Effects of heat on embryos and foetuses.

OBJECTIVES: This paper reviews the effects of elevated maternal temperature on embryo and foetal development in experimental animals and in humans. CONCLUSIONS: Hyperthermia during pregnancy can cause embryonic death, abortion, growth retardation and developmental defects. Processes critical to embryonic development, such as cell proliferation, migration, differentiation and programmed cell death (apoptosis) are adversely affected by elevated maternal temperatures, showing some similarity to the effects of ionizing radiation. The development of the central nervous system is especially susceptible: a 2.5 degrees C elevation for 1 h during early neural tube closure in rats resulted in an increased incidence of cranio-facial defects, and a 'spike' temperature elevation of 2-2.5 degrees C in an exposure of 1 h during early neurogenesis in guinea pigs caused an increase in the incidence of microencephaly. However, in general, thresholds and dose-response relationships vary between species and even between different strains of the same species, depending on genotype. This precludes rigorous quantitative extrapolation to humans, although some general principles can be inferred. In humans, epidemiological studies suggest that an elevation of maternal body temperature by 2 degrees C for at least 24 h during fever can cause a range of developmental defects, but there is little information on thresholds for shorter exposures. Further experimental and epidemiological studies are recommended, focusing on stage-specific developmental effects in the central nervous system using a variety of sensitive assays.     

Non-small cell lung cancer and CHART (continuous hyperfractionated accelerated radiotherapy)--where do we stand?

This paper reviews the use of hyperfractionated and/or accelerated radiation therapy in the curative treatment of non-small cell lung cancer, and explains the scientific rationale behind the development of these regimes. The indications, practicalities and economics of introducing them routinely are addressed. Novel radiotherapy techniques are further discussed in the context of current developments and on-going clinical trials.     

Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus

Esophageal cancer has been associated with tobacco smoking, and nitrosamines are possible causative agents for this cancer. The present study investigated the metabolism of the tobacco carcinogens N'- nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK), and N-nitrosodimethylamine (NDMA), as well as the presence of xenobiotic-metabolizing enzymes in human esophageal tissues from individuals in the United States and Huixian, Henan Province, China (a high-risk area for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal samples from China than the USA. All microsomal samples activated NDMA. However, most of the microsomal samples did not activate NNK. Troleandomycin (an inhibitor of cytochrome P450 3A) decreased the formation of NNN-derived keto acid by 20-26% in the esophageal microsomes. The activities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NAD(P)H: quinone oxidoreductase and glutathione S-transferase were present in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal microsomal samples. The activities for nitrosamine metabolism and xenobiotic- metabolizing enzymes were decreased (by 30-50%) in the squamous cell carcinomas compared with their corresponding non-cancerous mucosa. The presence of activation and detoxification enzymes in the esophagus may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and 2E1 are involved in the activation of NNN and NDMA, respectively, in the human esophagus.      

Fatal shoulder dystocia: a review of 56 cases reported to the Confidential Enquiry into Stillbirths and Deaths in Infancy

Objective To use information collected by the Confidential Enquiry into Stillbirths and Deaths in Infancy to help obstetric, midwifery and paediatric practice in the management of shoulder dystocia.
Design Review of casenotes by a multidisciplinary focus group.
Sample All 56 cases reported to the Confidential Enquiry into Stillbirths and Deaths in Infancy from England, Wales and Northern Ireland in 1994 and 1995, where stillbirth or neonatal death was attributed to shoulder dystocia.
Main outcome measures Case notes were reviewed with respect to a range of perinatal variables. Comparisons were made with normative data from other studies when appropriate.
Results Maternal obesity and big babies were over-represented in pregnancies complicated by fatal shoulder dystocia. Fetal compromise was recorded in 26% of labours. The median time interval between delivery of the head and the rest of the body was only five minutes. The lead professional at the time the head was delivered was a midwife in 65% of cases. Middle grade or senior obstetric staff were supervising 47% of cases by the time the body was delivered.
Conclusions Antenatal prediction of shoulder dystocia is imprecise, and the majority of deliveries are attended by midwives. A relatively brief delay in delivery of the shoulders may be associated with a fatal outcome.     

Evidence for coexistence of enkephalin and glutamate in axon terminals and cellular sites for functional interactions of their receptors in the rat locus coeruleus

The authors previously showed that a subset of axon terminals in the locus coeruleus (LC) contains methionine5-enkephalin (ENK) and gamma-aminobutyric acid (GABA) immunoreactivities. However, numerous ENK-labeled terminals lacked GABA and exhibited synaptic specializations that were characteristic of excitatory-type transmitters. To determine whether ENK coexists with glutamate in the LC, preembedding immunoperoxidase detection of ENK or immunogold-silver was combined with postembedding identification of glutamate using a gold marker. Indeed, 28% of the ENK-labeled axon terminals examined (n = 250 axon terminals) also contained glutamate. To define further sites for functional interactions between opiate ligands and excitatory amino acid receptors, the ultrastructural localization of the mu-opioid receptor (MOR) was examined with respect to either the kainate receptor (KAR) or the R1 subunit of the N-methyl-D-aspartate (NR1)-type glutamate receptor in the LC. Gold-silver labeling for MOR and peroxidase labeling for either KAR or NR1 indicated that the MOR often was localized to the plasma membrane of dendrites that also exhibited immunolabeling for either glutamate receptor subtype. In contrast to the KAR, which was identified primarily in somata and dendrites, NR1 immunoreactivity also was found frequently in axon terminals as well as in glial processes. Glial processes containing NR1 occasionally exhibited immunolabeling for MOR and sometimes were directly apposed to MOR-containing dendrites in the LC. Furthermore, NR1-labeled receptors in axon terminals sometimes were presynaptic to MOR-labeled dendrites. The authors concluded that ENK and glutamate may be cotransmitters in LC afferents. Moreover, ligands at the KAR may modulate directly MOR-containing neurons in the LC, whereas actions at NR1 receptors may affect opioid-sensitive neurons through multiple cellular mechanisms, i.e., through presynaptic, postsynaptic, or glial actions.     

