The Impact of Plasmodium Infection on Placental Histomorphology: A Stereological Preliminary Study.

Background: Malaria during pregnancy may threaten the mother's health and cause serious structural damage to the internal architecture of the placenta, which subsequently affects the pregnancy outcome. A better understanding of the impact of malaria parasites on the placenta morphology is crucial for better management of pregnant women and their babies. Aim: To assess by stereology the histomorphology of selected placental structures in placenta malaria compared with normal placentae at term. Method: A total of 10 placentae comprising 5 controls and 5 cases were selected from 50 placentae that were collected at term (38 weeks ± 2 weeks) from the maternal delivery suit of Korle-Bu Teaching Hospital in Accra, Ghana. Blood from the placentae was collected for both rapid diagnostic test and microscopic examinations. Samples collected were examined for Plasmodium parasites, after which they were classified as study group (Plasmodium positive) or control (Plasmodium negative). Stereological quantification using systematic uniform random sampling technique with test point and intersection counting of photomicrographs were employed to estimate the mean volume densities of syncytial knots, syncytial necrosis, foetal capillaries, and intervillous spaces of the placentae on a total of 1,600 photomicrographs. Results: Out of the fifty placental samples from the maternal side tested for Plasmodium, six representing 12% were found to be infected with the parasite by both rapid diagnostic test and microscopy. On stereological assessment, the mean volume density of syncytial knots was significantly higher in the placental malaria group compared with the control placentae at term (P = 0.0080), but foetal capillaries (P = 0.7813), intervillous spaces (P = 0.8078), and syncytial necrosis (P = 0.8249) were not significantly different. Conclusion: This preliminary result indicates that placental malaria may cause significant increase in the syncytial knots but not foetal capillaries, intervillous spaces, or syncytial necrosis. This finding signifies early maturation of the placenta and may be crucial in understanding perinatal outcomes.

Corrigendum: Perinatal autopsy in Ghana: healthcare workers knowledge and attitude.

[This corrects the article DOI: 10.3389/fgwh.2022.1021474.].

Perinatal autopsy in Ghana: Healthcare workers knowledge and attitude.

Background: Perinatal mortality refers to stillbirths and early neonatal deaths. Stillbirth, the death of a foetus from 28 weeks or with a birth weight below 1,000 g, and early neonatal deaths, the death of a new-born within 24 h of delivery, are among the most distressing global health problems, with approximately 2 million stillbirths occurring annually. Although a post-mortem examination of the stillborn baby is essential for understanding and learning the cause of stillbirth, many couples decline the procedure. Sub-Saharan Africa has one of the highest stillbirth rates in the world, yet there is a dearth of studies on post-mortem uptake from the region. Aim: To explore healthcare professionals' views and perceptions of perinatal autopsy in Ghana. Methods: Mixed-method approach consisted of semi-structured interviews and an electronic cross-sectional survey to evaluate the views and perceptions of healthcare professionals at Korle-Bu Teaching Hospital on autopsy for stillbirths and early neonatal deaths. Descriptive quantitative data were summarised in frequencies and percentages, and statistical results and descriptions were tabulated and coded in terms of types of barriers. For the qualitative aspect, the audio-taped interviews were transcribed, themes generated, and direct quotes and descriptions were coded for all knowledge, beliefs, attitudes and practices concerning the barriers and facilitators for post-mortem. Results: Ninety-nine healthcare professionals participated. No participant had formal training regarding counselling for perinatal autopsy and 40% had " no idea " who is responsible for counselling and obtaining consent for a perinatal autopsy. Forty-four percent (44%) of the participants knew of only the "Conventional/ Full" autopsy and <4% were aware of less invasive methods of performing an autopsy. Qualitative data showed healthcare worker influence, religious and financial considerations impede the implementation of perinatal autopsies. Despite the low uptake of perinatal autopsies, interviews from healthcare workers suggest acceptance rates would improve if parents knew about different options, especially less invasive procedures. Conclusion: At Ghana's largest referral centre, perinatal autopsy counselling and uptake are at extremely low levels. Most healthcare professionals have little knowledge, skills, and capacity to advise parents regarding perinatal autopsies. Training is needed to update the workforce on recommended perinatal autopsy practices.

Factors Associated with Ruptured Ectopic Pregnancy: A 10-Year Review at a District Hospital in Ghana.

