Altered gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia.

The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques.

A randomized controlled trial of mindfulness-based stress reduction to prevent flare-up in patients with inactive ulcerative colitis.

BACKGROUND/AIMS: The primary therapeutic goals in ulcerative colitis (UC) are to maintain excellent quality of life (QOL) by treating flare-ups when they occur, and preventing flare-ups. Since stress can trigger UC flare-ups, we investigated the efficacy of mindfulness-based stress reduction (MBSR) to reduce flare-ups and improve QOL. METHODS: Patients with moderately severe UC, in remission, were randomized to MBSR or time/attention control. Primary outcome was disease status. Secondary outcomes were changes in markers of inflammation and disease activity, markers of stress and psychological assessments. RESULTS: 55 subjects were randomized. Absence of flares, time to flare and severity of flare over 1 year were similar between the two groups. However, post hoc analysis showed that MBSR decreased the proportion of participants with at least one flare-up among those with top tertile urinary cortisol and baseline perceived stress (30 vs. 70%; p < 0.001). MBSR patients who flared demonstrated significantly lower stress at the last visit compared to flared patients in the control group (p = 0.04). Furthermore, MBSR prevented a drop in the Inflammatory Bowel Disease Quality of Life Questionnaire during flare (p < 0.01). CONCLUSION: MBSR did not affect the rate or severity of flare-ups in UC patients in remission. However, MBSR might be effective for those with high stress reactivity (high perceived stress and urinary cortisol) during remission. MBSR appears to improve QOL in UC patients by minimizing the negative impact of flare-ups on QOL. Further studies are needed to identify a subset of patients for whom MBSR could alter disease course.

High hydrostatic pressure modification of whey protein concentrate for use in low-fat whipping cream improves foaming properties.

Whey is the inevitable by-product of cheese production. Whey can be incorporated into a variety of foods, but little has been done to investigate its suitability in whipping cream. The objective of this work was to evaluate the foaming properties of selected low-fat whipping cream formulations containing whey protein concentrate (WPC) that did or did not undergo high hydrostatic pressure (HHP) treatment. Fresh whey was concentrated by ultrafiltration, pasteurized, and standardized to 8.23% total solids and treated with HHP at 300 MPa for 15 min. Viscosity, overrun, and foam stability were determined to assess foaming properties. Sensory evaluation was conducted with 57 panelists using a duo-trio difference test. The optimal whipping time for the selected formulations was 3 min. Whipping cream containing untreated WPC and HHP-treated WPC resulted in greater overrun and foam stability than the control whipping cream without WPC. Panelists distinguished a difference between whipping cream containing untreated WPC and whipping cream containing HHP-treated WPC. High hydrostatic pressure-treated WPC can improve the foaming properties of low-fat whipping cream, which may justify expansion of the use of whey in whipping cream and application of HHP technology in the dairy industry.

High hydrostatic pressure modification of whey protein concentrate for improved functional properties.

Whey protein concentrate (WPC) has many applications in the food industry. Previous research demonstrated that treatment of whey proteins with high hydrostatic pressure (HHP) can enhance solubility and foaming properties of whey proteins. The objective of this study was to use HHP to improve functional properties of fresh WPC, compared with functional properties of reconstituted commercial whey protein concentrate 35 (WPC 35) powder. Fluid whey was ultrafiltered to concentrate proteins and reconstituted to equivalent total solids (8.23%) as reconstituted commercial WPC 35 powder. Solutions of WPC were treated with 300 and 400 MPa (0- and 15-min holding time) and 600 MPa (0-min holding time) pressure. After HHP, the solubility of the WPC was determined at both pH 4.6 and 7.0 using UDY and BioRad protein assay methods. Overrun and foam stability were determined after protein dispersions were whipped for 15 min. The protein solubility was greater at pH 7.0 than at pH 4.6, but there were no significant differences at different HHP treatment conditions. The maintenance of protein solubility after HHP indicates that HHP-treated WPC might be appropriate for applications to food systems. Untreated WPC exhibited the smallest overrun percentage, whereas the largest percentage for overrun and foam stability was obtained for WPC treated at 300 MPa for 15 min. Additionally, HHP-WPC treated at 300 MPa for 15 min acquired larger overrun than commercial WPC 35. The HHP treatment of 300 MPa for 0 min did not improve foam stability of WPC. However, WPC treated at 300 or 400 MPa for 15 min and 600 MPa for 0 min exhibited significantly greater foam stability than commercial WPC 35. The HHP treatment was beneficial to enhance overrun and foam stability of WPC, showing promise for ice cream and whipping cream applications.

