Diarrhea after kidney transplantation: A study of risk factors and outcomes.

Background: Diarrhea in kidney transplant recipients (KTRs) can be associated with significant morbidity. Material and Methods: We evaluated 198 KTRs for a history of diarrhea post-kidney transplant at a tertiary care center in western India over 1 year. A protocol-based evaluation of diarrhea was done with respect to clinical features, diagnostic evaluation, associated acute allograft dysfunction, and its impact on long-term allograft function. Primary outcomes of interest were: chronic allograft injury (CAI) and the need for mycophenolate mofetil (MMF) withdrawal. We also assessed the effect of MMF withdrawal on the risk of the development of CAI. Results: Eighty-five of 198 (42.5%) recipients experienced diarrhea and a total of 140 diarrheal episodes were evaluated. The mean age of these 85 recipients was 38 ± 12 years and 72 (84.7%) were males. 73 of 85 recipients were on MMF at the time of diarrhea and in 35 (48%) of them MMF withdrawal was needed for chronic and persistent symptoms. Diarrhea was attributed to infective etiologies in 90 of 140 (64.2%) cases. Among the microbiologically confirmed infective diarrheal episodes, giardia and cryptosporidium were the common pathogens in 11/28 (39%) and 6/28 (21.4%) episodes respectively. One hundred and twenty-eight episodes out of 140 (91.4%) episodes were complicated by acute allograft dysfunction. Forty-one of 85 recipients (48.2%) developed chronic allograft injury and 12 (14.1%) developed allograft rejection (acute and/or chronic). Probability of chronic allograft injury was higher in those with MMF withdrawal. Conclusion: Diarrhea post-kidney transplant adversely affects graft function, especially after MMF withdrawal.

Monodispersed ZnO nanoparticles and their use in heterojunction solar cell.

Monodispersed ZnO nanoparticles have been synthesised in ethylene glycol medium using zinc acetate and sodium hydroxide at room temperature through ultrasonic treatment. The monodispersed ZnO nanoparticles were characterized by XRD, TEM, SEM, and optical spectroscopy. The results indicate that ZnO shows the hexagonal wurtzite structure having 8 nm average particle size with the band gap of 3.93 eV. ZnO nanoparticles blended with P3HT show the improvement in the interchains and intrachains ordering as compared to pure P3HT. The power conversion efficiency of P3HT/ZnO solar cell is found to be 0.88%, which is comparable with the result obtained by other researchers.

Assessment of Nasal Obstruction in Patients Undergoing Functional Endoscopic Sinus Surgery.

Aim & objectives-To assess and compare the nasal obstruction in patients before and after undergoing FESS using Visual analogue scale, Rhinomanometry and Diagnostic nasal endoscopy. Introduction- Chronic Rhinosinusitis with, or without nasal polyps can lead to nasal obstruction. Patients refractory to medical treatment undergo Functional endoscopic sinus surgery (FESS). FESS has been shown to improve subjective quality of life outcomes and objective endoscopic improvement. Material & methods- A prospective study conducted in the department of Ear, Nose & Throat, of a tertiary care medical college and associated Hospital between January 2021 and October 2022. Subjective and objective assessment of nasal obstruction was done using Visual analogue scale, Rhinomanometry and Diagnostic nasal endoscopy before and after surgery at 1st, 3rd and 6th month. Results- Post FESS, there was a significant improvement in nasal obstruction on Visual analogue scale, sinuses were healthy and drainage was adequate on Diagnostic nasal endoscopy, statistically significant (P < 0.05) decrease in nasal resistance was seen on Rhinomanometry. Conclusion- A good subjective outcome on Visual analogue scale and a good objective outcome on Diagnostic nasal endoscopy and Rhinomanometry can be obtained with FESS in patients with Chronic Rhinosinusitis.

Effect of home-based newborn care on neonatal and infant mortality: a cluster randomised trial in India.

