Predominance of null mutations in ataxia-telangiectasia

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.      

Transient heating of expressed breast milk up to 65°C inactivates HIV‐1 in milk: A simple,rapid, and cost‐effective method to prevent postnatal transmission

The postnatal transmission of human immunodeficiency virus (HIV) from mothers to children occurs through breastfeeding. Although heat treatment of expressed breast milk is a promising approach to make breastfeeding safer, it is still not popular, mainly because the recommended procedures are difficult to follow, or time‐consuming, or because mothers do not know which temperature is sufficient to inactivate HIV without destroying the nutritional elements of milk. To overcome these drawbacks, a simple and rapid method of heat treatment that a mother could perform with regular household materials applying her day‐to‐day art of cooking was examined. This structured experiment has demonstrated that both cell‐free and cell‐associated HIV type 1 (HIV‐1) in expressed breast milk could be inactivated once the temperature of milk reached 65°C. Furthermore, a heating method as simple as heating the milk in a pan over a stove to 65°C inhibited HIV‐1 transmission retaining milk's nutritional key elements, for example, total protein, IgG, IgA, and vitamin B₁₂. This study has highlighted a simple, handy, and cost‐effective method of heat treatment of expressed breast milk that mothers infected with HIV could apply easily and with more confidence. J. Med. Virol. 85:187–193, 2013. © 2012 Wiley Periodicals, Inc.     

Effects of intraoperative blood loss during liver resection on patients’ outcome: a single-center experience

Background/aim Operative bleeding is one of the major determinants of outcome in liver surgery. This study aimed to describe the impact of intraoperative blood loss on the postoperative course of liver resection (LR). Materials and methods The data of 257 patients who were treated with LR between January 2007 and October 2018 were retrospectively analyzed. LRs were performed via intermittent portal triad clamping (PTC) under low central venous pressure. Results LRs were performed for 67.7% of patients with a malignant disease and 32.3% of patients with a benign disease. Major LR was performed in 89 patients (34.6%). The mean PTC period was 20.32 min (±13.7). The median intraoperative bleeding amount was 200 mL (5–3500 mL), the 30-day mortality rate was 4.3%, and the morbidity rate was 31.9%. The hospital stay (p = 0.002), morbidity (p = 0.009), and 30-day mortality (p = 0.041) of patients with a bleeding amount of more than 500 mL significantly increased. Conclusion Surgeons should consider the adverse effects of intraoperative bleeding during liver resection on patients’ outcome. Favorable outcomes would be obtained with diligent postoperative care.     

Effect of the preservation-to-surgery interval on corneal allograft survival in low-risk patients.

BACKGROUND AND OBJECTIVE: To investigate the role of the preservation-to-surgery interval on corneal allograft survival in low-risk patients. PATIENTS AND METHODS: Eighteen donor corneas obtained from an overseas eye bank were preserved and transported overseas in Optisol-GS solution (Chiron Vision, Irvine, CA) in Group 1. Thirty fresh, young, healthy, and unscreened donor corneas soaked in the same medium were used in Group 2. Average preservation-to-surgery time was more than 8 days in Group 1 and less than 30 hours in Group 2. Corneal allograft survival rates were determined by Kaplan-Meier estimates of the survivor functions. The log-rank test was used to determine statistical significance of the differences between groups. was 233.3 +/- 37.7 hours in Group 1 and 20.8 +/- 4.6 hours in Group 2 (P < .05 for the comparison of average times). There were significant differences between the groups with respect to donors' age and enucleation time, but there were no statistically significant differences between the groups in terms of graft diameter and recipient diameter or for corneal allograft survival in low-risk patients. The graft survival rate was 83.3% in Group 1 and 93.3% in Group 2 at the end of the follow-up period. CONCLUSIONS: Preservation-to-surgery time has no effect on corneal allograft survival in low-risk patients. However, prospective, randomized, long-term and large-scale clinical trials are necessary to confirm these findings.     

Is phenytoin contraindicated in patients receiving cranial irradiation ?