High hydrostatic pressure modification of whey protein concentrate for improved body and texture of lowfat ice cream.

Previous research demonstrated that application of high hydrostatic pressure (HHP), particularly at 300 MPa for 15 min, can enhance foaming properties of whey protein concentrate (WPC). The purpose of this research was to determine the practical impact of HHP-treated WPC on the body and texture of lowfat ice cream. Washington State University (WSU)-WPC was produced by ultrafiltration of fresh separated whey received from the WSU creamery. Commercial whey protein concentrate 35 (WPC 35) powder was reconstituted to equivalent total solids as WSU-WPC (8.23%). Three batches of lowfat ice cream mix were produced to contain WSU-WPC without HHP, WSU-WPC with HHP (300 MPa for 15 min), and WPC 35 without HHP. All lowfat ice cream mixes contained 10% WSU-WPC or WPC 35. Overrun and foam stability of ice cream mixes were determined after whipping for 15 min. Ice creams were produced using standard ice cream ingredients and processing. The hardness of ice creams was determined with a TA-XT2 texture analyzer. Sensory evaluation by balanced reference duo-trio test was carried out using 52 volunteers. The ice cream mix containing HHP-treated WSU-WPC exhibited the greatest overrun and foam stability, confirming the effect of HHP on foaming properties of whey proteins in a complex system. Ice cream containing HHP-treated WSU-WPC exhibited significantly greater hardness than ice cream produced with untreated WSU-WPC or WPC 35. Panelists were able to distinguish between ice cream containing HHP-treated WSU-WPC and ice cream containing untreated WPC 35. Improvements of overrun and foam stability were observed when HHP-treated whey protein was used at a concentration as low as 10% (wt/wt) in ice cream mix. The impact of HHP on the functional properties of whey proteins was more pronounced than the impact on sensory properties.

Influence of salt-to-moisture ratio on starter culture and calcium lactate crystal formation.

The occurrence of L(+)-lactate crystals in hard cheeses continues to be an expense to the cheese industry. Salt tolerance of the starter culture and the salt-to-moisture ratio (S:M) in cheese dictate the final pH of cheese, which influences calcium lactate crystal (CLC) formation. This research investigates these interactions on the occurrence of CLC. A commercial starter was selected based on its sensitivity to salt, less than and greater than 4.0% S:M. Cheddar cheese was made by using either whole milk (3.25% protein, 3.85% fat) or whole milk supplemented with cream and ultrafiltered milk (4.50% protein, 5.30% fat). Calculated amounts of salt were added at milling (pH 5.40 +/- 0.02) to obtain cheeses with less than 3.6% and greater than 4.5% S:M. Total and soluble calcium, total lactic acid, and pH were measured and the development of CLC was monitored in cheeses. All cheeses were vacuum packaged and gas flushed with nitrogen gas and aged at 7.2 degrees C for 15 wk. Concentration of total lactic acid in high S:M cheeses ranged from 0.73 to 0.80 g/100 g of cheese, whereas that in low S:M cheeses ranged from 1.86 to 1.97 g/100 g of cheese at the end of 15 wk of aging because of the salt sensitivity of the starter culture. Concentrated milk cheeses with low and high S:M exhibited a 30 to 28% increase in total calcium (1,242 and 1,239 mg/100 g of cheese, respectively) compared with whole milk cheeses with low and high S:M (954 and 967 mg/100 g of cheese, respectively) throughout aging. Soluble calcium was 41 to 35% greater in low S:M cheeses (low-salt whole milk cheese and low-salt concentrated milk cheese; 496 and 524 mg/100 g of cheese, respectively) compared with high S:M cheeses (high-salt whole milk cheese and high-salt concentrated milk cheese; 351 and 387 mg/100 g of cheese, respectively). Because of the lower pH of the low S:M cheeses, CLC were observed in low S:M cheeses. However, the greatest intensity of CLC was observed in gas-flushed cheeses made with milk containing increased protein concentration because of the increased content of calcium available for CLC formation. These results show that the occurrence of CLC is dependent on cheese milk concentration and pH of the cheese, which can be influenced by S:M and cheese microflora.

