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Abstract Periodic climate zoning is an essential classification of land cover to account for anthropogenic activities resulting from population increase and urbanization that affect key climate response parameters. Rainfall, relative humidity (RH), maximum (Tmax) and minimum temperature (Tmin) data from the Ghana Meteorological Agency were used to zone Ghana by adopting cluster and PCA analysis methods and verifying the groupings with the seasonal trend and Tukey Honestly Significance Difference (HSD) analysis. The cluster analysis grouped the synoptic stations into four major homogenous clusters while the PCA distributed them into three sub‐divisions with reference to 1976–2018. Rainfall, RH, Tmax and Tmin were characterized by five, three, two and three factors with factor loadings in the range of 0.71–0.78, 0.53–0.70, 0.54–0.74 and 0.50–0.72, respectively. HSD found transition stations like Bole and Kete Krachi in cluster 1 and 2 to have no significant difference with cluster 1, while Wenchi, Sunyani, Sefwi Bekwai and Koforidua in cluster 2 had no significant difference with cluster 3. Accra station which was classified in cluster 3 showed the seasonal pattern of cluster 4 and was confirmed by HSD to belong in cluster 4. Therefore, Ghana‐based on‐point analysis is climatically grouped into Savannah (11°0′0′′N–7°46′11′′N), Forest (from 7°46′11′′N to the coast) and Coastal (about 30 km from the Gulf of Guinea coastline) based on the assessed parameters. These findings are vital for planners and decision‐makers especially for industries that depend on weather and climatic conditions for their activities.

Human epidemiological studies suggest an association between rapid acetylator phenotype and colorectal cancer. Acetylator genotype-dependent expression by the human colon of arylamine N-acetylation capacity, catalyzed by acetyl coenzyme A-dependent N-acetyltransferase(s) (EC 2.3.1.5) (NAT), may be an important risk factor in the initiation of colorectal cancer. Human colon cytosols from 48 fresh surgical samples were investigated for NAT activity toward p-aminobenzoic acid and the arylamine carcinogens 4-aminobiphenyl, 2-aminofluorene, and beta-naphthylamine. Apparent Vmax determinations of NAT activity toward these substrates indicated that 40 of these colons segregated into 3 distinct phenotypes. The distribution of the patients into rapid (5), intermediate (18), or slow (17) acetylators is a ratio that is not significantly different from the expected Hardy-Weinberg distribution of 3:16:21 (chi 2 = 2.206, P = 0.363). Significantly greater mean apparent Vmax levels were found in colons from rapid as compared to intermediate acetylators (1.5-3-fold) (P less than 0.001) and intermediate as compared to slow (2.5-3-fold) (P less than 0.005) acetylator phenotypes for the four arylamine substrates. Apparent Km determinations indicated that human colon NAT from rapid acetylators had a significantly lower affinity for the arylamine substrates (P less than 0.05) compared to intermediate or slow acetylator groups. No difference in apparent Km was detected for the cofactor acetyl coenzyme A between the three acetylator phenotypes. The colon samples were also tested for cytosolic N-hydroxy-2-acetylaminofluorene sulfotransferase activity and found to be monomorphically distributed for this enzyme activity. Of the 40 colon samples, 37 were from individuals of known pathology, 25 with colorectal cancer and 12 with no diagnosed neoplasia. Comparisons between mean apparent Vmax and mean apparent Km levels for each of the acetylator phenotypes indicated no significant differences between non-cancer and colorectal cancer patients. The distribution of rapid, intermediate, and slow acetylator phenotypes among the colon samples derived from colorectal cancer patients was precisely that predicted from published frequencies for the rapid and slow acetylator allele in Americans of African and European ancestry.

