Observational evidence for interhemispheric hydroxyl-radical parity.

The hydroxyl radical (OH) is a key oxidant involved in the removal of air pollutants and greenhouse gases from the atmosphere. The ratio of Northern Hemispheric to Southern Hemispheric (NH/SH) OH concentration is important for our understanding of emission estimates of atmospheric species such as nitrogen oxides and methane. It remains poorly constrained, however, with a range of estimates from 0.85 to 1.4 (refs 4, 7-10). Here we determine the NH/SH ratio of OH with the help of methyl chloroform data (a proxy for OH concentrations) and an atmospheric transport model that accurately describes interhemispheric transport and modelled emissions. We find that for the years 2004-2011 the model predicts an annual mean NH-SH gradient of methyl chloroform that is a tight linear function of the modelled NH/SH ratio in annual mean OH. We estimate a NH/SH OH ratio of 0.97 ± 0.12 during this time period by optimizing global total emissions and mean OH abundance to fit methyl chloroform data from two surface-measurement networks and aircraft campaigns. Our findings suggest that top-down emission estimates of reactive species such as nitrogen oxides in key emitting countries in the NH that are based on a NH/SH OH ratio larger than 1 may be overestimated.

Nonreciprocal Transmission and Reflection of a Chirally Coupled Quantum Dot.

We report strongly nonreciprocal behavior for quantum dot exciton spins coupled to nanophotonic waveguides under resonant laser excitation. A clear dependence of the transmission spectrum on the propagation direction is found for a chirally coupled quantum dot, with spin up and spin down exciton spins coupling to the left and right propagation directions, respectively. The reflection signal shows an opposite trend to the transmission, which a numerical model indicates is due to direction-selective saturation of the quantum dot. The chiral spin-photon interface we demonstrate breaks reciprocity of the system and opens the way to spin-based quantum optical components such as optical diodes and circulators in a chip-based solid-state environment.

Sulfhydryl groups and estradiol-receptor interaction.

The characteristic ability of rat uteri to take up tritiated estradiol in vitro or to retain estradiol previously incorporated either in vivo or in vitro is destroyed by treating the tissue with various sulfhydryl-blocking reagents. The two radioactive estradiol-receptor complexes, observed in uterine homogenates in the supernatant fraction and in an extract of the nuclear fraction, respectively, are disrupted by brief exposure to organic mercurials in the cold. Sulfhydryl groups of uterine receptor substances apparently play a vital role in estradiol binding, perhaps indirectly through contribution to receptor conformation.

An experimental approach to relate a tumor-associated enzyme marker to tumor cell numbers.

Alkaline phosphatase was monitored in 17 mice with s.c.-implanted tumors to relate the total circulating alkaline phosphatase to the total number of tumor cells in each mouse. There was a semilogarithmic relationship between the alkaline phosphatase units and the number of tumor cells. A time-independent standard plot of alkaline phosphatase and the number of tumor cells was used to estimate the size of disseminated and localized tumors. In animals treated with cyclophosphamide, the alkaline phosphatase marker was used to monitor the regression and recurrence of the neoplasm in vivo.

Should dental teams be doing more to make adolescents aware of the health risks of water pipe tobacco smoking (shisha)?

The prevalence of waterpipe tobacco smoking (also known as shisha, hookah, narghile or hubble bubble) is increasing worldwide and is especially popular among adolescents of all cultures, ethnicities and socio-economic backgrounds. This increased prevalence is thought to be due to a number of factors including the relationship between the social aspect of waterpipe smoking and a thriving café culture, lack of regulatory or policy framework specific to waterpipe use, the perception of reduced harm and the evolution of social media. This opinion paper discusses the prevalence of shisha use among adolescents, associated risks and oral health conditions and effective shisha cessation interventions. The implications for the dental team are also discussed.

Breast Cancer Metastasis Suppressor 1 (BRMS1): Robust Biological and Pathological Data, But Still Enigmatic Mechanism of Action.