Inkjet printable-photoactive all inorganic perovskite films with long effective photocarrier lifetimes.

Photoactive perovskite quantum dot films, deposited via an inkjet printer, have been characterized by x-ray diffraction and x-ray photoelectron spectroscopy. The crystal structure and bonding environment are consistent with CsPbBr3 perovskite quantum dots. The current-voltage (I-V) and capacitance-voltage (C-V) transport measurements indicate that the photo-carrier drift lifetime can exceed 1 ms for some printed perovskite films. This far exceeds the dark drift carrier lifetime, which is below 50 ns. The printed films show a photocarrier density 109 greater than the dark carrier density, making these printed films ideal candidates for application in photodetectors. The successful printing of photoactive-perovskite quantum dot films of CsPbBr3, indicates that the rapid prototyping of various perovskite inks and multilayers is realizable.

Cheese pH, protein concentration, and formation of calcium lactate crystals.

The occurrence of calcium lactate crystals (CLC) in hard cheeses is a continual expense to the cheese industry, as consumers fail to purchase cheeses with this quality defect. This research investigates the effects of the protein concentration of cheese milk and the pH of cheese on the occurrence of CLC. Atomic absorption spectroscopy was used to determine total and soluble calcium concentrations in skim milk (SM1, 8.7% total solids), and skim milk supplemented with nonfat dry milk (CSM1, 13.5% total solids). Calcium, phosphorus, lactic acid, and citrate were determined in cheeses made with skim milk (SM2, 3.14% protein), skim milk supplemented with ultrafiltered milk (CSM2, 6.80% protein), and nonfat dry milk (CSM3, 6.80% protein). Supplementation with nonfat dry milk increased the initial total calcium in CSM1 (210 mg/100 g of milk) by 52% compared with the total calcium in SM1 (138 mg/100 g of milk). At pH 5.4, soluble calcium concentrations in CSM1 were 68% greater than soluble calcium in SM1. In cheeses made from CSM2 and CSM3, total calcium was 26% greater than in cheeses made from SM2. As the pH of cheeses made from SM2 decreased from 5.4 to 5.1, the concentration of soluble calcium increased by 61.6%. In cheeses made from CSM2 and CSM3, the concentrations of soluble calcium increased by 41.4 and 45.5%, respectively. Calcium lactate crystals were observed in cheeses made from SM2 at and below pH 5.1, whereas CLC were observed in cheeses from CSM2 and CSM3 at and below pH 5.3. The increased presence of soluble calcium can potentially cause CLC to occur in cheese manufactured with increased concentrations of milk solids, particularly at and below pH 5.1.

Nonstarter lactic acid bacteria biofilms and calcium lactate crystals in Cheddar cheese.

A sanitized cheese plant was swabbed for the presence of nonstarter lactic acid bacteria (NSLAB) biofilms. Swabs were analyzed to determine the sources and microorganisms responsible for contamination. In pilot plant experiments, cheese vats filled with standard cheese milk (lactose:protein = 1.47) and ultrafiltered cheese milk (lactose:protein = 1.23) were inoculated with Lactococcus lactis ssp. cremoris starter culture (8 log cfu/mL) with or without Lactobacillus curvatus or Pediococci acidilactici as adjunct cultures (2 log cfu/mL). Cheddar cheeses were aged at 7.2 or 10 degrees C for 168 d. The raw milk silo, ultrafiltration unit, cheddaring belt, and cheese tower had NSLAB biofilms ranging from 2 to 4 log cfu/100 cm2. The population of Lb. curvatus reached 8 log cfu/g, whereas P. acidilactici reached 7 log cfu/g of experimental Cheddar cheese in 14 d. Higher NSLAB counts were observed in the first 14 d of aging in cheese stored at 10 degrees C compared with that stored at 7.2 degrees C. However, microbial counts decreased more quickly in Cheddar cheeses aged at 10 degrees C compared with 7.2 degrees C after 28 d. In cheeses without specific adjunct cultures (Lb. curvatus or P. acidilactici), calcium lactate crystals were not observed within 168 d. However, crystals were observed after only 56 d in cheeses containing Lb. curvatus, which also had increased concentration of D(-)-lactic acid compared with control cheeses. Our research shows that low levels of contamination with certain NSLAB can result in calcium lactate crystals, regardless of lactose:protein ratio.