The polymorphic acetyltransferase isozyme expressed in homozygous rapid acetylator inbred hamster liver cytosol was purified over 2000-fold by sequential Q-Sepharose fast-flow anion-exchange chromatography, Sephacryl S-200 high-resolution size-exclusion chromatography, Mono Q anion-exchange fast-protein liquid chromatography, and preparative polyacrylamide gel electrophoresis. The isozyme migrated as a single homogeneous monomer following both preparative and sodium dodecyl sulfate-polyacrylamide electrophoresis. The molecular weight was estimated at 34,170 following elution via size-exclusion chromatography and 35,467 following migration via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The homogeneous polymorphic acetyltransferase exhibited a broad substrate specificity; it catalyzed the acetyl coenzyme A-dependent N-acetylation of p-aminobenzoic acid, carbocyclic arylamine carcinogens such as 2-aminofluorene, 4-aminobiphenyl and beta-naphthylamine, and heterocyclic arylamine carcinogens such as 2-aminodipyrido[1,2-a:3'2'd]imidazole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole. It also readily catalyzed the acetyl coenzyme A-dependent metabolic activation (via O-acetylation) of N-hydroxy-2-aminofluorene to DNA adducts but not the metabolic activation (via intramolecular, N,O-acetyltransfer) of N-hydroxy-2-acetylaminofluorene or N-hydroxy-4-acetylaminobiphenyl to DNA adducts. Conversely, the partially purified monomorphic acetyltransferase isozyme from the same hamsters readily catalyzed the metabolic activation of N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl, and rates of metabolic activation of these substrates did not differ between homozygous rapid and slow acetylator liver, intestine, kidney, and lung cytosols. Heat inactivation rates for the purified polymorphic acetyltransferase isozyme were first order and indistinguishable for the acetyl coenzyme A-dependent N-acetylation and O-acetylation activities. The results strongly suggest the expression of a single polymorphic acetyltransferase product of the hamster polymorphic acetyltransferase gene that catalyzes both acetyl coenzyme A-dependent N-acetylation and O-acetylation of arylamine and N-hydroxyarylamine carcinogens but not the metabolic activation of N-hydroxy-N-acetylarylamines (arylhydroxamic acids) via intramolecular N,O-acetyltransfer. Consequently, acetylator genotype-dependent metabolic activation of N-hydroxyarylamines to a DNA adduct in hamster is catalyzed by direct O-acetylation of the hydroxyl group and not via sequential N-acetylation followed by N,O-acetyltransfer.

Human epidemiological studies suggest an association between rapid acetylator phenotype and the incidence of colorectal cancer. Genetic regulation of acetyl coenzyme A-dependent N-acetyltransferase (NAT) and O-acetyltransferase (OAT) enzymatic activities may play a role in the metabolic activation of arylamine chemicals in the intestine and colon. In this study, the inheritance of acetyltransferase activity in the intestine and colon was investigated in the Syrian inbred hamster model. Relatively high levels of both arylamine NAT and N-hydroxyarylamine OAT activities were expressed in hamster intestine and colon cytosols, at levels similar to those in the liver. Acetylator genotype-dependent levels of NAT activity were expressed towards p-aminobenzoic acid and the carbocyclic arylamine carcinogens 2-aminofluorene (AF), 4-aminobiphenyl, and beta-naphthylamine. However, acetylator genotype-independent activity was found with the heterocyclic arylamine carcinogens 2-aminodipyrido[1,2-a:3',2'd]imidazole, 3-amino-1-methyl-5H-pyrido[4,3-b]indole, and 2-amino-9H-pyrido-[2,3,b]indole. F1 hybrid heterozygous acetylator progeny expressed unimodal levels of acetyltransferase activity intermediate between the homozygous rapid and slow acetylator parental strains. F2 generation progeny segregated into three modes (low, intermediate, and high) in a ratio of 1/2/1, and both sets of backcrosses yielded bimodal distributions of low and intermediate or high and intermediate in equal ratios. The genetic data is consistent with simple autosomal Mendelian inheritance of two codominant alleles (rapid and slow) at a single genetic locus, the polymorphic acetyltransferase gene. Levels of N-hydroxy-2-aminofluorene OAT activity were acetylator genotype-dependent in liver, intestine, and colon cytosols, which correlated well with AF NAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)

