Twin combination of Omicron and Delta variants triggering a tsunami wave of ever high surges in COVID-19 cases: A challenging global threat with a special focus on the Indian subcontinent.

The emergence of Omicron (B.1.1.529) variant of SARS-CoV-2 has resulted into a very massive surge in COVID-19 cases worldwide. Due to continuous emergence of multiple variants of SARS-CoV-2, the ongoing pandemic has caused severe morbidity and mortality in last two years. The rate of infectivity of Omicron variant is much higher than Delta variant and in a very quick time Omicron has displaced the Delta variant and now become a dominant variant across the globe. The twin combination of Omicron and Delta variant is triggering a Tsunami wave of ever high surges in COVID-19 cases worldwide. This article highlights the global threats and challenges posed by Omicron, and strategies to counter it with a particular focus on Indian sub-continent.

Efficacy and safety of fixed dose combination of arterolane maleate and piperaquine phosphate in comparison with chloroquine phosphate in children with acute uncomplicated Plasmodium vivax malaria: A phase III, randomised, multicentric study.

BACKGROUND & OBJECTIVES: In India, the burden of Plasmodium vivax malaria has been projected to be highest in some areas. This study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate (AM) 37.5 mg and piperaquine phosphate 187.5 mg (PQP) dispersible tablets and (not with) chloroquine in the treatment of uncomplicated vivax malaria in pediatric patients. METHODS: This multicentric, open-label trial was carried out at 12 sites in India. A total of 164 patients aged 6 months to 12 years with P. vivax malaria were randomized in a ratio of 2:1 to AM-PQP (111 patients) or chloroquine (53 patients) arms. The duration of follow up was 42 days. RESULTS: At 72 hours, the proportion of a parasitaemic and afebrile patients was 100% in both treatment arms in per protocol (PP) population, and 98.2% and 100% [95% CI: -1.8 (-6.33 to 5.08)] in AM-PQP and chloroquine arms, respectively, in intent to treat (ITT) population. The efficacy and safety of AM-PQP was found to be comparable to chloroquine in the treatment of uncomplicated P. vivax malaria in pediatric patients. Overall, the cure rate at Day 28 and 42 was >95% for both AM-PQP or CQ. The commonly reported clinical adverse event was vomiting. No patient was discontinued for any QTc abnormality. INTERPRETATION & CONCLUSION: The efficacy and safety of FDC of arterolane maleate and piperaquine phosphate was found to be comparable to chloroquine for treatment of uncomplicated P. vivax malaria in pediatric patients.

Assessment of Efficacy and Safety of Arterolane Maleate-Piperaquine Phosphate Dispersible Tablets in Comparison With Artemether-Lumefantrine Dispersible Tablets in Pediatric Patients With Acute Uncomplicated Plasmodium falciparum Malaria: A Phase 3, Randomized, Multicenter Trial in India and Africa.

BACKGROUND: Administration of artemisinin-based combination therapy (ACT) to infant and young children can be challenging. A formulation with accurate dose and ease of administration will improve adherence and compliance in children. The fixed-dose combination dispersible tablet of arterolane maleate (AM) 37.5 mg and piperaquine phosphate (PQP) 187.5 mg can make dosing convenient in children. METHODS: This multicenter (India and Africa), comparative, parallel-group trial enrolled 859 patients aged 6 months to 12 years with Plasmodium falciparum malaria. Patients were randomized in a ratio of 2:1 to AM-PQP (571 patients) once daily and artemether-lumefantrine (AL) (288 patients) twice daily for 3 days and followed for 42 days. RESULTS: The cure rate (ie, polymerase chain reaction-corrected adequate clinical and parasitological response) in the per-protocol population at day 28 was 100.0% and 98.5% (difference, 1.48% [95% confidence interval {CI}, .04%-2.91%]) in the AM-PQP and AL arms, respectively, and 96.0% and 95.8% (difference, 0.14% [95% CI, -2.68% to 2.95%]) in the intention-to-treat (ITT) population. The cure rate was comparable at day 42 in the ITT population (AM-PQP, 94.4% vs AL, 93.1%). The median parasite clearance time was 24 hours in both the arms. The median fever clearance time was 6 hours in AM-PQP and 12 hours in the AL arm. Both the treatments were found to be safe and well tolerated. Overall, safety profile of both the treatments was similar. CONCLUSIONS: The efficacy and safety of fixed-dose combination of AM and PQP was comparable to AL for the treatment of uncomplicated P. falciparum malaria in pediatric patients. CLINICAL TRIALS REGISTRATION: CTRI/2014/07/004764.