Low etiologic fraction for human papillomavirus in larynx squamous cell carcinoma.

BACKGROUND: Human Papillomavirus (HPV) is a cause of oropharyngeal squamous cell carcinoma (OPSCC), but its pathogenic role in larynx squamous cell carcinoma (LSCC) remains unclear. MATERIAL AND METHODS: A single-institutional, retrospective case-series was performed to estimate the etiological fraction (EF) for HPV in LSCC. Eligible cases included 436 consecutive cases of LSCC diagnosed (2005-2014) at The Ohio State University Medical Center. HPV DNA presence was detected by consensus primer PCR (Inno-LiPa) and HPV type-specific qPCR. HPV E6/E7 mRNA expression was detected by type-specific qRT-PCR. Tumor p16 expression was evaluated by immunohistochemistry (IHC). RESULTS: HPV DNA was detected by Inno-LiPa in 54 of 404 (13.4%, 95% CI 10.2-17.1) evaluable samples but was confirmed by HPV type-specific qPCR in only 14 (3.5%, 95% CI 1.9-5.7). Only 7 of 404 (1.7%, 95% CI 0.7-3.5) LSCC were positive for HPV E6/E7 mRNA expression, including HPV16 (n=4) and 1 each for 11, 26 and 33. In the HPV11-positive tumor, Sanger sequencing discovered 6 nucleotide mutations in the upstream regulation region, E6 and E7. Of 404 LSCC, 18 had strong and diffuse p16 expression. In comparison to a gold standard of HPV E6/E7 mRNA expression, p16 expression had a sensitivity of 71.4% (95% CI 29.0-96.3), specificity of 96.7% (95% CI 94.5-98.3), positive-predictive-value (PPV) of 27.8% (95% CI 9.7-53.5) and negative-predictive-value of 99.5% (95% CI 98.1-99.9). CONCLUSION: The EF for HPV in LSCC is low (1.7%) in a geographic region with high EF for OPSCC. Low-risk HPV may rarely cause LSCC. Finally, p16 expression has poor PPV for HPV in LSCC.

Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies.

BACKGROUND: Neuronal ceroid lipofuscinosis (NCL), a fatal neurodegenerative disease, has been diagnosed in young adult Australian Cattle Dogs. OBJECTIVE: Characterize the Australian Cattle Dog form of NCL and determine its molecular genetic cause. ANIMALS: Tissues from 4 Australian Cattle Dogs with NCL-like signs and buccal swabs from both parents of a fifth affected breed member. Archived DNA samples from 712 individual dogs were genotyped. METHODS: Tissues were examined by fluorescence, electron, and immunohistochemical microscopy. A whole-genome sequence was generated for 1 affected dog. A TaqMan allelic discrimination assay was used for genotyping. RESULTS: The accumulation of autofluorescent cytoplasmic storage material with characteristic ultrastructure in tissues from the 4 affected dogs supported a diagnosis of NCL. The whole-genome sequence contained a homozygous nonsense mutation: CLN5:c.619C>T. All 4 DNA samples from clinically affected dogs tested homozygous for the variant allele. Both parents of the fifth affected dog were heterozygotes. Archived DNA samples from 346 Australian Cattle Dogs, 188 Border Collies, and 177 dogs of other breeds were homozygous for the reference allele. One archived Australian Cattle Dog sample was from a heterozygote. CONCLUSIONS AND CLINICAL IMPORTANCE: The homozygous CLN5 nonsense is almost certainly causal because the same mutation previously had been reported to cause a similar form of NCL in Border Collies. Identification of the molecular genetic cause of Australian Cattle Dog NCL will allow the use of DNA tests to confirm the diagnosis of NCL in this breed.