Metastasis requires coordinated expression of multiple genetic cassettes, often via epigenetic regulation of gene transcription. BRMS1 blocks metastasis, but not orthotopic tumor growth in multiple tumor types, presumably via SIN3 chromatin remodeling complexes. Although there is an abundance of strong data supporting BRMS1 as a metastasis suppressor, the mechanistic data directly connecting molecular pathways with inhibition of particular steps in metastasis are not well defined. In this review, the data for BRMS1-mediated metastasis suppression in multiple tumor types are discussed along with the steps in metastasis that are inhibited.

UTLS water vapour from SCIAMACHY limb measurementsV3.01 (2002-2012).

The SCanning Imaging Absorption spectroMeter for Atmospheric CHartographY (SCIAMACHY) aboard the Envisat satellite provided measurements from August 2002 until April 2012. SCIAMACHY measured the scattered or direct sunlight using different observation geometries. The limb viewing geometry allows the retrieval of water vapour at about 10-25 km height from the near-infrared spectral range (1353-1410 nm). These data cover the upper troposphere and lower stratosphere (UTLS), a region in the atmosphere which is of special interest for a variety of dynamical and chemical processes as well as for the radiative forcing. Here, the latest data version of water vapour (V3.01) from SCIAMACHY limb measurements is presented and validated by comparisons with data sets from other satellite and in situ measurements. Considering retrieval tests and the results of these comparisons, the V3.01 data are reliable from about 11 to 23 km and the best results are found in the middle of the profiles between about 14 and 20 km. Above 20 km in the extra tropics V3.01 is drier than all other data sets. Additionally, for altitudes above about 19 km, the vertical resolution of the retrieved profile is not sufficient to resolve signals with a short vertical structure like the tape recorder. Below 14 km, SCIAMACHY water vapour V3.01 is wetter than most collocated data sets, but the high variability of water vapour in the troposphere complicates the comparison. For 14-20 km height, the expected errors from the retrieval and simulations and the mean differences to collocated data sets are usually smaller than 10 % when the resolution of the SCIAMACHY data is taken into account. In general, the temporal changes agree well with collocated data sets except for the Northern Hemisphere extratropical stratosphere, where larger differences are observed. This indicates a possible drift in V3.01 most probably caused by the incomplete treatment of volcanic aerosols in the retrieval. In all other regions a good temporal stability is shown. In the tropical stratosphere an increase in water vapour is found between 2002 and 2012, which is in agreement with other satellite data sets for overlapping time periods.

Reversion at the HiS1 locus of yeast.

The his1 gene (chromosome V) of Saccharomyces cerevisiae specifies phosphoribosyl transferase (E.C.2.4.2.17), the first enzyme of histidine biosynthesis. This hexameric enzyme has both catalytic and regulatory functions. The spontaneous reversion rates of seven his1 mutations were studied. The reversion rates of the alleles at the proximal end of the locus (relative to the centromere) were about 50-fold higher than distal alleles. Spontaneous reversion to prototrophy was studied in diploids homoallelic for each of the seven his1 mutations. Based on tetrad analysis, the prototrophy revertants could be assigned to three classes: (1) revertant tetrads that carried a prototrophic allele indistinguishable from wild type; (2) revertant tetrads that carried a prototrophic allele characterized by histidine excretion and feedback resistance; and (3) revertant tetrads that did not contain a prototrophic spore, but rather a newly derived allele that complemented the original allele intragenically. Four of the seven his1 mutations produced the excretor revertant class, and two mutations produced the complementer revertant class. The significance of these findings to our understanding of gene organization and the catalytic and regulatory functions of gene products are discussed.

Nebulized isoetharine and fenoterol in acute attacks of asthma.