The genetic constitution of mammalian enzymes involved in the metabolism of xenobiotics is one of the important factors responsible for large inter-individual differences in the rate of biotransformation and consequently the magnitude of genotoxic effects exerted in target tissues. The present study examines the mutagenic activation of 2-aminofluorene (AF) with hepatic post-mitochondrial (S9) preparations derived from homozygous rapid (Patr/Patr) acetylator and homozygous slow (Pats/Pats) acetylator Syrian inbred hamsters and its relationship to acetylator genotype. These hamster strains differ in their capacities for acetyl coenzyme A (AcCoA)-dependent, N-acetylation and O-acetylation of carcinogenic arylamines and their N-hydroxyarylamine metabolites. AF N-acetyltransferase activities determined in hepatic S9 fractions were 72.2 +/- 4.2 nmol/min/mg in rapid acetylator hamsters and 6.65 +/- 0.37 nmol/min/mg in slow acetylators, and were unaffected by the presence of 0.1 mM paraoxon. Mutagenic activation of AF was measured by reversion to histidine prototrophy in Salmonella typhimurium strain TA98. The metabolic activation of AF utilizing standard hepatic S9 preparations exhibited typical saturation kinetics that did not differ between acetylator genotypes. However, the addition of AcCoA to the standard S9 mix resulted in a dose-dependent reduction in the number of histidine revertants. In dose-response studies in which the concentrations of AF, AcCoA or S9 protein were varied, higher numbers of revertants were consistently generated with hepatic S9 derived from the slow acetylator compared to the rapid acetylator hamsters. These results indicate an acetylator genotype-dependent modulation of arylamine genotoxicity was reflected as a reduction in the levels of mutagenic metabolites generated in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective controlled randomized study of the use of extracorporeal membrane oxygenation to treat newborns with respiratory failure was carried out using the "randomized play-the-winner" statistical method. In this method the chance of randomly assigning an infant to one treatment or the other is influenced by the outcome of treatment of each patient in the study. If one treatment is more successful, more patients are randomly assigned to that treatment. A group of 12 infants with birth weight greater than 2 kg met objective criteria for high mortality risk. One patient was randomly assigned to conventional treatment (that patient died); 11 patients were randomly chosen for extracorporeal membrane oxygenation (all survived). Intracerebral hemorrhage occurred in one of 11 surviving children. Extracorporeal membrane oxygenation allows lung rest and improves survival compared to conventional ventilator therapy in newborn infants with severe respiratory failure.

Almost all types of newborn respiratory failure are reversible. However, supportive treatment (oxygen and positive airway pressure) can damage the lung, and newborn respiratory failure remains a major cause of morbidity and death in infants. Prolonged extracorporeal membrane oxygenation (ECMO) provides life support while allowing the lung to "rest." We have used ECMO in 45 moribund newborn infants; 25 survived. Neonatologists referred patients who were unresponsive to maximal therapy. The right atrium and aortic arch were cannulated via the jugular vein and carotid artery. Heparin was infused continuously to main activated clotting time at 200 to 300 seconds. Airway oxygenation and pressure were reduced to low levels. Primary diagnoses were hyaline membrane disease, 14 (6 survived, 8 died); meconium aspiration, 22 (15 survived, 7 died); persistent fetal circulation including diaphragmatic hernia, 5 (3 survived, 2 died); and sepsis, 4 (1 survived, 3 died). Growth, development, and brain and lung function are normal in 20 of 25 survivors. ECMO decreased newborn respiratory failure mortality and morbidity rates in this phase I trial. A controlled randomized study is underway. The results suggest that ECMO may be effective in older patients if used before irreversible lung damage occurs.

Recent studies from our laboratory have shown relatively high levels of polymorphic N-acetyltransferase (NAT)(EC 2.3.1.5) activity toward carcinogenic arylamines in urinary bladder cytosol of humans and in the inbred hamster model of the N-acetylation polymorphism. The expression of this polymorphism is of interest because of the higher incidence of bladder cancer among human slow acetylators with documented exposures to arylamine bladder carcinogens. In this study, arylamine NAT activity was partially purified and characterized in inbred hamster urinary bladder cytosols of defined acetylator genotype. Acetylator gene-dose response relationships were observed for the N-acetylation of p-aminobenzoic acid, p-aminosalicyclic acid, and the arylamine carcinogens 2-aminofluorene, 4-aminobiphenyl, and beta-naphthylamine in hamster bladder cytosol. Partial purification of hamster bladder cytosol by anion-exchange fast protein liquid chromatography yielded two NAT isozymes that catalyzed the N-acetylation of each of the arylamine substrates. The catalytic activity of the first isozyme was acetylator genotype-dependent (polymorphic), whereas the second isozyme appeared to be acetylator genotype-independent (monomorphic). Catalytic activities between homozygous rapid, heterozygous, and homozygous slow acetylator genotypes were compared with respect to both initial rates and apparent maximum velocities. Comparison of homozygous rapid and slow acetylator bladder cytosol showed that the apparent Vmax for 2-aminofluorene NAT activity was significantly higher in rapid than slow acetylators (6-fold in cytosol, 50-fold in the polymorphic NAT isozyme). These results suggest a key role for a polymorphic NAT isozyme, regulated by the acetylator genotype and expressed in urinary bladder cytosol, in the initiation of bladder cancer via arylamine carcinogens.