Folic acid: The key to a healthy pregnancy - A prospective study on fetomaternal outcome.

Objectives: The objective of the study is to study the fetomaternal outcome associated with folic acid deficiency in pregnancy. Materials and Methods: This hospital-based observational study was conducted in the Department of Obstetrics and Gynaecology at Base Hospital, Delhi Cantt, and a total of 351 participants were enrolled who were fulfilling the inclusion criteria. The plasma folic acid level of the selected patients was measured in the booking visit by automated chemiluminescence assay. The cutoff levels of folic acid were taken at 8.6 ng/mL. Based on these values, the study population was divided into two groups, one with folic acid values <8.6 ng/mL and the other with values ≥8.6 ng/mL. Plasma Vitamin B12 levels were measured to check for any concurrent deficiencies. Obstetric outcomes included first- and second-trimester miscarriages, development of anemia, gestational hypertension/preeclampsia, gestational diabetes mellitus, hypothyroidism, placental abruption, and intrauterine fetal growth restriction (FGR). Furthermore, the period of gestation at delivery, fetal weights, APGAR scores at 5 min were documented. The study also considered fetal neural tube defects, intrauterine fetal demise for data collection. Collected data were analyzed statistically to find the association of the above-mentioned outcomes with levels of folic acid. Results: The rate of preterm deliveries was significantly higher in the folic acid group with levels <8.6 ng/mL (16.94%). The incidence of small for gestational age/FGR was higher in the folic acid group with levels <8.6 ng/mL (27.11%) compared to the high folic acid group with levels ≥8.6 ng/mL (13.38%). The differences in the incidence of anemia, gestational hypertension, gestational diabetes, and preeclampsia between the two groups were not statistically significant and no cases of intrauterine fetal demise or placental abruption were observed in either group. Moreover, there was no significant difference in the relative risk of low Apgar scores at 5 min between the two groups. Conclusion: The present study suggests that low folic acid levels during pregnancy are associated with a higher risk of adverse pregnancy outcomes such as anemia, miscarriages, preterm delivery, and FGR. Therefore, adherence to nutritional recommendation of folic acid supplementation during pregnancy is essential to prevent these adverse outcomes.

Analytical Study of Mandible: Prerequisite for Sex Determination.

Background: Human skull consists of various bones. One of them is mandible which is quite resistant, tough and shows systemic differences in form between individuals of different sex. It resists putrefaction also. There are characteristic features in the mandible that help us to differentiate sex in case of unknown victims like in mass disasters or in case fragmentary remains of the skeleton are found. Analysis of mandible with regard to its features is of great assistance in the determination of sex. Materials and Methods: A total of 80 dry mandible bones were collected. Morphological and morphometric parameters were studied to determine their sex. A total of nine parameters, i.e., three non-metric and six metric parameters were observed for each mandible. Data was collected for each parameter. Results: Among 80 dry mandible bones, 55 were males and 25 were females. 81.2% males bones had a square chin whereas, 80% females had a rounded chin. Gonial flare was everted in 89% males and inverted in 68% females. Conclusion: Mandible exhibits significant sexual differences. Various morphological and morphometric parameters are essential for sex determination in case of mandible bone.

The reliability and advantages of the sentinel vein as a microsurgical recipient vessel.