BACKGROUND: Home-based newborn care has been found to reduce neonatal mortality in rural areas. Study evaluated effectiveness of home-based care delivered by specially recruited newborn care workers- Shishu Rakshak (SR) and existing workers- anganwadi workers (AWW) in reducing neonatal and infant mortality rates. METHODS: This three-arm, community-based, cluster randomised trial was conducted in five districts in India. Intervention package consisted of pregnancy surveillance, health education, care at birth, care of normal/low birthweight neonates, identification and treatment of sick neonates and young infants using oral and injectable antibiotics and community mobilisation. The package was similar in both intervention arms-SR and AWW; difference being healthcare provider. The control arm received routine health services from the existing health system. Primary outcomes were neonatal and young infant mortality rates at 'endline' period (2008-2009) assessed by an independent team from January to April 2010 in the study clusters. FINDINGS: A total of 6623, 6852 and 5898 births occurred in the SR, AWW and control arms, respectively, during the endline period; the proportion of facility births were 69.0%, 64.4% and 70.6% in the three arms. Baseline mortality rates were comparable in three arms. During the endline period, the risk of neonatal mortality was 25% lower in the SR arm (adjusted OR 0.75, 95% CI 0.57 to 0.99); the risks of early neonatal mortality, young infant mortality and infant mortality were also lower by 32%, 27%, and 33%, respectively. The risks of neonatal, early neonatal, young infant, infant mortality in the AWW arm were not different from that of the control arm. INTERPRETATION: Home-based care is effective in reducing neonatal and infant mortality rates, when delivered by a dedicated worker, even in settings with high rates of facility births. TRIAL REGISTRATION NUMBER: The study was registered with Clinical Trial Registry of India (CTRI/2011/12/002181).

Cardiovascular disease risk management in HIV patients, experiences from Greater Manchester.

Antiretroviral (ARV) therapy in HIV patients can cause hyperlipidaemia, glucose intolerance and insulin resistance, which increase the risk of cardiovascular disease (CVD). An audit carried out in Manchester found that CVD risk factors were common among HIV patients receiving ARVs; however, the management of risk factors was not satisfactory. Adopting a formal system to identify and manage CVD risk factors as well as appropriate referral for specialist management of complications of ARV therapy would improve patient care.

Traumatic haemorrhage into an occult phaeochromocytoma: presentation and management in a patient with septic shock.

Phaeochromocytomas can have a variety of presentations; however, traumatic haemorrhage into a phaeochromocytoma is a rare presentation. Diagnosing and managing a critically ill, septic patient with a phaeochromocytoma can be very challenging. We report a case of a 57-year-old man, with a previously undiagnosed phaeochromocytoma, who presented initially with bowel perforation following an assault. Following a laparotomy for bowel resection and anastomosis, whilst on the intensive care unit, he developed paroxysmal severe hypertension overlying septic shock. Phaeochromocytoma was confirmed using a computed tomography scan and urinary assay of metanephrines and catecholamines. We managed the haemodynamic instability using labetalol and noradrenaline infusions. As his septic state improved he was started on conventional therapy and following control of his symptoms over the next few weeks, he underwent an uncomplicated right sided adrenalectomy. He made a full recovery.

Rural poverty reduction through centrally sponsored schemes.

This paper discusses the evolving profile of poverty in India and reviews the national performance of selected anti-poverty programmes between 1997-1998 and 2005. For each programme, it outlines the budgetary allocation principle used for the States and districts and analyzes budgetary performance over the period. The main objective is to explore the extent to which the anti-poverty programmes are reaching their target groups effectively. Finally, it identifies the specific factors responsible for under-performance and provides a set of recommendations for policy makers and programme implementers which could help improve the outcomes of the schemes.

Activation of tumor suppressor LKB1 by honokiol abrogates cancer stem-like phenotype in breast cancer via inhibition of oncogenic Stat3.