Velopharyngeal insufficiency following adenoidectomy1

Velopharyngeal insufficiency (VPI) is a well recognized but rare complication of adenoidectomy. Twenty children with this condition were seen and assessed at Great Ormond Street Hospital between 1993 and 2000. The commonest aetiology was occult submucous cleft palate (n = 5) but there was a wide range of other causes. Two children with severe behavioural disorders and normal palates developed mild symptoms, an aetiology not previously reported. Only two children had a classical submucous cleft palate. Nine children required surgical intervention and three revision procedures. Of the 15 treated children for whom follow‐up data was available, 13 regained normal or near‐normal speech. Many cases of postadenoidectomy VPI was not foreseeable. Following referral to a specialist cleft unit, normal or near‐normal speech can be achieved in the majority with a combination of surgery and speech therapy.     

Preliminary report on the association of apolipoprotein E polymorphisms, with postoperative peak serum creatinine concentrations in cardiac surgical patients

BACKGROUND: Renal dysfunction after cardiac surgery occurs in up to 8% of patients and is associated with major increases in morbidity, mortality, and cost. Genetic polymorphisms have been implicated as a factor in the progression of chronic renal disease, but a genetic basis for the development of acute renal impairment has not been investigated. The authors therefore tested the hypothesis that apolipoprotein E alleles are associated with different postoperative changes in serum creatinine after cardiac surgery. METHODS: The authors performed a prospective observational study with use of data from 564 coronary bypass surgical patients who were enrolled in an ongoing investigation of apolipoprotein E genotypes and organ dysfunction at a university hospital between 1989-1999. Renal function was assessed among apolipoprotein E genotype groups by comparisons of preoperative (CrPre), peak in-hospital postoperative (CrMax) and perioperative change (DCr) in serum creatinine values. RESULTS: The epsilon4 allele grouping (E2 = 2/2,2/3,2/4; E3 = 3/3; E4 = 3/4,4/4) was associated with a smaller increase in postoperative serum creatinine (perioperative change: E4, +0.17; E3, +0.26; E4, +0.27 mg/dl) and a lower peak postoperative creatinine than the epsilon2 and epsilon3 in univariate and multivariate analysis (peak in-hospital postoperative serum creatinine multivariate P = 0.015 vs. epsilon3, P = 0.038 vs. epsilon2). There was no difference in baseline creatinine among allele groups. CONCLUSIONS: Inheritance of the apolipoprotein epsilon4 allele is associated with reduced postoperative increase in serum creatinine after cardiac surgery, compared with the epsilon3 or epsilon2 allele. This is the first report of a possible genetic basis for acute renal impairment. These data may contribute to renal risk stratification for cardiac surgery and raise questions regarding apolipoprotein E and the pathophysiology of acute renal injury.     

Noninvasive monitoring of murine tumor blood flow during and after photodynamic therapy provides early assessment of therapeutic efficacy.

PURPOSE: To monitor tumor blood flow noninvasively during photodynamic therapy (PDT) and to correlate flow responses with therapeutic efficacy. EXPERIMENTAL DESIGN: Diffuse correlation spectroscopy (DCS) was used to measure blood flow continuously in radiation-induced fibrosarcoma murine tumors during Photofrin (5 mg/kg)/PDT (75 mW/cm2, 135 J/cm2). Relative blood flow (rBF; i.e., normalized to preillumination values) was compared with tumor perfusion as determined by power Doppler ultrasound and was correlated with treatment durability, defined as the time of tumor growth to a volume of 400 mm3. Broadband diffuse reflectance spectroscopy concurrently quantified tumor hemoglobin oxygen saturation (SO2). RESULTS: DCS and power Doppler ultrasound measured similar flow decreases in animals treated with identical protocols. DCS measurement of rBF during PDT revealed a series of PDT-induced peaks and declines dominated by an initial steep increase (average +/- SE: 168.1 +/- 39.5%) and subsequent decrease (59.2 +/- 29.1%). The duration (interval time; range, 2.2-15.6 minutes) and slope (flow reduction rate; range, 4.4 -45.8% minute(-1)) of the decrease correlated significantly (P = 0.0001 and 0.0002, r2= 0.79 and 0.67, respectively) with treatment durability. A positive, significant (P = 0.016, r2= 0.50) association between interval time and time-to-400 mm3 was also detected in animals with depressed pre-PDT blood flow due to hydralazine administration. At 3 hours after PDT, rBF and SO2 were predictive (P < or = 0.015) of treatment durability. CONCLUSION: These data suggest a role for DCS in real-time monitoring of PDT vascular response as an indicator of treatment efficacy.