Nebulized, selective beta 2-adrenergic agents were shown to be a safe and effective alternative to subcutaneous epinephrine chloride in the treatment of acute asthma attacks. Results of a trial of nebulized 1% isoetharine hydrochloride and 0.5% fenoterol in 40 patients with acute attacks of wheezing is reported. Both groups showed significant improvement on forced expiratory volume in one second (FEV1), maximum expiratory flow at 25% and 50% vital capacity but those who received fenoterol therapy showed more significant bronchodilation after one hour. Based on clinical criteria and the ability to raise and maintain for four hours an FEV, by 15% above baseline, ten (50%) of the patients who received isoetharine and 16 (80%) of the patients who received fenoterol therapy were successes. Mild side effects were encountered in eight patients of each treatment group. Fenoterol therapy was significantly more effective and had a longer duration of action.

Thrombotic thrombocytopenic purpura seen as pulmonary hemorrhage.

A 33-year-old woman was seen with fever, confusion, and respiratory distress. A diagnosis of thrombotic thrombocytopenic purpura (TTP) was made when renal failure, microangiopathic hemolytic anemia, and thrombocytopenia subsequently developed. An open kidney biopsy confirmed the clinical diagnosis. The patient initially was seen with the roentgenographic and clinical appearance of pulmonary hemorrhage, which was confirmed histologically and, to our knowledge, previously has not been associated with TTP.

A prospective evaluation emphasizing pulmonary involvement in patients with mixed connective tissue disease.

Pulmonary involvement in mixed connective tissue disease (MCTD) is common, frequently severe, and is often clinically inapparent and variably responsive to corticosteroid/cyclophosphamide treatment. Serial pulmonary evaluation of patients with MCTD is important, since deterioration, as in the diffusing capacity over time, may alert the physician to the need for more invasive evaluation. Patients with a greater degree of overlap in rheumatological symptoms with an element of systemic sclerosis (PSS) may later develop severe disease. Nailfold capillary microscopy also may help in determining which patients will develop severe pulmonary involvement. Significant pulmonary hypertension occurs and cannot be accurately predicted on the basis of history, physical examination, pulmonary function tests, gallium scanning, or exercise testing. The characteristic pathological finding was intimal proliferation with medial muscular hypertrophy in the pulmonary arterioles. In contrast, pulmonary interstitial abnormalities were minimal, suggesting the proliferative vascular lesions are more closely associated with pulmonary hypertension in MCTD. Some patients develop rapidly progressive disease with varying response to corticosteroid and cytotoxic agents. More commonly, however, MCTD patients with long-term disabling disease, including pulmonary dysfunction, have had significant improvement with steroid and/or cyclophosphamide treatment, and clinical remission has occurred in 38% of the patients in this series.

Human recombinant DNA-derived antihemophilic factor in the treatment of previously untreated patients with hemophilia A: final report on a hallmark clinical investigation.

BACKGROUND: Development of recombinant factor VIII (rFVIII) replacement therapy represents a milestone in the treatment of hemophilia A. OBJECTIVE: The objective of this long-term, multicenter study was to assess the safety, efficacy and rate of inhibitor formation of rFVIII (Kogenate) in the treatment of hemophilia A in a group of previously untreated patients (PUPs). PATIENTS AND METHODS: Between January 1989 and October 1997, 102 evaluable patients (mean age 3.9 years) were treated with rFVIII as sole therapy for prophylaxis against bleeding or for hemorrhage. Patients with mild hemophilia were treated for > or =2 years, while those with moderate or severe hemophilia were treated for > or =5 years or 100 exposure days. RESULTS: All patients responded well to therapy, so that 82% of bleeding episodes required a single infusion for treatment. Only four mild drug-related adverse events were recorded during the study for an overall rate of 0.03% (4/13 464 infusions). No viral seroconversions were observed. The inhibitor incidence in PUPs with severe hemophilia was 29% (19/65). Overall, inhibitory antibodies developed in 21 patients (20.6%). Inhibitor titers were low (<10 Bethesda Units) in nine of the 21 patients despite continued episodic treatment with rFVIII and transient in eight patients receiving episodic treatment (seven low titer, one high titer). Eight high-titer inhibitor patients were treated with immune-tolerance induction therapy; five had successful outcomes. CONCLUSIONS: The observed incidence of inhibitor formation is similar to studies of PUPs receiving plasma-derived FVIII. These results demonstrate the safety and efficacy of rFVIII in long-term treatment of hemophilia A.