Low-dose captopril: its use in mild to moderate hypertension unresponsive to diuretic treatment.

The effect of low doses (25 mg three times a day) of captopril was evaluated in 16 patients with mild to moderate essential hypertension, previously uncontrolled by hydrochlorothiazide. After a no-treatment period, mean eight-hour seated diastolic blood pressure (SDBP, mm Hg) was 103 +/- 5 on placebo, 95 +/- 8 after a single dose of captopril, 96 +/- 4 after two weeks of captopril alone, and 90 +/- 6 after its combination with hydrochlorothiazide. Though nine patients had at least a 10% fall in SDBP after the initial dose of captopril, only three had a comparable fall after two weeks; after captopril and hydrochlorothiazide, however, 12 patients had such a response. Captopril decreased mean angiotensin-converting enzyme activity and plasma aldosterone, though to a lesser extent with continued therapy. Because its side effects appear dose related, low doses of captopril combined with a diuretic are effective and may be better tolerated.

Characterization of myocyte enhancer factor 2 (MEF2) expression in B and T cells: MEF2C is a B cell-restricted transcription factor in lymphocytes.

Our studies examined the expression and DNA binding activity of myocyte enhancer factor 2 (MEF2A-D) transcription factors in lymphopoietic tissues, cell lines, and primary lymphocytes. Our analyses demonstrate that mef2C expression is restricted to B cells within the lymphocyte lineage. Using in situ hybridization, mef2C is detected in foci in fetal liver and postnatal thymic medulla, and both mef2B and mef2C are expressed in areas of the postnatal spleen and lymph node that also express kappa light chain (Ckappa), a B cell-specific marker. Reverse transcriptase-PCR (RT-PCR) analyses demonstrate that all mef2 family members are expressed in B cell lines, and all except mef2C are expressed in T cell lines. Immunoblot analyses of cell lines and primary thymic and splenic lymphocytes show that MEF2C and MEF2D proteins are expressed in B cells and that MEF2D is expressed in T cells; however, MEF2A protein is not detected in lymphocytes. Electrophoretic mobility shift assays (EMSA) demonstrate that B cell lines have MEF2C-containing, MEF2-specific DNA binding complexes whereas T cells do not. Our data is the first to describe mef2C expression in the lymphocyte lineage, and this finding suggests possible roles for MEF2C activity in B cell development and function.

Sulindac disposition when given once and twice daily.

To investigate whether sulindac once daily in the evening might be equivalent to the currently recommended twice-daily dose schedule in sustaining plasma concentrations of bioactive sulfide metabolite, 12 healthy subjects received, in a randomized crossover study, sulindac, 200 mg b.i.d. (at 9:00 A.M. and 9:00 P.M.) and 400 mg once daily (at 9:00 P.M.), each for 7 days. At steady state the area under the plasma concentration-time curve (AUC) over 24 hr for sulfide metabolite was greater after once-daily dosing (112 and 84 micrograms . hr . ml-1, P less than 0.05), while mean trough concentrations did not differ. The greater AUC seemed to be related to diurnal variation in metabolite cumulation. A circadian rhythm was apparent at steady state during twice-daily dosing; the mean AUC and peak plasma concentration (C(max)) were greater between 9 A.M. and 9 P.M. than between 9 P.M. and 9 A.M. (50 and 34 micrograms . hr . ml-1; 6.85 and 4.23 micrograms/ml). Although C(max) values of sulfide were higher after morning doses of sulindac, it was apparent that much of the plasma sulfide after morning doses was actually derived from the previous evening dose. This may be a consequence of circadian rhythm in gallbladder emptying. While renal clearance of sulindac was related to urinary pH, diurnal changes in urinary acidity did not cause the fluctuations in the plasma sulfide. Since once-daily sulindac in the evening is as, if not more, effective than twice-daily drug in sustaining plasma sulfide levels, further studies on the therapeutic efficacy of once-daily dosing are warranted.