Extracorporeal membrane oxygenators (ECMO) can give total respiratory support for neonates with PPHN without the barotrauma of hyperventilation. ECMO has resulted in survival of infants with PPHN who had been unresponsive to maximal ventilatory and medical support.

Intracranial hemorrhage is a complication of extracorporeal membrane oxygenation for the treatment of neonatal respiratory failure. A retrospective review of 35 neonates treated with extracorporeal membrane oxygenation was performed; ten had intracranial hemorrhage. Infants with intracranial hemorrhage had lower birth weights and were gestationally younger than infants with intracranial hemorrhage. Eight of eight neonates of less than 35 weeks' gestational age sustained intracranial hemorrhage. Six died immediately after extracorporeal membrane oxygenation was stopped. Two lived less than 1 year. Two of 27 neonates older than 34 weeks' gestational age sustained intracranial hemorrhage. One child is normal, the other died at 18 months of age. Based on the results of this study, the risk of intracranial hemorrhage appears low in neonates of greater than 34 weeks' gestational age who undergo extracorporeal membrane oxygenation treatment for severe respiratory failure. The use of extracorporeal membrane oxygenation, as it is presently performed, is contraindicated in neonates of less than 35 weeks' gestational age because of the risk of intracranial hemorrhage.

Extracorporeal membrane oxygenation, using venoarterial or venovenous perfusion, is a safe and effective procedure in the term of near-term infant with life-threatening respiratory failure. Without extracorporeal membrane oxygenation, due to the severity of their disease, these children are at high risk for neurologic damage, chronic lung disease, and death. Because survival is not expected without extracorporeal membrane oxygenation therapy, there is no corresponding control group to which these survivors may be compared. In this report, we reviewed the outcome at 1 to 3 years in the first 14 survivors of extracorporeal membrane oxygenation treated at our institution. Seven of 14 neonatal extracorporeal membrane oxygenation survivors (50%) were normal or near normal at between 1 and 3 years of age. Ten (71%) had normal mental ability. We conclude that in neonates with high mortality risk from respiratory failure, near-normal growth and development can be expected in the majority who survive with extracorporeal membrane oxygenation treatment.

Human epidemiological studies suggest a genetic predisposition to bladder cancer among slow N-acetylators. The capacity of human bladder to N-acetylate arylamines, catalyzed by acetyl coenzyme A-dependent N-acetyltransferase(s) (EC 2.3.1.5) (NAT), may be an important step in the activation and/or deactivation of arylamines in the pathways leading to the initiation of bladder cancer. Another possible activation step is the direct O-acetylation of N-hydroxyarylamines via O-acetyltransferase(s) (OAT) to DNA-binding electrophiles. Human bladder cytosol from nine fresh autopsy specimens were investigated for NAT activity towards p-aminobenzoic acid, and the arylamine carcinogens 4-aminobiphenyl, 2-aminofluorene, and beta-naphthylamine. Apparent Km determinations indicated little difference in NAT affinity (100-300 microM) for any of the substrates between the nine individual bladders. However, the apparent Vmax determinations indicated that the bladders could be classified into rapid or slow acetylator phenotypes based on their NAT activity towards 4-aminobiphenyl, 2-aminofluorene, and beta-naphthylamine. Four of the bladder cytosols had mean activities significantly (P less than 0.01) higher (approximately 10-fold) than the mean NAT activities of the other five bladder cytosols towards each arylamine carcinogen. However, no significant difference was detected in their NAT activities using p-aminobenzoic acid as a substrate. The human bladder cytosols were also tested for their capacity to activate N-hydroxy-3,2'-dimethyl-4-aminobiphenyl to a DNA-binding electrophile through a direct OAT-mediated catalysis. The N-hydroxyarylamine OAT activity also discriminated between two levels of activation, being significantly (P = 0.0002) higher (about twofold) in the rapid N-acetylator bladder cytosols, that correlated (r = 0.94) with the measured levels of NAT activity in each bladder cytosol. These results suggest that NAT activity and OAT activity of the human bladder vary concordantly with N-acetylator phenotype. The polymorphic expression of these acetylation activities may be important risk factors in human susceptibility to bladder cancer from arylamine carcinogens.