Tumor suppressor and upstream master kinase Liver kinase B1 (LKB1) plays a significant role in suppressing cancer growth and metastatic progression. We show that low-LKB1 expression significantly correlates with poor survival outcome in breast cancer. In line with this observation, loss-of-LKB1 rendered breast cancer cells highly migratory and invasive, attaining cancer stem cell-like phenotype. Accordingly, LKB1-null breast cancer cells exhibited an increased ability to form mammospheres and elevated expression of pluripotency-factors (Oct4, Nanog and Sox2), properties also observed in spontaneous tumors in Lkb1-/- mice. Conversely, LKB1-overexpression in LKB1-null cells abrogated invasion, migration and mammosphere-formation. Honokiol (HNK), a bioactive molecule from Magnolia grandiflora increased LKB1 expression, inhibited individual cell-motility and abrogated the stem-like phenotype of breast cancer cells by reducing the formation of mammosphere, expression of pluripotency-factors and aldehyde dehydrogenase activity. LKB1, and its substrate, AMP-dependent protein kinase (AMPK) are important for HNK-mediated inhibition of pluripotency factors since LKB1-silencing and AMPK-inhibition abrogated, while LKB1-overexpression and AMPK-activation potentiated HNK's effects. Mechanistic studies showed that HNK inhibited Stat3-phosphorylation/activation in an LKB1-dependent manner, preventing its recruitment to canonical binding-sites in the promoters of Nanog, Oct4 and Sox2. Thus, inhibition of the coactivation-function of Stat3 resulted in suppression of expression of pluripotency factors. Further, we showed that HNK inhibited breast tumorigenesis in mice in an LKB1-dependent manner. Molecular analyses of HNK-treated xenografts corroborated our in vitro mechanistic findings. Collectively, these results present the first in vitro and in vivo evidence to support crosstalk between LKB1, Stat3 and pluripotency factors in breast cancer and effective anticancer modulation of this axis with HNK treatment.

Leptin promotes the proliferative response and invasiveness in human endometrial cancer cells by activating multiple signal-transduction pathways.

An increase in the risk of cancer is one of the consequences of obesity. The predominant cancers associated with obesity have a hormonal basis and include breast, prostate, endometrium, colon and gall-bladder cancers. Leptin, the key player in the regulation of energy balance and body weight control also acts as a growth factor on certain organs in both normal and disease states. Therefore, it is plausible that leptin acts to promote cancer growth by acting as a mitogenic agent. However, a direct role for leptin in endometrial cancer has not been demonstrated. In this study, we analyzed the proliferative role of leptin and the mechanism(s) underlying this action in endometrial cancers which express both short and long isoforms of leptin receptors. Treatment with leptin resulted in increased proliferation of ECC1 and Ishikawa cells. The promotion of endometrial cancer cell proliferation by leptin involves activation of STAT3 and ERK2 signaling pathways. Moreover, leptin-induced phosphorylation of ERK2 and AKT was dependent on JAK/STAT activation. Therefore blocking its action at the JAK/STAT level could be a rational therapeutic strategy for endometrial carcinoma in obese patients. We also found that leptin potently induces invasion of endometrial cancer cells in a Matrigel invasion assay. Leptin-stimulated invasion was effectively blocked by pharmacological inhibitors of JAK/STAT (AG490) and phosphatidylinositol 3-kinase (LY294002). Taken together these data indicate that leptin promotes endometrial cancer growth and invasiveness and implicate the JAK/STAT and AKT pathways as critical mediators of leptin action. Our findings have potential clinical implications for endometrial cancer progression in obese patients.

Oral misoprostol for prevention of postpartum hemorrhage by paramedical workers in India.