Background: Approximately 1-2% of all pregnancies are ectopic. Despite a decline in ectopic pregnancy-related mortality, there is still a paucity of information on the factors associated with clinical presentation and outcomes in Sub-Saharan Africa which is essential in determining the most appropriate treatment modalities. Methods: We performed a ten-year retrospective chart review of cases of ectopic pregnancies managed at the Lekma hospital and assessed them for peculiar risk factors, clinical presentation, and outcomes. Associations between patients' sociodemographic characteristics, clinical presentation, and treatment outcome were evaluated using multiple logistic regression and reported as adjusted odds ratios (AOR). The confidence interval (CI) was set at 95%, and a p value <0.05 were considered significant. Results: Over the ten-year period, there were 115 ectopic pregnancies and 14,450 deliveries (7.9/1,000). The mean age ± standard deviation of the 115 patients was 27.61 ± 5.56. More than half of the patients were single (59/115, 51.3%). The majority (71.3%) of the patients presented with a ruptured ectopic pregnancy. After adjusting for covariates, the odds of an ectopic pregnancy presenting as ruptured among single patients was 2.63 times higher than that of married patients (AOR = 3.63, 95% CI: 1.33-9.93, p=0.01). Ectopic pregnancies located in the isthmic region of the tube had a 77% lower odds of presenting as ruptured than those located in the ampullary region (AOR = 0.23, 95% CI: 0.07-0.74, p=0.01). The odds of rupturing were 1.69 times increased for every additional week after the missed period (AOR = 2.69, 95% CI: 1.56-4.64, p < 0.01). No mortalities were reported as a result of an ectopic pregnancy. Conclusion: Most of the cases of ectopic pregnancy presented ruptured. Marital status and period of amenorrhoea were significantly associated with rupture.

Testicular Sperm Extraction and Intracytoplasmic Sperm Injection in Management of Obstructive Azoospermia: A Two-Year Multicenter Review in Ghana.

Background: The objective of this study was to evaluate treatment outcomes and assess predictors of clinical pregnancy in obstructive azoospermia cases treated with testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI) in Ghana. Methods: This study was a retrospective study conducted on 67 men seeking treatment for obstructive azoospermia at two study sites in Ghana from January 2018 to December 2019. First, archived data were reviewed and treatment outcomes of cases of obstructive azoospermia from the hospital records were evaluated. Infertile men who met the inclusion criteria were recruited. Descriptive data were expressed in the form of frequencies and percentages. The dependent and independent variables were analyzed using multiple logistic regression and reported as odds ratios (ORs). The confidence interval (CI) was set at 95% and a p-value <0.05 was considered significant. Results: The mean age of male participants was 42.43±9.11 years (mean±SD) while the mean age of their partners was 32.89±5.73 years (mean±SD). The average duration of infertility before intervention was 5.01±3.60 years (mean±SD). Successful pregnancy was observed in 52.2% (35/67) of the participants. After adjusting for confounders, the rate of a successful clinical pregnancy was 0.07 lower for every additional year increase in the male's age [AOR=0.93 (95%CI=0.87-0.99), p=0.02]. Conclusion: Overall the rate of clinical pregnancy following TESE/ICSI from our study was 52.2%. A man's age was a strong predictor of successful clinical pregnancy among couples treated with TESE-ICSI for obstructive azoospermia in Ghana.

Photochemical oxidants: effect on starch hydrolysis in leaves.

Starch-filled leaves of plants which have been subjected to low dosages of naturally occurring photochemical oxidants, ozone, or peroxyacetyl nitrate hydrolyze their starch more slowly when placed in the dark. Delayed hydrolysis occurs irrespective of whether the oxidants were applied during the light or dark period. Occasionally this effect is evident only in the intervenal areas.

Plate tectonics 2.5 billion years ago: evidence at kolar, South India.

The Archean Kolar Schist Belt, south India, is a suture zone where two gneiss terranes and at least two amphibolite terranes with distinct histories were accrted. Amphibolites from the eastern and western sides of the schist belt have distinct incompatible element and isotopic characteristics sugesting that their volcanic protoliths were derived from dint mantle sources. The amphibolite and gneiss terranes were juxtaposed by horizontal compression and shearing between 2530 and 2420 million years ago (Ma) along a zone marked by the Kolar Schist Belt. This history of accretion of discrete crustal terranes resembles those of Phanerozoic convergent margins and thus suggests that plate tectonics operated on Earth by 2500 Ma.