Niacin revisited: clinical observations on an important but underutilized drug.

STUDY OBJECTIVE: To evaluate the efficacy and side effects of niacin therapy in dyslipidemic individuals. DESIGN: A retrospective analysis of patients' charts. SETTING: An outpatient referral-based clinic specializing in the treatment of lipid disorders. PATIENTS: All patients with dyslipidemia treated by niacin (n = 82) at the Atherosclerosis Detection and Prevention Clinic during 1987 to 1990, including a subgroup of 17 dyslipidemic heart transplant recipients. RESULTS: Niacin was well tolerated in 83% of the nontransplant group (n = 65) at an average dose of 2.5 +/- 0.9 g/day. Similar beneficial lipoprotein effects were found in the transplant and nontransplant patients. The high-density lipoprotein cholesterol (HDL-C) response to niacin therapy was independent of the baseline (HDL-C level. In the transplant group, 11 patients (65%) discontinued treatment, primarily because of hyperglycemia; this was especially prominent in those patients with pretreatment diabetes mellitus. Of the 15 patients using sustained-release niacin, eight cases of hepatitis were recorded, some during therapy with relatively low niacin doses. Several different sustained-release preparations were responsible for this phenomenon, suggesting that the cause was not a contaminant in the preparation. No cases of hepatitis were documented in the 67 patients using regular niacin. One case of hepatitis was recently observed in a patient who switched from one type to regular niacin to another; however, we have data to suggest that the substituted preparation was not an immediate-release niacin. A familial predisposition to hepatitis is suggested by the occurrence of this side effect in identical twin brothers and two sisters. A pharmacy survey disclosed that most pharmacists are unaware of the relationship of sustained-release niacin to hepatitis, have a negative impression of regular niacin, and do not stock this formulation. Finally, we found that in this small sample of patients, niacin used with lovastatin is a particularly effective drug combination and appears to have few side effects beyond those seen with niacin alone. CONCLUSIONS: Our experience supports the fact that regular niacin is a useful lipid-modifying drug. When used appropriately, patients can usually tolerate adequate doses for prolonged periods and achieve meaningful results. However, this requires a certain amount of physician skill and patient motivation. The use of sustained-release preparations to overcome this problem can lead to harmful consequences and should only be done under strict medical supervision. In our opinion, the availability of sustained-release niacin as a nonprescription drug is unjustified and should be reexamined. Finally, we have observed that reduction of very-low-density lipoprotein cholesterol (VLDL-C) with niacin alone leads to an elevation in low-density lipoprotein cholesterol in many patients; this indicates to us that the mechanism whereby niacin lowers VLDL-C and total cholesterol is not solely the result of a decreased synthesis of VLDL-C.

Exploration of biologically relevant conformations of anandamide, 2-arachidonylglycerol, and their analogues using conformational memories.