OBJECTIVE: To study whether paramedical workers from rural primary health centers in India are able to administer oral misoprostol and actively manage the third stage of labor to prevent postpartum hemorrhage (PPH). METHOD: Cluster randomization was used to enroll 1200 women at 30 peripheral health centers from 5 states in India, 600 forming the study's intervention group (active management of the third stage of labor with 600 mug of oral misoprostol) and 600 forming the comparison group (in which the current government guidelines for the prevention of PPH were followed). The primary outcome was blood loss after delivery, which was measured using a calibrated blood collection drape. RESULTS: Age, literacy level, occupation, and gravidity were similar in the 2 groups. More than 70% of women in both groups had moderate anemia (hemoglobin level <10 g/dL). Paramedical workers followed instructions in almost all deliveries in the intervention group (99%). There was a significant reduction in duration of the third stage of labor (7.9 +/- 4.2 min vs. 10.9 +/- 4.3 min; p < .001) and median blood loss after delivery (100 mL vs. 200 mL; p < .001) in the intervention group. Overall, a low incidence of PPH was observed (<1%) in both groups. A greater number of women had moderate to severe shivering (12.7% vs. 0.5%) and a temperature higher than 38 degrees C (9.7% vs. 4.3%) in the intervention group, which was statistically significant. CONCLUSION: Simple interventions can be easily implemented in rural health care settings to reduce the blood loss during labor. This finding has significant implications for developing countries, in which the prevalence of anemia is high.

Nonoxynol-9 vaginal pessary: a preliminary Indian experience.

BACKGROUND: Barrier methods of contraception do not have systemic effects and allow the user complete control over their use. For women, the ease of use of a contraceptive is often more important than its efficacy. Hence, barrier methods could be offered as a useful alternative method of contraception. Nonoxynol-9 (a spermicide) is a locally acting, non-hormonal method free from systemic side-efforts. It is a woman-controlled, reversible method which is to be used before intercourse. There are little data available on its efficacy, side-effects and acceptability among Indian women. METHODS: The vaginal pessary nonoxynol-9 was offered as a contraceptive option to 3200 women attending the Family Planning clinics at 31 Human Reproduction Research Centres (HRRCs) of the Indian Council of Medical Research. The other contraceptives offered included an intrauterine device, oral pills, condoms, Norplant, tubal sterilization and vasectomy using the cafeteria approach. Those who accepted nonoxynol-9 were followed up to assess the rates of continuation, failure and side-effects. RESULTS: The nonoxynol-9 pessary was accepted by 541 women who were followed up for 3470 woman-months of use. The reasons given for acceptance were that it was user-controlled and/or they did not wish to use other methods because of the side-effects or contraindications of these methods. The overall continuation rates were 41.2% and 33% at 9 and 12 months of use, respectively. Most women (31.3%) discontinued its use due to personal reasons such as husband dissatisfaction, desire for further pregnancy, irregular use of pessary and difficulty in insertion. Twenty-nine women became pregnant during the study period (15 due to method failure and 14 due to user failure) giving a use-effectiveness of 8.8% at 12 months. The method failure rate was 4.3% at 12 months of use. The failure rates were lower compared with the reported failure rates of barrier contraceptives (1%-30% at 1 year of use) and the side-effects were minimal. CONCLUSION: Nonoxynol-9 had low acceptability (16.9%) and overall continuation rates--41.2% and 33% at 9 and 12 months of use. It could be offered to women looking for a short term, user-controlled contraceptive.

Maternal mortality in seven districts of Uttar Pradesh--an ICMR task force study.