Low kV versus dual-energy virtual monoenergetic CT imaging for proven liver lesions: what are the advantages and trade-offs in conspicuity and image quality? A pilot study.

PURPOSE: Single-energy low tube potential (SE-LTP) and dual-energy virtual monoenergetic (DE-VM) CT images both increase the conspicuity of hepatic lesions by increasing iodine signal. Our purpose was to compare the conspicuity of proven liver lesions, artifacts, and radiologist preferences in dose-matched SE-LTP and DE-VM images. METHODS: Thirty-one patients with 72 proven liver lesions (21 benign, 51 malignant) underwent full-dose contrast-enhanced dual-energy CT (DECT). Half-dose images were obtained using single tube reconstruction of the dual-source SE-LTP projection data (80 or 100 kV), and by inserting noise into dual-energy projection data, with DE-VM images reconstructed from 40 to 70 keV. Three blinded gastrointestinal radiologists evaluated half-dose SE-LTP and DE-VM images, ranking and grading liver lesion conspicuity and diagnostic confidence (4-point scale) on a per-lesion basis. Image quality (noise, artifacts, sharpness) was evaluated, and overall image preference was ranked on per-patient basis. Lesion-to-liver contrast-to-noise ratio (CNR) was compared between techniques. RESULTS: Mean lesion size was 1.5 ± 1.2 cm. Across the readers, the mean conspicuity ratings for 40, 45, and 50 keV half-dose DE-VM images were superior compared to other half-dose image sets (p < 0.0001). Per-lesion diagnostic confidence was similar between half-dose SE-LTP compared to half-dose DE-VM images (p ≥ 0.05; 1.19 vs. 1.24-1.32). However, SE-LTP images had less noise and artifacts and were sharper compared to DE-VM images less than 70 keV (p < 0.05). On a per-patient basis, radiologists preferred SE-LTP images the most and preferred 40-50 keV the least (p < 0.0001). Lesion CNR was also higher in SE-LTP images than DE-VM images (p < 0.01). CONCLUSION: For the same applied dose level, liver lesions were more conspicuous using DE-VM compared to SE-LTP; however, SE-LTP images were preferred more than any single DE-VM energy level, likely due to lower noise and artifacts.

Evaluation of low-frequency operational limit of proposed ITER low-field-side reflectometer waveguide run including miter bends.

The present design concept for the ITER low-field-side reflectometer transmission line (TL) consists of an ∼40 m long, 6.35 cm diameter helically corrugated waveguide (WG) together with ten 90° miter bends. This paper presents an evaluation of the TL performance at low frequencies (33-50 GHz) where the predicted HE11 mode ohmic and mode conversion losses start to increase significantly. Quasi-optical techniques were used to form a near Gaussian beam to efficiently couple radiation in this frequency range into the WG. It was observed that the output beams from the guide remained linearly polarized with cross-polarization power levels of ∼1.5%-3%. The polarization rotation due to the helical corrugations was in the range ∼1°-3°. The radiated beam power profiles typically show excellent Gaussian propagation characteristics at distances >20 cm from the final exit aperture. The round trip propagation loss was found to be ∼2.5 dB at 50 GHz and ∼6.5 dB at 35 GHz, showing an inverse increase with frequency. This was consistent with updated calculations of miter bend and ohmic losses. At low frequencies (33-50 GHz), the mode purity remained very good at the exit of the waveguide, and the losses are perfectly acceptable for operation in ITER. The primary challenge may come from the future addition of a Gaussian telescope and other filter components within the corrugated guide, which will likely introduce additional perturbations to the beam profile and an increase in mode-conversion loss.

Structural basis of spectral shifts in the yellow-emission variants of green fluorescent protein.