The endogenous cannabinoid anandamide (N-arachidonoylethanolamide) has been shown to possess higher affinity for the cannabinoid CB1 receptor than for the CB2 receptor. Carrier-mediated transport has been proposed to be essential for the termination of the biological effects of anandamide, while hydrolysis of anandamide is performed by a membrane-bound amidohydrolase, fatty acid amidohydrolase (FAAH). As interaction of anandamide with each of these targets occurs in different environments, the conformations of anandamide for interaction with each target may differ. To ascertain what conformations of anandamide, a highly flexible molecule, are favored in polar and nonpolar environments, the new method of Conformational Memories (CM) was used. CM has been shown to achieve complete conformational sampling of highly flexible ligands, to converge in a very practical number of steps, and to be capable of overcoming energy barriers very efficiently (Guarnieri et al. J. Am. Chem. Soc. 1996, 118, 5580). The generalized Born/surface area (GB/SA) continuum solvation models for chloroform and for water were used in the CM calculations. As a means of validation, CM was first applied to arachidonic acid because both experimental and theoretical conformational studies of arachidonic acid have been reported. CM was also applied to sn-2-arachidonylglycerol (2-AG), another endogenous CB ligand; to a 1,1-dimethylheptyl derivative of anandamide, an analogue with higher CB1 affinity than anandamide; and to N-(2-hydroxyethyl)prostaglandin-B2-ethanolamide (PGB2-EA), a prostanoid ligand which does not bind to CB1. Consistent with the literature, arachidonic acid was found to exist in an extended, angle-iron shape and in back-folded conformations which were U, J, or helical in shape. The angle-iron and U-shapes were both highly populated conformations with the angle-iron preferred in CHCl3 and the U-shape preferred in H2O. Results for anandamide and 2-AG paralleled those for arachidonic acid with the exception that anandamide in water does not adopt a pure extended conformation but, rather, favors a hybrid-extended/U-shape. For the dimethyl-heptyl derivative of anandamide, the U-shape was found to be predominant in both environments (42% in CHCl3, 38% in H2O), but the population of the angle-iron shape was still significant (25% in CHCl3, 29% in H2O). For all of these ligands, J-shaped conformers constituted from 7% to 17% of the conformer population, while the helical shape was less than 5%. In both CHCl3 and H2O, the presence of the five-membered ring attenuates the ability of PGB2-EA to adopt an extended conformation. PGB2-EA was found instead to exist predominantly in an L-shape (i.e., distorted U-shape). The low probability of PGB2-EA adopting an extended conformation may be why PGB2-EA shows such low affinity for the CB1 receptor. The conformational information obtained here for anandamide and 2-AG may be useful in the design of rigid analogues which mimic the preferred molecular conformations (shapes) of these ligands. Such rigid analogues may be useful in deducing the bioactive conformation of these endogenous cannabinoids, not only at the CB receptors but also at the FAAH enzyme active site and possibly at the binding site(s) on the newly proposed anandamide transporter.

Beta-adrenoceptor activity of the stereoisomers of the bufuralol alcohol and ketone metabolites.

The stereoisomers of 2-[(tert-butylamino)methyl]-7-methyl-2,7-benzofurandimethanol (2) and 2-[2-(tert-butylamino)-1-hydroxyethyl]-7-benzofuranyl methyl ketone (3), the alcohol and ketone metabolites of bufuralol, have been prepared and examined for beta-adrenoceptor activity in rats. All the stereoisomers with the S configuration hydroxylamine side chain showed potent beta 2-antagonist activity comparable to (S)-bufuralol (1a). In contrast, a wide range of antagonist potencies was observed at the beta 1-receptor; only alcohol diastereomer 9a was more active than 1a. This suggests that the shape of the 7-substituent in these benzofurans influences the degree of interaction with the beta 1-receptor much more than with the beta 2-receptor. Partial beta 1-agonist activity was associated not only with all the stereoisomers with the S configuration hydroxylamine side chain but also with some of the R configuration derivatives, especially (R)-ketone 3b. The results suggest that the margin of difference in beta-adrenoceptor activity between compounds epimeric at the hydroxylamine side chain can be significantly influenced by a suitable substituent in the aromatic nucleus.

Beta 1-selective adrenoceptor antagonists. 3. 4-Azolyl-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines has been prepared and examined for beta-adrenoceptor activity. The 4-substituents, di- and triazole ring systems connected to the phenoxy ring by different length chains, were chosen as a means of introducing cardioselectivity. This has been achieved, especially in the 1-[4-[(4-chloropyrazol-1-yl)methoxy] phenoxy]-3-(isopropylamino)-2-propanol (11), the 4-[(2H-1,2,3-triazol-2-yl)methoxy] analogue (21), and the 4-[2-(2H-1,2,3-triazol-2-yl)ethoxy] analogue (22), which show potent beta 1-blockade with selectivity ratios in excess of 100:1. Structure-activity relationships are discussed, and the optimum position of the heteroatom in the 4-substituent is defined.

beta 1-selective adrenoceptor antagonists. 2. 4-ether-linked phenoxypropanolamines.