Maternal mortality is a major health and development concern. The available information on maternal mortality in rural India is inadequate and scanty. This study presented maternal mortality data from the demographically and developmentally (including for health) poor performing state of Uttar Pradesh. A descriptive, cross-sectional survey was conducted utilizing a stratified cluster sampling design between 1989-90 in eight districts of Uttar Pradesh. Four good performing districts namely, Agra, Farrukhabad, Ghaziabad and Badaun from the western region and four poor performing districts from the eastern region namely, Gorakhpur, Basti, Varanasi and Pratapgarh were chosen. A door-to-door household interview survey was carried out in the selected villages covering a population of 11.67 lakhs in 889 villages. Maternal mortality rates during 1989 ranged between 533745 per 100,000 live births except in Ghaziabad district where the rate was as low as 101 per 100,000 live births. The rate in Eastern U.P. was higher (573 per 100,000 live births) as compared to that in Western U.P. (472 per 100,000 live births). A total of 286 maternal deaths were reported during the study period. The direct obstetric causes accounted for 55.7% of maternal deaths with haemorrhage (26.4%) being the most prevalent. Anaemia and jaundice (17.4%) were the most prevalent indirect causes of maternal deaths. Most of the maternal deaths could have been prevented if timely medical care was available.

Effects of elevating [Na]i on membrane currents of canine ventricular myocytes: role of intracellular Ca ions.

OBJECTIVES: Our first objective was to study how elevating [Na]i can modify the background membrane conductance in canine ventricular myocytes (CVM). In particular, we wanted to find evidence for a Nai-activated K current (IK,Na) in these cells. The second objective was to compare the effects of elevating [Na]i on membrane currents without and with intracellular Ca buffering. METHODS: Whole-cell currents were recorded and [Na]i was elevated either by using a pipette perfusion device that allowed [Na] in the pipette solution to be varied (from 0 to 50 mM), or by 50 microM ouabain. RESULTS: Although an outward current attributable to IK,Na was confirmed in guinea-pig ventricular myocytes (GPVM) under our recording conditions, no such current was seen in 29 CVM examined. With Cai buffering, the main effect of elevating [Na]i on CVM was an increase in inward current around and negative to the resting membrane potential. Based on the dependence of this Nai-induced inward current on K ions and its pharmacological properties, especially the effects of low concentrations of external Ba ions (< or = 5 microM) at strongly hyperpolarized voltages, we hypothesize that this current was carried by extracellular K ions through the inward rectifier (IK1) channels that had been modified by the high level of [Na]i. With Cai buffering, elevating [Na]i by ouabain had few or no effects on the L-type Ca channel current (ICa) or the slow delayed rectifier current (IKs). Without Cai buffering, ouabain induced a rapid reduction of both currents along with an increase in a time-independent outward current at voltages positive to -60 mV. CONCLUSION: Our data suggest that there are species variations in K channel expression and/or K channel modulation by intracellular Na ions. Furthermore, intracellular Ca ions play a crucial role in mediating the effects of Nai loading on membrane currents in canine ventricular myocytes.

Aldehydes potentiate alpha(2)(I) collagen gene activity by JNK in hepatic stellate cells.

Hepatic stellate cells (HSCs) are responsible for type I collagen deposition in liver fibrosis that leads to cirrhosis. The purpose of this study was to examine potential molecular signals that lead to increased alpha(2)(I) collagen gene expression by acetaldehyde, the primary metabolite of alcohol and malondialdehyde (MDA), a lipid peroxidation product known to be associated with chronic liver injury. MDA and the combination of MDA and acetaldehyde were employed to determine the effect on alpha(2)(I) collagen gene expression as assessed by transient transfection analysis and reverse transcriptase polymerase chain reaction (RT-PCR). Immunoblot and subsequent immunoprecipitation analysis examined stress-activated protein kinase (SAPK) activity. Cotransfection with a dominant negative mutant for c-jun nuclear kinase (dnJNK1) was also employed with the alpha(2)(I) collagen promoter. MDA increased alpha(2)(I) collagen gene expression nearly 2.5- to 3-fold, however there was no synergistic effect of the combination of acetaldehyde and MDA on alpha(2)(I) collagen gene activation and expression. Acetaldehyde, MDA, or both significantly increased JNK activity when compared to untreated stellate cells. The dnJNK1 expression vector abrogated alpha(2)(I) collagen transgene activity. In conclusion, JNK activation appears to be critical in the signaling cascade of oxidative metabolites of chronic alcohol-related liver injury and collagen gene activation.