BACKGROUND: Because of its ability to spontaneously generate its own fluorophore, the green fluorescent protein (GFP) from the jellyfish Aequorea victoria is used extensively as a fluorescent marker in molecular and cell biology. The yellow fluorescent proteins (YFPs) have the longest wavelength emissions of all GFP variants examined to date. This shift in the spectrum is the result of a T203Y substitution (single-letter amino acid code), a mutation rationally designed on the basis of the X-ray structure of GFP S65T. RESULTS: We have determined the crystal structures of YFP T203Y/S65G/V68L/S72A and YFP H148G to 2.5 and 2.6 A resolution, respectively. Both structures show clear electron density for nearly coplanar pi-pi stacking between Tyr203 and the chromophore. The chromophore has been displaced by nearly 1 A in comparison to other available structures. Although the H148G mutation results in the generation of a solvent channel to the chromophore cavity, intense fluorescence is maintained. The chromophore in the intact protein can be titrated, and the two variants have pKa values of 7.0 (YFP) and 8.0 (YFP H148G). CONCLUSIONS: The observed red shift of the T203Y YFP variant is proposed to be mainly due to the additional polarizability of the pi-stacked Tyr203. The altered location of the chromophore suggests that the exact positions of nearby residues are not crucial for the chemistry of chromophore formation. The YFPs significantly extend the pH range over which GFPs may be employed as pH indicators in live cells.

Methamphetamine-induced rapid and reversible changes in dopamine transporter function: an in vitro model.

This laboratory has demonstrated that a single methamphetamine (METH) injection rapidly and reversibly decreases the activity of the dopamine transporter (DAT), as assessed ex vivo in synaptosomes prepared from treated rats. This decrease does not occur because of residual drug introduced by the original injection or nor is it associated with a change in binding of the DAT ligand WIN35428. The purpose of this study was to elucidate the mechanism or mechanisms of this METH effect by determining whether direct application of this stimulant to synaptosomes causes changes in DAT similar to those observed ex vivo. Similar to the ex vivo effect, incubation of striatal synaptosomes with METH decreased DAT activity, but not WIN35428 binding: the effect on activity was not eliminated by repeated washing of synaptosomes. Also, as observed ex vivo, incubation with 3,4-methylenedioxymethamphetamine, but not cocaine or methylphenidate, caused a METH-like reduction in DAT function. The rapid and reversible METH-induced diminution in DAT activity did not occur because of a change in membrane potential, as assessed in vitro and ex vivo by [(3)H]tetraphenylphosphonium accumulation. However, the METH-related decline in DAT function may be attributed to phosphorylation because NPC15437, a protein kinase C inhibitor, attenuated the METH-induced decline in DAT function. Similarities between previously reported effects ex vivo of a single METH injection on serotonin and norepinephrine transporter function and effects of direct METH application in vitro were also found. Together, these data demonstrate that the in vitro incubation model mimics the rapid and reversible effects observed after a single METH injection.

Cloning and sequence analysis of the dimethylsulfoxide reductase structural gene from Rhodobacter capsulatus.

The dimethylsulfoxide reductase structural gene (dorA) of Rhodobacter capsulatus was cloned from a lambda expression library. The nucleotide sequence of the dorA gene was determined and it was found to encode a protein of 825 amino acids. Comparison of the deduced amino-acid sequence of DorA with N-terminal sequence of purified dimethylsulfoxide reductase from Rhodobacter capsulatus showed that the pre-protein possesses a 41-amino-acid N-terminal signal polypeptide. All of the conserved segments which have been described in bacterial enzymes which bind molybdopterin guanine dinucleotide (Berks, B.C., Ferguson, S.J., Moir, J.W.B. and Richardson, D.J. (1995) Biochim, Biophys. Acta 1232, 97-173) were identified in Rhodobacter capsulatus dimethylsulfoxide reductase.

Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum-fed and schedule-fed rats.