Free flaps to the scalp, calvaria, and anterior and middle cranial fossae are typically transferred to the superficial temporal artery and vein. Occasionally the superficial temporal vein is unsuitable for microvascular anastomosis. In such cases, we have had success using the sentinel vein, a perforating vein located in the anterior aspect of the deep temporal fat pad. This article describes the pertinent anatomy, our clinical experience, and the advantages of the sentinel vein as a microsurgical recipient vessel.

External doppler monitoring of free flaps through negative pressure dressings.

The negative pressure dressing is a highly effective modality for coverage and bolstering of skin grafts in the early postoperative period. In the situation of a skin graft over a free flap, the surgeon might be inclined to avoid this modality out of concern that the dressing would deleteriously effect flap survival or impede flap monitoring. This case series supports the safety of the negative pressure dressing and demonstrates a technical modification that permits external Doppler monitoring of the flap through the dressing. Thus, this technique provides an ideal environment for skin graft healing while maintaining the ability to monitor the flap in a straightforward manner and also simplifies nursing care.

NFkappaB selectivity of estrogen receptor ligands revealed by comparative crystallographic analyses.

Our understanding of how steroid hormones regulate physiological functions has been significantly advanced by structural biology approaches. However, progress has been hampered by misfolding of the ligand binding domains in heterologous expression systems and by conformational flexibility that interferes with crystallization. Here, we show that protein folding problems that are common to steroid hormone receptors are circumvented by mutations that stabilize well-characterized conformations of the receptor. We use this approach to present the structure of an apo steroid receptor that reveals a ligand-accessible channel allowing soaking of preformed crystals. Furthermore, crystallization of different pharmacological classes of compounds allowed us to define the structural basis of NFkappaB-selective signaling through the estrogen receptor, thus revealing a unique conformation of the receptor that allows selective suppression of inflammatory gene expression. The ability to crystallize many receptor-ligand complexes with distinct pharmacophores allows one to define structural features of signaling specificity that would not be apparent in a single structure.

Phase I clinical studies of the advanced glycation end-product (AGE)-breaker TRC4186: safety, tolerability and pharmacokinetics in healthy subjects.

BACKGROUND AND OBJECTIVE: Advanced glycation end-products (AGEs) have been implicated in the pathogenesis of diabetic complications through a variety of mechanisms including endothelial dysfunction and structural abnormalities in the vasculature and myocardium. Reducing the AGEs burden and their ensuing pro-inflammatory, pro-oxidative and pro-coagulant effect with associated dysfunctional proteins in various target tissues may retard the progression of and even reverse diabetic macro- and microvascular complications. Pyridinium, 3-[[2-(methylsulfonyl) hydrazino] carbonyl]-1-[2-oxo-2-2-thienyl) ethyl]-chloride (TRC4186) has demonstrated AGE-breaking activities in in vitro experiments and improvement in the endothelial and myocardial function in animal models of diabetes mellitus with reduction of AGEs accumulation in tissues over time. The safety of TRC4186 has been established in in vitro and in vivo preclinical studies. Thus, this drug is being developed for the treatment of complications associated with diabetes. This investigation set out to evaluate the safety, tolerability and pharmacokinetics of TRC4186 in healthy human subjects after single and multiple ascending doses, fixed doses in elderly male and female subjects, and with food and different formulations of the compound. METHODS: Four studies were conducted during phase I clinical development of TRC4186. These were: (i) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in healthy male subjects with doses of TRC4186 ranging from 250 to 2500 mg administered as an oral solution (total six doses); (ii) a randomized, double-blind, placebo-controlled, multiple-dose, dose-ascending study in healthy male subjects with three doses of TRC4186 ranging from 500 to 2000 mg twice daily for 6 days with a final single dose on day 7; (iii) a randomized, open-label, three-way crossover study to assess the effect of food (fasted vs fed) and formulation (solution vs tablet) with TRC4186 500 mg; (iv) a randomized, double-blind, placebo-controlled, single-dose, dose-ascending study in elderly male and female subjects at a dose of TRC4186 500 mg followed by TRC4186 1000 mg after a 7-day washout period. The safety and tolerability of TRC4186 were assessed by considering adverse events (AEs), ECG findings, vital signs and laboratory investigation results. RESULTS: TRC4186 was rapidly absorbed, with maximum plasma concentrations (C(max)) attained within 1-4 hours. C(max) and area under the plasma concentration-time curve (AUC) were dose proportional over the range 250-2500 mg for a single dose and 500-2000 mg for multiple doses with twice-daily administration. Steady-state conditions were attained within 6 days at different dose levels. C(max) and AUC were not affected by age, sex, race or type of formulation. The tablet formulation of TRC4186 was bioequivalent with the solution form of the drug under fasting conditions and systemic availability of the tablet formulation was reduced by 40% when administered under fed conditions. Terminal elimination and renal clearance in the elderly male (age 69.1 +/- 6.0 years) were not significantly different compared with younger subjects (age 31 +/- 8.6 years). CONCLUSION: TRC4186 was safe and well tolerated when administered orally with either a single or multiple doses across the different ages, sexes, races and formulations studied. A dose-proportional increase in plasma TRC4186 concentration was seen, with steady state being achieved within 6 days.