A series of 4-substituted phenoxypropanolamines was prepared and examined for beta-adrenoceptor activity. Some of the compounds, especially the [4-[2-[[2-(4-fluorophenyl)ethyl] oxy]ethoxy]phenoxy]propanolamines (14, 15, and 24), showed potent beta 1-blockade with virtually no beta 2-blockade at doses over a 1000 times greater. The compounds also possessed partial agonist activity. Structure-activity relationships are discussed, and conclusions are drawn about the binding sites on beta-adrenoceptors.

The bioactive conformation of aminoalkylindoles at the cannabinoid CB1 and CB2 receptors: insights gained from (E)- and (Z)-naphthylidene indenes.

The aminoalkylindoles (AAIs) are agonists at both the cannabinoid CB1 and CB2 receptors. To determine whether the s-trans or s-cis form of AAIs is their receptor-appropriate conformation, two pairs of rigid AAI analogues were studied. These rigid analogues are naphthylidene-substituted aminoalkylindenes that lack the carbonyl oxygen of the AAIs. Two pairs of (E)- and (Z)-naphthylidene indenes (C-2 H and C-2 Me) were considered. In each pair, the E geometric isomer is intended to mimic the s-trans form of the AAIs, while the Z geometric isomer is intended to mimic the s-cis form. Complete conformational analyses of two AAIs, pravadoline (2) and WIN-55, 212-2 (1), and of each indene were performed using the semiempirical method AM1. S-trans and s-cis conformations of 1 and 2 were identified. AM1 single-point energy calculations revealed that when 1 and each indene were overlayed at their corresponding indole/indene rings, the (E)- and (Z)-indenes were able to overlay naphthyl rings with the corresponding s-trans or s-cis conformer of 1 with an energy expense of 1.13/0.69 kcal/mol for the C-2 H (E/Z)-indenes and 0.82/0.74 kcal/mol for the C-2 Me (E/Z)-indenes. On the basis of the hypothesis that aromatic stacking is the predominant interaction of AAIs such as 1 at the CB receptors and on the demonstration that the C-2 H (E/Z)- and C-2 Me (E/Z)-indene isomers can mimic the positions of the aromatic systems in the s-trans and s-cis conformers of 1, the modeling results support the previously established use of indenes as rigid analogues of the AAIs. A synthesis of the naphthylidene indenes was developed using Horner-Wittig chemistry that afforded the Z isomer in the C-2 H series, which was not produced in significant amounts from an earlier reported indene/aldehyde condensation reaction. This approach was extended to the C-2 Me series as well. Photochemical interconversions in both the C-2 H and C-2 Me series were also successful in obtaining the less favored isomer. Thus, the photochemical process can be used to provide quantities of the minor isomers C-2 H/Z and C-2 Me/E. The CB1 and CB2 affinities as well as the activity of each compound in the twitch response of the guinea pig ileum (GPI) assay were assessed. The E isomer in each series was found to have the higher affinity for both the CB1 and CB2 receptors. In the rat brain membrane assay versus [3H]CP-55,940, the Ki's for the C-2 H/C-2 Me series were 2.72/2.89 nM (E isomer) and 148/1945 nM (Z isomer). In membrane assays versus [3H]SR141716A, a two-site model was indicated for the C-2 H/C-2 Me (E isomers) with Ki's of 10. 8/9.44 nM for the higher-affinity site and 611/602 nM for the lower-affinity site. For the Z isomers, a one-site model was indicated with Ki's of 928/2178 nM obtained for the C2 H/C-2 Me analogues, respectively. For the C-2 H/C-2 Me series, the CB2 Ki's obtained using a cloned cell line were 2.72/2.05 nM (E isomer) and 132/658 nM (Z isomer). In the GPI assay, the relative order of potency was C-2 H E > C-2 Me E > C-2 H Z > C-2 Me Z. The C-2 H E isomer was found to be equipotent with 1, while the C-2 Me Z isomer was inactive at concentrations up to 3.16 microM. Thus, results indicate that the E geometric isomer in each pair of analogues is the isomer with the higher CB1 and CB2 affinities and the higher pharmacological potency. Taken together, results reported here support the hypothesis that the s-trans conformation of AAIs such as 1 is the preferred conformation for interaction at both the CB1 and CB2 receptors and that aromatic stacking may be an important interaction for AAIs at these receptors.