A case is presented in which congestive heart failure and thrombocytopenia were complications of an inoperable hemangioma in a neonate. Selective embolization of the hemangioma in the patient achieved significant diminution in the congestive failure and tided this infant through the first few days of life while awaiting positive effects from the steroids and external compression. The combined treatment modalities of selective embolization, external compression, and short course of low-dose systemic steroids resulted in a rapid and complete resolution of this life-threatening problem.

Venoarterial (VA) extracorporeal membrane oxygenation (ECMO) has been successful in support of neonates with respiratory failure but requires right common carotid artery ligation. While no short-term neurologic complications have resulted from neonatal carotid ligation, late complications may occur. For both VA ECMO and venovenous (VV) ECMO, blood is drained from the right atrium via a right internal jugular cannula, oxygenated by a membrane lung, and returned to the patient. VV ECMO spares the carotid by perfusing the oxygenated blood into a vein. VV ECMO gave total respiratory support to three neonates with respiratory failure and each infant survived. In comparison with three similar VA ECMO patients, the VV patients required higher ECMO circuit flow rates and had lower systemic arterial Po2s. Length of time on ECMO, length of hospital stay, and neurologic outcome were similar in the VV and VA patients. Differences among the patients were related to their primary disease rather than to the mode of ECMO support. The VV patients had cannulation of the femoral vein for perfusion of oxygenated blood. Late complications may occur from femoral vein ligation as well as from carotid ligation so long-term follow-up is needed to assess these two ECMO techniques.

Acetyl-coenzyme A (AcCoA)-dependent arylamine N-acetyltransferase (NAT) activity (EC 2.3.1.5) was examined in liver cytosol derived from homozygous rapid acetylator (Bio. 87.20) and homozygous slow acetylator (Bio. 82.73/H) Syrian inbred hamsters. Expression of NAT activity toward p-aminobenzoic acid (PABA), 2-aminofluorene (AF), and 4-aminobiphenyl (ABP) was acetylator genotype-dependent, whereas N-acetyltransferase activity toward isoniazid was acetylator genotype-independent. Two isozymes of NAT activity were partially purified by anion exchange fast protein liquid chromatography from the hepatic cytosol of both homozygous rapid and homozygous slow acetylator hamsters. The first eluting NAT isozyme exhibited a polymorphic expression toward AF, ABP, and PABA although the second eluting NAT isozyme exhibited a monomorphic expression across acetylator genotypes toward the same substrates. Determination of Michaelis-Menten kinetic constants in hepatic cytosol of homozygous rapid and slow acetylator hamsters suggests that PABA, AF, and ABP NAT activities were acetylator genotype-dependent because of catalysis by polymorphic NAT isozyme that is both an apparent Km and Vmax variant, whereas, the acetylator genotype-independent expression of isoniazid NAT activity appeared to result from catalysis via a common monomorphic NAT isozyme in both acetylator genotypes. Additional kinetic studies on the partially purified NAT isozymes of homozygous rapid and slow acetylator hamster liver confirmed that the polymorphic NAT isozyme exhibited a substantially higher apparent maximum velocity in homozygous rapid acetylators than slow acetylators toward PABA, AF, and ABP as well as acetylator genotype-related differences in the apparent Km toward each of these substrates. In contrast, the monomorphic NAT isozyme of both acetylator genotypes showed apparent Vmax levels of NAT activity that did not vary with acetylator genotype. Furthermore, the monomorphic NAT isozyme did not show acetylator genotype-related variations in apparent Km toward the arylamine carcinogens AF and ABP, although differences were noted for PABA and AcCoA. These results suggest that the acetylator genotype-dependent expression of AcCoA-dependent NAT activity in hamster hepatic cytosol toward arylamines is primarily accountable by structural variants (allozymes) of polymorphic NAT under the genetic regulation of the acetylator gene locus. The acetylator genotype-independent expression of isoniazid NAT activity is attributable to a common monomorphic NAT isozyme in both acetylator genotypes.