Characterization of lactate dehydrogenase of Plasmodium knowlesi.

Some properties of purified lactate dehydrogenase, (EC. 1.1.1.27) from schizonts of Plasmodium knowlesi are described. The plasmodial enzyme migrated as single entity on polyacrylamide gel, and resembled rabbit muscle (M4) lactate dehydrogenase in its electrophoretic mobility. The P. knowlesi enzyme consisted of four identical subunits of 31 kDa. Purified lactate dehydrogenase was inhibited almost completely when incubated with 100 microM p-chloromercuribenzoate, Ag+ or Hg+ and such inhibition could be reversed by the addition of beta-mercaptoethanol or L-cysteine. Metal chelators did not show any remarkable effect. Oxalic acid is a competitive inhibitor of pyruvate reduction by this enzyme with apparent Ki of approximately equal to 0.41 mM.

Effect of Plasmodium yoelii nigeriensis infection and chloroquine on the hepatic mixed function oxidase system of mice.

Plasmodium yoelii nigeriensis infection in albino mice significantly altered the hepatic microsomal mixed function oxidase system. Cytochrome P-450 (the terminal monooxygenase) and other monooxygenases, viz. aniline hydroxylase, aminopyrine-N-demethylase and benzo(a)pyrene hydroxylase were significantly lowered while microsomal heme showed 4-fold increase at 80% parasitaemia. Noticeable impairment in the other components like NADH:cytochrome b5 reductase, NADPH:cytochrome c reductase, cytochrome b5 and glucose-6-phosphatase was also observed. Oral treatment of normal and P. y. nigeriensis infected mice with chloroquine (64 mg per kg body weight for 4 days) caused lowering of mixed function oxidase activities which however showed a recovering trend, a week after cessation of treatment.

Synthesis and antiviral activity of some 7-[(2-hydroxyethoxy)methyl]pyrazolo[3,4-d]pyrimidine analogues of sangivamycin and toyocamycin.

The sodium salt of 4-amino-3-cyanopyrazolo[3,4-d]pyrimidine (1) was condensed with (2-acetoxyethoxy)methyl bromide (2) to provide the corresponding protected acyclic nucleoside, 4-amino-3-cyano-1-[(2-acetoxyethoxy)methyl]-pyrazolo[3,4-d]pyrimid ine (3). Treatment of 3 with sodium methoxide in methanol provided a good yield of methyl 4-amino-1-[(2-hydroxyethoxy)methyl]pyrazolo[3,4-d]pyrimidine-3- formimidate (4). Treatment of the imidate (4) with sodium hydrogen sulfide gave the thiocarboxamide derivative 5. Aqueous base transformed 4 into 4-amino-1-[(2-hydroxyethoxy)methyl]pyrazolo[3,4-d]pyrimidine-3- carboxamide (6) in good yield. Treatment of 5 with mercuric chloride furnished the toyocamycin analogue 7. Evaluation of compounds 1, 3-7 revealed that only the heterocycle (1) and the thiocarboxamide acyclic nucleoside (5) were active. Compound 5 was the more potent with activity against human cytomegalovirus and herpes simplex virus type 1.

Synthesis and antiviral activity of certain 4-substituted and 2,4-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines.