Single-unit activity of cerebellar nuclear cells in the awake genetically dystonic rat.

The purpose of this study was to characterize neuronal activity in the deep cerebellar nuclei of the unanesthetized genetically dystonic rat during the neonatal period when the clinical signs of the dystonic syndrome first appear. Previous lesion studies have established cerebellar output as critical to the expression of the dystonic rat's motor syndrome, a disorder that closely resembles generalized dystonia in humans. In the dystonic rat, both cerebellectomy and selective lesions of the deep cerebellar nuclei decrease the frequency of abnormal motor signs and improve performance on tests of motor function. Single-unit activity was recorded from the medial, interpositus and lateral cerebellar nuclei in awake normal (N=49) and dystonic (N=54) rats at postnatal days 12-26. One hundred and eighty-three cells were isolated, 91 from normal and 92 from dystonic rats. Interspike interval histograms, autocorrelations and ratemeter histograms were generated for each cell's spike train. Interspike interval histograms were modeled with single and double gamma distributions. Cells from dystonic rats as young as 12 days of age showed bursting firing patterns, positively skewed or bimodal interspike interval histograms, and sinusoidal autocorrelations. Bursting activity increased linearly with postnatal age in dystonic rats. Cells from normal rats demonstrated non-sinusoidal autocorrelations and unimodal interspike interval histograms. Spike frequency increased linearly with postnatal age in both normal and dystonic rats. There were no statistically significant group differences in spike frequency between normal and dystonic rats. These findings show that functional neuropathology can be detected at the level of single neurons in the deep cerebellar nuclei at the earliest behavioral stages of the dystonic rat's movement disorder. The degree of abnormality in spike train parameters correlates with the severity of the movement disorder. Independent of neuronal firing rates, abnormal neuronal firing patterns can serve as a guide to the localization of pathological cell populations within the central nervous system. These results provide additional evidence that abnormal cerebellar output plays a critical role in the pathophysiology of the dystonic rat's motor syndrome.

Newborn screening for sickle cell disease: effect on mortality.

Newborn screening for sickle cell disease has been recommended as a method of decreasing patient mortality. However, its effectiveness in accomplishing this has not been reliably measured. To help determine the effectiveness, 10 years of experience in newborn screening have been summarized. The effects of early patient enrollment in a comprehensive treatment program on long-term morbidity and mortality are reported. From 1975 to 1985, 84,663 newborns were screened regardless of race or ethnic background. Bart's hemoglobin was present in 5%, hemoglobin AS in 2.6%, and hemoglobin AC in 0.75%. Excluding Bart's, approximately 3.6% of all newborns were carriers for hemoglobinopathy. Sickle cell disease occurred in 1:951 births (58 hemoglobin SS, 25 hemoglobin FSC, three hemoglobin S-beta +-thalassemia, and three hemoglobin S-beta O-thalassemia). In addition, one in every 4,233 newborns had a clinically significant thalassemia syndrome (eight hemoglobin FE, ten hemoglobin F only, two hemoglobin H). Compared with other newborn screening programs in California, (congenital hypothyroidism, 1:3,849; phenylketonuria 1:22,474, galactosemia 1:74,103), hemoglobinopathies are the most prevalent congenital disease. Eighty-one newborns with sickle cell disease were followed for 7.2 years. Patients experienced 513 hospitalizations, including 13 episodes of sepsis with or without meningitis and ten acute sequestration crises. The overall mortality rate for patients with sickle cell anemia diagnosed in the newborn period was 1.8%. In comparison, the clinical course of 64 patients with sickle cell anemia diagnosed after 3 months of age and followed for an average of 9.4 years was analyzed. Five of these patients died. In two of these, sickle cell anemia was diagnosed at the time of the death.(ABSTRACT TRUNCATED AT 250 WORDS)