Effects of enalapril, a new converting enzyme inhibitor, in hypertension.

The new angiotensin converting enzyme inhibitor enalapril maleate was given in single oral doses of 2.5, 5, and 10 mg to 11 hospitalized patients with uncomplicated essential hypertension who were on a 150-mEq sodium diet. All doses of enalapril induced reduction of mean seated diastolic blood pressure (SDBP). The magnitude of the initial SDBP reduction was not dose related, but the duration of effect was longer (greater than 12 hr) after the 5 and 10 mg. After dosing, mean plasma angiotensin converting enzyme activity (ACE) and aldosterone concentration (PAC) fell, while plasma renin activity (PRA) rose. Serum concentrations of the active diacid from of enalapril increased linearly with dosage; ACE was inhibited maximally at concentrations above 10 ng/ml. During repeated dosing in the outpatient trial there was attenuation of the antihypertensive effect (12 to 24 hr after dosing) in eight of 10 patients. Despite dose increases only two patients achieved SDBP control (less than or equal to 90 mm Hg). In the five patients in whom 50 mg/day hydrochlorothiazide was added near the end of the trail mean SDBP was further reduced. Enalapril was well tolerated. Further studies of the drug, especially in combination with diuretic, are needed.

Efficacy of a vibratory stimulus for the relief of HIV-associated neuropathic pain.

Pain related to HIV disease is frequently debilitating. Of the many pain syndromes that occur in persons with HIV, distal symmetrical polyneuropathy (DSPN) is particularly devastating. Because DSPN often responds, at best, only partially to available pharmacologic interventions, non-pharmacologic interventions need to be investigated. Vibration has been suggested to be effective for reducing pain in other populations with chronic pain. This randomized, sham-controlled, double-masked study tested the short-term efficacy of a 45-min vibration treatment for DSPN foot pain in persons infected with HIV. Vibration therapy was delivered using a portable platform foot vibrator that provided stimulation at a frequency of 60 Hz. For all patients, the control box for the vibrator emitted an audible hum and part of the control box lit up during treatment, but only patients randomized to active treatment received vibration. Pain intensity (0-10) was measured immediately prior to and after treatment. Subjects were also questioned regarding pain relief (0-100%) immediately after the treatment. The mean percentage pain relief was 61.0+/-33.1% (median 70.0; range 0-100) for all patients, 67.3+/-34.0% (median 80.0; range 0-100) for vibration patients, and 55.0+/-32.0% (median 60.0; range 0-100) for sham patients. No statistically significant differences were found between the vibration and sham groups with respect to percentage pain relief (Mann-Whitney test; P=0.19) or the pre- and post-treatment current-pain difference (Mann-Whitney test; P=0.92). These results underscore the necessity for control groups in studies of non-pharmacologic therapies for pain.

Dihydropyrimidine calcium channel blockers. 3. 3-Carbamoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters as orally effective antihypertensive agents.

In order to explain the potent antihypertensive activity of the modestly active (IC50 = 3.2 microM) dihydropyrimidine calcium channel blocker 5, we carried out drug metabolism studies in the rat and found 5 is metabolized to compounds 6-10. Two of the metabolites, 6 (IC50 = 16 nM) and 7 (IC50 = 12 nM), were found to be responsible for the antihypertensive activity of compound 5. Potential metabolism of 6 into 7 in vivo precluded our interest in pursuing compounds related to 6. Structure-activity studies aimed at identifying additional aryl-substituted analogues of 7 led to 17g,j,p with comparable potential in vivo, though these compounds were less potent than 7 in vitro. To investigate the effects of absolute stereochemistry on potency, we resolved 7 via diastereomeric ureas 19a,b, prepared from 18 by treatment with (R)-alpha-methylbenzylamine. Our results demonstrate that the active R-(-)-enantiomer 20a of 7 is both more potent and longer acting than nifedipine (1) as an antihypertensive agent in the SHR. The in vivo potency and duration of 20a is comparable to the long-acting dihydropyridine amlodipine. The superior oral antihypertensive activity of 20a compared to that of previously described carbamates 2 (R2 = COOEt) could be explained by its improved oral bioavailability, possibly resulting from increased stability of the urea functionality.