Treatment of the sodium salt of 4-chloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (3) has provided 4-chloro-2-(methylthio)-7[(2-acetoxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (4). Ammonolysis of 4 at room temperature gave 4-chloro-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (5). However, ammonolysis of 5 at 130 degrees C furnished 4-amino-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]-pyrrolo[2,3- d]pyrimidine (6), which on desulfurization with Raney Ni yielded 4-amino-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (7) (acyclic analogue of tubercidin). The oxidation of 6 with m-chloroperbenzoic acid provided the sulfone derivative 8. A nucleophilic displacement of the 2-methylsulfonyl group from 8 with methoxide anion provided 4-amino-2-methoxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (9). Demethylation of 9 with iodotrimethylsilane gave 4-amino-2-hydroxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (10). Treatment of 2,4-dichloropyrrolo[2,3-d]pyrimidine (11) with 3 gave the protected acyclic compound 12, which on deacetylation and ammonolysis under controlled reaction conditions gave 2,4-dichloro-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (13) and 4-amino-2-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (14), respectively. The condensation of 2-acetamido-4-chloropyrrolo[2,3-d]pyrimidine (15) with 3 gave the protected acyclic compound 16, which on concomitant deacetylation and ammonolysis with methanolic ammonia at an elevated temperature yielded 2,4-diamino-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (17) in moderate yield. In tests involving human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), only slight activity and cytotoxicity were observed. The most active compounds (12 and 13) were slightly more active against HCMV than acyclovir, but both compounds were inactive against HSV-1. The activity against HCMV, however, was not well separated from cytotoxicity leading to the conclusion that these compounds did not merit further study.

Synthesis and antiviral activity of certain 4- and 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines.

In vitro evaluation of a series of previously prepared tubercidin analogues revealed that certain 5-halogen-substituted analogues were active against human cytomegalovirus (HCMV) at concentrations lower than those that produced comparable cytotoxicity in uninfected cells. In contrast, tubercidin was cytotoxic at all antiviral concentrations. Even though the antiviral selectivity of the 5-substituted compounds was slight, this observation led us to prepare a series of acyclic analogues. Treatment of the sodium salt of 4-chloropyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (2a) provided the acyclic nucleoside 4-chloro-7-[(2-acetoxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (3). A nucleophilic displacement of the 4-chloro group with methoxide, methylamine, and dimethylamine yielded the corresponding 4-substituted compounds 4, 5, and 6, respectively, in good yield. Electrophilic substitution (chlorination, bromination, and iodination) was effected at the C-5 position of compound 3 with N-chlorosuccinimide, N-bromosuccinimide, and iodine monochloride, respectively, in methylene chloride. Removal of the acetyl group from these intermediates (7a-9a) with methanolic ammonia at room temperature afforded the 5-chloro (7b), 5-bromo (8b), and 5-iodo (9b) derivatives of 4-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine. Treatment of compounds 7b-9b with methanolic ammonia at an elevated temperature produced the corresponding 5-halotubercidin analogues 10, 11, and 12, respectively. An alternate procedure for the preparation of these 4,5-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines involved an electrophilic substitution prior to the condensation of the heterocycle with 2a. Treatment of 2 with N-chlorosuccinimide and N-bromosuccinimide gave compounds 13a and 13b, respectively. The condensation of 13a and 13b with 2a and subsequent treatment with methylamine and ethylamine furnished the corresponding 5-halo-4-substituted-pyrrolo[2,3-d]pyrimidines 14a, 14b, 14c, and 14d, respectively. Evaluation of the target compounds (4-6, 7b-9b, 10-12, and 14a-14d) for cytotoxicity and activity against HCMV and herpes simplex virus type 1 (HSV-1) revealed that all compounds except the 5-halogen-substituted compounds 10, 11, and 12 were inactive. Compounds 10, 11, and 12 were active against both viruses at noncytotoxic concentrations. The activity of compound 11 was particularly noteworthy, being at least 10-fold more potent than acyclovir.

Alterations in host regulatory glycolytic enzymes during pathogenesis of primate malaria and following chloroquine therapy.

Hexokinase, phosphofructokinase and pyruvate kinase, the regulatory enzymes of the glycolytic sequence, showed progressive increases in their activities with the rise of parasitaemia in Plasmodium knowlesi-infected rhesus monkey serum and red blood cells. Chloroquine therapy cleared the parasitaemia in 72 h and brought the elevated levels of these enzymes back to almost normal in about 30 days.