively inhibited by peptide IV. In addition, the antibody inhibits HK-dependent clotting activity of normal human plasma and dextran sulfate-mediated activation of prekallikrein in plasma and retards cleavage of HK in normal plasma after contact activation with dextran sulfate. Also, purified Fab fragments of MoAb 115-21 inhibited the HK-dependent coagulant activity and dextran sulfate-mediated prekallikrein activation in normal plasma. Since the kd for HK-MoAb 115- 21 interaction is ten times lower than that of HK-prekallikrein, our data suggest that binding of MoAb 115-21 to HK's peptide IV site increases the free prekallikrein concentration in plasma and thus results in the decreased efficiency of factor XIIa-mediated activation of prekallikrein. Decreased levels of kallikrein thus formed may be responsible for the inhibition of HK-dependent clotting activity and the decrease in rate and extent of HK cleavage in normal plasma on contact activation with dextran sulfate. MoAb 115-21 may thus prove very useful, especially with its high affinity for HK, in further delineation of the role of HK and prekallikrein in contact activation and kinin-related human pathology.     

Translational development of splice-modifying antisense oligomers

Introduction: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention.

Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints.

Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.     

Sudden infant death syndrome and diphtheria-tetanus-pertussis-poliomyelitis vaccination status

Summary— Because diphtheria, tetanus, pertussis and poliomyelitis vaccine is routinely given during the period of highest incidence of sudden infant death syndrome (SIDS), we carried out a retrospective case-control study to assess whether such vaccination increased the risk of SIDS. The vaccination status of 118 SIDS and 332 control children, matched for sex, date of birth and age of the victims at death, was compared: the victims of SIDS were not significantly more often vaccinated than control children, the odds ratio was estimated at 1.9 with a 95% confidence interval from 0.9 to 3.9. There was a statistical difference between vaccination status of SIDS cases and controls aged less than three months. Nine percent of SIDS cases under 3 months had been vaccinated whereas the matched controls had not. In our study DTCP vaccination was not a risk factor for SIDS; although more of the SIDS infants less than 3 months of age had been vaccinated. This result however, concerns only one subgroup of the population studied and needs to be confirmed with another study of only SIDS infants less than 3 months of age, because DTCP vaccination was not a risk factor for SIDS when considering the total sample of the study.     

Transfusion-related acute lung injury caused by an NB2 granulocyte- specific antibody in a patient with thrombotic thrombocytopenic purpura

HLA and granulocyte-specific antibodies have been implicated in the production of transfusion-related acute lung injury (TRALI). Reported here is a case that suggests that the patient's preexisting condition may play an important role in determining whether TRALI develops upon transfusion of blood products containing anti-white cell (WBC) antibodies. A 29-year-old woman with thrombotic thrombocytopenic purpura (TTP) underwent an uneventful 1.5-volume plasma exchange, which was followed by the transfusion of 2 red cell (RBC) units. At the end of the second RBC transfusion, the patient developed clinical signs and symptoms of noncardiogenic pulmonary edema. Serologic studies demonstrated that the serum from the second RBC donor had no HLA antibodies but did have a granulocyte-specific antibody (anti-NB2) that caused the agglutination of the recipient's granulocytes, which were NB2 positive. Serum from the donor of the first RBC unit and serum from the donors of units used in the exchange had no HLA or granulocyte-specific antibodies that reacted with the recipient's WBCs. Because the donor implicated in this reaction had a history of 21 blood donations, none of which had been associated with a transfusion reaction, we suggest that the patient's preexisting condition played a significant role in this episode of TRALI, owing to the granulocyte-specific antibody.     

Mycobacterial Infections After Renal Transplantation

Mycobacterial infections occurred in 11 of 633 (1.7 per cent)recipients of successful renal transplants. There were no casesof tuberculosis in patients receiving chemoprophylaxis, butamongst those who did not receive prophylaxis disease occurredin six of the 27 (22 per cent) high-risk patients. The majorcause of morbidity during treatment was renal allograft rejection,largely due to reduction in immunosuppressive drug therapy.     

Laparoscopic Right Hemicolectomy for Ileocolic Intussusception Secondary to Caecal Neoplasm

Intussusception in adults is a rare cause of abdominal pain. Unlike its paediatric counterpart, intussusception in adults is associated with obvious pathology. We describe a case of ileocolic intussusception extending to the splenic flexure. We were able to reduce the intussusception partially and pedicle was stapled carefully. The specimen was delivered through a small incision and right hemicolectomy was performed adhering to oncological principles. We recommend laparoscopic-assisted surgery is considered for adult intussusceptions.