Three recent publications have reported the development of erythema multiforme and Stevens-Johnson syndrome in patients receiving cranial irradiation and sodium phenytoin. Some authors have recommended that patients receiving whole brain radiation therapy and who have had seizures should not be prescribed phenytoin but an alternative anticonvulsant. This article reviews the current literature pertaining to the development of this potentially lethal complication in patients receiving whole brain radiation and phenytoin, with reference to the single recorded case of Stevens-Johnson syndrome in a patient receiving cranial irradiation and phenytoin in Auckland, New Zealand. While the clinical picture in the 16 patients reported in the literature and the current case report differed from the classical form of erythema multiforme, a similar pattern of presentation and outcome appeared in all patients reviewed, suggesting that the combination of phenytoin, cranial irradiation and the gradual reduction of concomitant steroids seem to lead to the development of erythema multiforme and/or Stevens-Johnson syndrome. The data presented, although sparse, suggest that phenytoin should not be prescribed in patients receiving cranial irradiation.     

Intestinal permeability in the newborn

Passive intestinal permeability in 33 newborn babies was studied using feeds containing lactulose and mannitol. Each marker is thought to pass across the gut wall by a different route; lactulose by a paracellular and mannitol by a transcellular pathway. Neither is metabolised and both are wholly and solely excreted by the kidney; urinary recovery is a measure of the intestinal uptake. Babies born before 34 weeks' gestation exhibited a higher intestinal permeability to lactulose than more mature babies, and all preterm babies showed an appreciable decline in lactulose absorption during the first week of oral feeds. Babies of 34 to 37 weeks' gestation achieved a 'mature' intestinal permeability to lactulose within four days of starting oral feeds. These findings may reflect the immaturity of the gut of the preterm baby rather than a process essential to adaptation to enteral nutrition.     

Ki-ras mutations are an early event and correlate with tumor stage in transplacentally-induced murine lung tumors

A previous study from this laboratory demonstrated that treatment of pregnant mice with 3-methylcholanthrene (MC) caused lung tumors in the offspring at 1 year after birth, the incidence of which correlated with fetal inducibility of Cyp1a1. Analysis by PCR amplification and allele- specific hybridization (ASO) of paraffin-embedded tumors generated from that study revealed the presence of point mutations in exon 1 of the Ki- ras gene. This work has now been expanded by PCR amplification and ASO analysis of 31 additional lesions. Point mutations were found in 37 of the 47 (79%) lesions analyzed in this and the previous study, the majority of which were G-->T transversions in the first or second base of codon 12. The mutational spectrum appeared to be dependent on the relative stage of differentiation of the lesion, as both the incidence of mutation and type of mutation produced correlated with malignant progression. Mutations occurred in 60% of the hyperplasias, 80% of the adenomas and 100% of the adenocarcinomas. In the lesions with mutations, GLY12-->CYS12 transversions occurred in 100% of the hyperplasias, 42% of the adenomas and 14% of the adenocarcinomas. The GLY12-->VAL12 transversions occurred in none of the hyperplasias, 42% of the adenomas and 57% of the adenocarcinomas. The remaining mutations, which consisted of ASP12 transitions and ARG13 transversions, occurred only in adenomas (17%) and adenocarcinomas (29%). Between this study and our previous analyses, the identity of the mutations obtained by ASO were confirmed by sequence analysis of eight of the 37 lesions that harbored mutations at the Ki-ras gene locus. There were no differences in the type or incidence of mutations relative to the metabolic phenotype or sex of the mice. These data suggest that mutational activation of the Ki-ras gene locus is an early event in transplacental lung tumorigenesis, and that the type of mutations produced by exposure to chemical carcinogens can influence the carcinogenic potential of the tumor. This may have prognostic significance in determining the malignant progression of the neoplasm.      

Low Dose Ketoconazole is an Effective and a Relatively Safe Alternative in the Treatment of Hirsutism*

Summary: Efficacy, clinical and hormonal effect of ketoconazole in 400 mg/day dose was tested in a prospectively-designed study. Twenty four patients with hirsutism according to the Ferriman and Gallwey score (>8) and elevated blood androgen levels were administered 400 mg/day ketoconazole for 6 months. Basal and posttherapy early follicular phase androgens and biochemical parameters were evaluated. In 22 patients significant improvement and in 2 slight improvement was seen in subjective complaints. No side-effects were observed in these patients other than 2 cases of pruritus (transient), 2 mild gastric upset and 1 mastodynia. All patients completed the study. Low dose ketoconazole seems to be effective in the treatment of hirsutism with relatively few side-effects but still should be reserved as an alternative choice due to the potential for deleterious hepatic effects.