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Dihydropyrimidinase (DHP, EC 3.5.2.2) is the second enzyme in the degradation pathway of uracil and thymine. It catalyses the degradation of both dihydrouracil and dihydrothymine to N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid, respectively. So far, four cases of dihydropyrimidinuria (McKusick 222748) have been reported (Duran et al 1991; Henderson et al 1993; Bakkeren et al, personal communication, 1994; Ohba et al 1994). The patients show a variable clinical phenotype comprising seizures or epileptic attacks (3 out of 4 patients) mental retardation (2 patients), growth retardation (1 patient) and dysmorphic features (1 patient). Since these patients excrete large amounts of dihydrouracil and dihydrothymine and moderate amounts of uracil and thymine in their urine, they can easily be detected (Van Gennip et al 1993). On the basis of the characteristic urinary metabolite profile it is assumed that the disease is caused by a deficiency of DHP. The direct measurement of the activity of DHP in patients has been hampered by the fact that the enzyme is almost exclusively expressed in liver tissue. Here, we provide for the first time direct evidence at the enzyme level for a deficient activity of DHP in liver in a patient with dihydropyrimidinuria.

Post-hypoxic-ischemic (HI) reperfusion induces endothelium and neurons to produce excessive amounts of nitric oxide and superoxide, leading to peroxynitrite formation, release of protein-bound metal ions (i.e. iron), and cytotoxic oxidants. We produced severe HI in 18 newborn lambs and serially determined plasma prooxidants (non-protein-bound iron), lipid peroxidation (malondialdehyde), and antioxidative capacity [ratio of ascorbic acid/dehydroascorbic acid (AA/DHA), alpha-tocopherol, sulfhydryl groups, allantoin/uric acid ratio, and vitamin A] in blood effluent from the brain before and at 15, 60, 120, and 180 min after HI. The lambs were divided in three groups: six received a placebo (CONT), six received low dose (10 mg/kg/i.v.) N omega-nitro-L-arginine (NLA-10) to block nitric oxide production, and six received high dose NLA (40 mg/kg/i.v.; NLA-40), immediately after completion of HI. Non-protein-bound iron increased in all groups after HI but was significantly lower in both NLA groups at 180 min post-HI (p < 0.05), the AA/DHA ratio showed a consistent decrease in CONT (at 60 min post-HI, p < 0.05), but remained stable in NLA lambs. alpha-Tocopherol decreased steadily in the CONT, but not in the NLA lambs [180 post-H: 1.9 +/- 0.9 versus 4.2 +/- 0.7 microM (NLA-40), p < 0.05). Malondialdehyde was significantly higher in CONT lambs 120 min post-H compared with NLA groups [0.61 +/- 017 versus 0.44 +/- 0.05 microM (NLA-40), p < 0.05]. Vitamin A and sulfhydryl groups did not differ among groups. We conclude that post-H inhibition of nitric oxide synthesis diminishes non-protein-bound iron increment and preserves antioxidant capacity.

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We report 2 siblings with the Aicardi-Goutieres syndrome (encephalopathy, basal ganglia calcifications, and persistent cerebrospinal fluid pleiocytosis). The eldest sibling is severely retarded; his younger brother has only mild, slowly progressive neurological deficits. To our knowledge, such a striking difference in clinical expression has not been reported previously.

We identified nine children with a leukoencephalopathy of similar type according to clinical and MRI findings. The patients included three affected sibling pairs. The age range was 3 to 19 years. The onset of the disease was in childhood; the course was both chronic-progressive and episodic. There were episodes of deterioration following infections and minor head traumas, and these could result in unexplained coma. In eight patients with advanced disease, MRI revealed a diffuse cerebral hemispheric leukoencephalopathy, in which increasing areas of the abnormal white matter had a signal intensity close to that of CSF on all pulse sequences. In one patient in the early stages of disease, initial MRI showed diffusely abnormal cerebral white matter, which only reached the signal characteristics of CSF at a later stage. In the patients in whom the disease was advanced, magnetic resonance spectroscopy (MRS) of the white matter showed an almost complete disappearance of all normal signals and the presence of glucose and lactate, compatible with the presence of mainly CSF and little brain tissue. Spectra of the cortex were much better preserved. However, in addition to the normal resonances, there were signals representing lactate and glucose. MRS of the white matter in the patient whose disease was at an early stage was much less abnormal. Autopsy in one patient confirmed the presence of extensive cystic degeneration of the cerebral white matter with reactive change and a preserved cortex. Typical involvement of pontine tegmental white matter was suggested by MRI and confirmed by autopsy. The disease probably has an autosomal recessive mode of inheritance, but the basic metabolic defect is not known.