Dihydropyrimidine calcium channel blockers. 2. 3-substituted-4-aryl-1,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines.

To enhance the intrinsic potency of dihydropyrimidine calcium channel blockers, we have modified the structure of previously described 2-heteroalkyl-1,4-dihydropyrimidines 2 to 3-substituted 1,4-dihydropyrimidines 3. Structure-activity studies using potassium-depolarized rabbit aorta show that ortho, meta-disubstituted aryl derivatives are more potent than either ortho- or meta-monosubstituted compounds. While vasorelaxant activity was critically dependent on the size of the C5 ester group, isopropyl ester being the best, a variety of substituents (carbamate, acyl, sulfonyl, alkyl) were tolerated at N3. Our results show dihydropyrimidines 3 are significantly more potent than corresponding 2-heteroalkyl-1,4-dihydropyrimidines 2 and only slightly less potent than similarly substituted 2-heteroalkyl-1,4-dihydropyridines 4 and 5. Whereas dihydropyridine enantiomers usually show 10-15-fold difference in activity, the enantiomers of dihydropyrimidine 3j show more than a 1000-fold difference in activity. These results strengthen the requirement of an enamino ester for binding to the dihydropyridine receptor and indicate a nonspecific role for the N3-substituent.

Neonatal hyperviscosity association with lower achievement and IQ scores at school age.

A longitudinal study was conducted to determine whether the early neurologic and motor impairment observed in children with neonatal polycythemia and hyperviscosity persisted into school age. Forty-nine children who had neonatal polycythemia and hyperviscosity were evaluated at a mean age of 7 years. Of these, 21 (group 1) received a partial plasma exchange transfusion, whereas 28 (group 2) received symptomatic care. Forty control children (group 3) with a normal neonatal hematocrit were also evaluated. Testing consisted of a battery of measures to evaluate IQ, achievement, neuromotor function, and gross and fine motor skills. Maternal education and IQ were also assessed to avoid potential confounding by differences in the home environment. The neonatal course of the children with polycythemia and hyperviscosity was characterized by an increased number of problems, including hypoglycemia and cyanosis. At 7 years of age, the 49 children who had hyperviscosity (groups 1 and 2) had significantly lower "spelling" and arithmetic achievement test results and gross motor skill scores. Scores for reading, visual motor integration, and neurologic signs did not differ significantly from group 3. Maternal IQ scores were similar for both groups. Left-hand preference was seen in 14% of group 1 and 2 children and 7% of group 3 children (not significant). The scores for IQ, achievement, neuromotor function, and visual motor integration were compared for the hyperviscosity group (groups 1 and 2) and the control group (group 3) by multivariate analysis of variance with sex and hyperviscous group as independent variables and maternal education and maternal IQ as covariates (P = .040).(ABSTRACT TRUNCATED AT 250 WORDS)

Bucindolol, a beta-adrenoceptor blocker with vasodilatory action: its effect in systemic hypertension.

Bucindolol is a newly developed, nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilator properties. In 14 patients with mild to moderate essential hypertension, the effects of bucindolol, hydrochlorothiazide and their combination on blood pressure (BP), heart rate (HR) and parameters of the renin-aldosterone system were compared with those after placebo. Bucindolol's antihypertensive effect was evident within the first hour after drug administration, maximal at 2 to 3 hours, and lasted for as long as 12 hours. Compared with placebo values (108 +/- 5 mm Hg), both bucindolol (97 +/- 9 mm Hg) and hydrochlorothiazide (99 +/- 10 mm Hg) alone significantly and comparably reduced the 12-hour averaged standing diastolic BP, with the combination resulting in approximately additive effects (91 +/- 9 mm Hg). Although bucindolol alone did not affect HR, it attenuated the hydrochlorothiazide-induced increase in HR. There was a tendency for bucindolol to decrease plasma renin activity. Except for transient postural hypotension in 2 patients, bucindolol was well tolerated.