Relatively little is known concerning the interaction of psychostimulants with hypothalamic neuropeptide systems or metabolic hormones implicated in regulation of energy balance. The present studies tested whether methamphetamine alters the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP), two important orexigenic neuropeptides, or proopiomelanocortin (POMC), the precursor for the anorexigenic peptide alpha-melanocyte-stimulating hormone, or the secretion of leptin, insulin and ghrelin, concomitant with inhibition of food intake. Female rats were either fed ad libitum (AL) or placed on a scheduled feeding (SF) regimen, with access to food limited to 4 h/day. Administration of (+/-)-methamphetamine (7.5 mg/kg, i.p.) 2 h prior to food presentation significantly inhibited food intake in SF animals, but did not affect intake in AL animals. In a separate study, AL and SF animals were killed just prior to expected food presentation, and expression of NPY, AgRP and POMC mRNAs in hypothalamus was determined using in situ hybridisation; concentrations of leptin, insulin and ghrelin in serum were determined with radioimmunoassays. In saline-treated, SF controls, NPY and AgRP mRNA expression in arcuate nucleus and serum ghrelin were significantly elevated, and serum leptin and insulin were significantly reduced. Methamphetamine reversed the up-regulation of NPY mRNA expression observed in the SF condition, without affecting AgRP mRNA or the serum concentrations of metabolic hormones. However, in AL animals, NPY mRNA expression in arcuate and dorsomedial nuclei was significantly increased by methamphetamine, which also reduced serum leptin and insulin and increased serum ghrelin concentrations. These findings suggest that the inhibition of NPY expression in SF animals may be a mechanism underlying the anorexigenic effect of methamphetamine seen in this condition. The increase in NPY expression produced by methamphetamine in AL animals may be mediated by the ability of this drug to decrease secretion of leptin and insulin and increase secretion of ghrelin.

Blockade of stimulant-induced preprodynorphin mRNA expression in the striatal matrix by serotonin depletion.

Cocaine and methamphetamine (METH) induce preprodynorphin (PPD) mRNA expression in the striatum. Cocaine induces PPD expression in both the patch and matrix compartments of the rostral striatum, whereas METH induces PPD expression in the patch compartment of the rostral striatum. In middle striatum, both stimulants increase PPD expression in the patch and matrix compartments. METH and cocaine treatment also increase extracellular serotonin (5-HT). Several studies have shown that 5-HT receptors are present on striatonigral neurons that express PPD mRNA, and that 5-HT is a positive regulator of striatal neuropeptide expression. The current study examined whether 5-HT plays a role in the patch/matrix expression of PPD mRNA induced by cocaine and METH in striatum. Male Sprague-Dawley rats were treated with p-chloroamphetamine (PCA; 8 mg/kg, i.p), a serotonin neurotoxin, 1 week prior to cocaine (30 mg/kg, i.p) and METH (15 mg/kg, s.c.) treatment. The 80% loss of 5-HT induced by PCA-pretreatment blocked cocaine-induced PPD expression in the rostral matrix compartment. Cocaine- and METH-induced PPD expression in the rostral patch compartment was unaffected by PCA-pretreatment. PCA-pretreatment also decreased both cocaine- and METH-induced PPD expression in the matrix, but not patch of middle striatum. PCA-induced 5-HT depletion did not affect stimulant-induced increases in PPT mRNA expression in the striatum. These data suggest that 5-HT plays a role in stimulant-induced PPD expression in the matrix compartment of rostral and middle striatum. Thus, 5-HT innervation may play a critical role in basal ganglia function.

Resolution of a soft-tissue sarcoma in a patient with rheumatoid arthritis after discontinuation of azathioprine therapy.

An 85-year-old woman with rheumatoid arthritis that was treated with azathioprine presented with a posterior thoracic soft-tissue mass. A computed tomographic scan demonstrated a large mass in the chest wall that extended into the pleural space and several pulmonary nodules that were consistent with metastatic disease. A fine-needle biopsy was performed, and a morphologic diagnosis of sarcoma was made. As the patient was relatively asymptomatic and the lesion was inaccessible to a surgical procedure, no therapy was recommended. Therapy with azathioprine was discontinued. One year later, the mass had resolved. To our knowledge, this is the first reported case of a soft-tissue sarcoma complicating azathioprine treatment of rheumatoid arthritis.

Failure to suspect and diagnose thalassemic syndromes. Interpretation of RBC indices by the nonhematologist.

A three-year review of the medical records of 76 patients with apparent thalassemic syndromes (mean corpuscular volume, greater than 75 cu micron; RBC count, greater than 5 X 10(6)/cu mm) was performed to assess overall physician response to this information at a midwestern teaching institution. Abnormal indices were recognized in only 50% of the cases; in only 32% of cases was a thalassemic syndrome considered in the differential diagnosis. Residents in internal medicine failed to recognize microcytic indices and to consider thalassemic syndromes 42% and 59% of the time, respectively. Even though hemoglobin electrophoresis was performed in 25 patients, in only 15 (56%) of the 25 cases was beta-thalassemia proved or alpha-thalassemia presumptively diagnosed. In 17% of all cases, the patients were treated with iron without diagnostic findings on iron studies and/or in spite of data suggesting a thalassemic syndrome. The RBC indices are an underused portion of the complete blood cell count, and readily apparent thalassemic syndromes are often not considered.