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Ventilation with nitric oxide (NO) is increasingly being used to treat pulmonary hypertension in the newborn. In the brain, NO has vasoactive properties and is involved in neurotransmission. However, the effect of inhaled NO on the cerebral blood flow (CBF) and on the cerebral activity is not known. Furthermore, there is little information on the influence of this free radical gas on the redox status in pulmonary vessels. We therefore investigated the effect of inhaled NO (2–60 ppm) on CBF, cerebral activity and redox status in blood effluent from the pulmonary circulation in 6 ventilated newborn lambs before and during group B streptococci (GBS)-induced pulmonary hypertension. Blood pressure in the pulmonary artery (Pap) and aorta (Pao), carotid artery blood flow (Qcar) to assess changes in CBF, and electrocortical activity were measured. Blood gases, indices of free radical status and methemoglobin were determined in blood samples obtained from the left ventricle. Inhalation of NO, before and during GBS-induced pulmonary hypertension, decreased Pap and PCO2 and increased PO2. Multiple linear regression revealed that Qcar was positively related to PCO2, but not to inhaled NO or PO2 before or during GBS conditions. Electrocortical activity and indices of antioxidative capacity and lipid peroxidation did not change significantly. Methemoglobin was not detected. In conclusion, inhalation of NO (up to 60 ppm) lowered Pap without directly affecting CBF, electrocortical activity, and redox status in the pulmonary vessels. CBF, however, can indirectly be influenced by NO-mediated changes in PCO2·

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Objective: To evaluate the effect of vaginal disinfection with chlorhexidine gel during labor on vertical transmission of group B streptococcus, as a method to prevent vertical transmission and subsequent neonatal early onset group B streptococcal disease. Study Design: A prospective study with randomization of 1020 parturients to one of three groups as soon as labor started. In all parturients, anus, introitus and cervix were cultured semiquantitatively. Two groups were treated double-blindly with 10 ml of either a 0.3% chlorhexidine gel or a placebo gel, applicated around the portio and into the fomices. If labor still continued, a second application was given after 10 h. The third group received no treatment. Ear, pharynx and umbilicus of all newborns were also cultured semiquantitatively. Results: Nine hundred and eighty one women were evaluated. The overall incidence of group B strep­ tococcal carriership was 19.4%. Vertical transmission was 52.4% in the chlorhexidine group, 71.4% in the placebo group and 66.7% in the control group (P = 0.069). When testing the transmission rates for the chlorhexidine versus the combined placebo plus control group (69.3%), the difference was 16.9% (P ~ 0.026). Conclusion: Vaginal disinfection with a chlorhexidine gel during labor modest­ ly reduces group B streptococcal vertical transmission. Because the method is cheap, simple and safe, it should be considered for routine use. Our results indicate that it may reduce the incidence of early onset group B streptococcal sepsis by 2-32%.

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Spatiotemporal dipole modelling of the generators of the readiness potential (RP) prior to voluntary movements has yielded diverging results concerning the contributions of supplementary motor area (SMA) and primary motor cortex. We applied an alternative approach (i.e. linear estimation theory) to measurements of the RP preceding fixed and freely selected finger movements, measured at 28 electrodes of the extended 10-20 system. The volume conductor properties of the head were modelled by 3 concentric spheres. Current densities were reconstructed on a spherical surface, placed at a depth of 5 mm from the inside of the skull. Lead field normalization was applied. The analysis shows activity on the midline as well as near the primary motor area. Although some features of the reconstructions are not readily interpretable, separate contributions of midline sources (including presumably SMA) and motor cortex to the RP are clearly distinguished.

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