Malignant histiocytosis resistant to anthracycline. Response to intensive treatment with etoposide and amsacrine.

A 36-year-old woman, presenting with fever, pancytopenia, hepatosplenomegaly, and striking effacement of the bone marrow by true malignant histiocytes, was found to have no benefit from the systemic administration of cyclophosphamide, vincristine sulfate, doxorubicin, prednisone, and high-dose methotrexate with calcium leucovorin rescue. Striking histologic and clinical improvement was noted after the administration of two cycles of etoposide and amsacrine, each cycle consisting of 100 mg/sq m/day of each agent for five days. We believe that this therapy should be considered for future patients demonstrating aggressive presentations of malignant histiocytosis.

Management of patients with shock and sepsis.

The pathophysiology of shock associated with sepsis in complex, but granulocyte activation and production of toxic oxygen radicals, is of major importance in producing endothelial cell injury. Multiple organ failure including a reversible cardiomyopathy with impairment of left ventricular ejection fraction, are known factors complicating, and in the latter, perpetuating, shock. When treating the severely shocked patient, a systolic pressure of 100 mmHg and a PaO2 of greater than 8 kPa (60 mmHg) should be aimed for. Non-response to oxygenation, respiratory support, volume, and metabolic control, may be an indication for insertion of a thermodilution catheter into the right heart, so that cardiac output can be measured and oxygen delivery maintained above 10 mmol/kg/min. Where, by manipulation of respiratory indices and inotropic support, achievement of this level is not possible, the prognosis is grave. Antibiotic therapy is discussed, therapy being instituted if at all possible once the haemodynamic state has been improved.

Effects of growth hormone (GH) administration on homocyst(e)ine levels in men with GH deficiency: a randomized controlled trial.

GH deficiency is associated with increased cardiovascular mortality and early manifestations of atherosclerosis. Elevated serum homocyst(e)ine levels have been found to be associated with increased cardiovascular risk. The effect of GH replacement on homocyst(e)ine has not been investigated to date. We evaluated the effect of GH replacement on fasting homocyst(e)inemia in a group of men with adult-onset GH deficiency in a randomized, single blind, placebo-controlled trial. Forty men with adult-onset GH deficiency were randomized to GH or placebo for 18 months, with dose adjustments made according to serum insulin-like growth factor I (IGF-I) levels. Fasting serum homocyst(e)ine, folate, vitamin B12, and total T(3) levels were determined at baseline and 6 and 18 months. Anthropometry, IGF-I levels, insulin, and glucose were measured at 1, 3, 6, 12, and 18 months. Nutritional assessment, body composition, total T(4), thyroid hormone binding index, and free T(4) index were assessed every 6 months. Homocyst(e)ine decreased in the GH-treated group compared with that in the placebo group (net difference, -1.2 +/- 0.6 micromol/L; confidence interval, -2.4, -0.02 micromol/L; P = 0.047). Homocyst(e)ine at baseline was negatively correlated with plasma levels of folate (r = -0.41; P = 0.0087). Total T(3) increased in the GH-treated group vs. that in the placebo group (net difference, 0.17 +/- 0.046 ng/dL; confidence interval, 0.071, 0.26 nmol/L; P = 0.0012). Folate and vitamin B12 levels did not significantly change between groups. Changes in homocyst(e)ine were negatively correlated with changes in IGF-I. For each 1 nmol/L increase in IGF-I, homocyst(e)ine decreased by 0.04 +/- 0.02 micromol/L (P = 0.029). In contrast, changes in homocyst(e)ine did not correlate with changes in folate, vitamin B12, total T(3), C-reactive protein, interleukin-6, or insulin levels. This study shows that GH replacement decreases fasting homocyst(e)ine levels compared with placebo. This may be one of the mechanisms involved in the putative modulation of atherosclerosis and cardiovascular risk by GH replacement.

Effects of SC-56525, a potent, orally active renin inhibitor, in salt-depleted and renal hypertensive dogs.

SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.