Synthesis and evaluation of novel 4-amino-4,6-androstadiene-3,17-dione: an analog of formestane.

Synthesis of 4-amino-4,6-androstadiene-3,17-dione 7, an analog of formestane used in breast cancer therapy as an aromatase inhibitor, from 4-acetoxy-4-androstene-3,17-dione 2 is described. This is the first report of a 4-amino diene (4,6) system in this series of molecules. The new (7) and reported molecules were screened by the National Cancer Institute (NCI, Bethesda, USA) for in vitro antitumor activity against 60 human cancer cell lines. Molecule 7 showed best activity against breast cancer cell line (MCF-7).

Molecular characterization of a B-ring unsaturated estrogen: implications for conjugated equine estrogen components of premarin.

Conjugated equine estrogens (CEEs) are routinely used for hormone replacement therapy (HRT), making it important to understand the activities of individual estrogenic components. Although 17beta-estradiol (17beta-E2), the most potent estrogen in CEE, has been extensively characterized, the actions of nine additional less potent estrogens are not well understood. Structural differences between CEEs and 17beta-E2 result in altered interactions with the two estrogen receptors (ERalpha and ERbeta) and different biological activities. To better understand these interactions, we have determined the crystal structure of the CEE analog, 17beta-methyl-17alpha-dihydroequilenin (NCI 122), in complex with the ERalpha ligand-binding domain and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator. NCI 122 has chemical properties, including an unsaturated B-ring and 17alpha-hydroxyl group, which are shared with some of the estrogens found in CEEs. Structural analysis of the NCI 122-ERalpha LBD-GRIP1 complex, combined with biochemical and cell-based comparisons of CEE components, suggests that factors such as decreased ligand flexibility, decreased ligand hydrophobicity and loss of a hydrogen bond between the 17-hydroxyl group and His524, contribute significantly to the reduced potency of CEEs on ERalpha.

Soil Biological Activity Contributing to Phosphorus Availability in Vertisols under Long-Term Organic and Conventional Agricultural Management.

Mobilization of unavailable phosphorus (P) to plant available P is a prerequisite to sustain crop productivity. Although most of the agricultural soils have sufficient amounts of phosphorus, low availability of native soil P remains a key limiting factor to increasing crop productivity. Solubilization and mineralization of applied and native P to plant available form is mediated through a number of biological and biochemical processes that are strongly influenced by soil carbon/organic matter, besides other biotic and abiotic factors. Soils rich in organic matter are expected to have higher P availability potentially due to higher biological activity. In conventional agricultural systems mineral fertilizers are used to supply P for plant growth, whereas organic systems largely rely on inputs of organic origin. The soils under organic management are supposed to be biologically more active and thus possess a higher capability to mobilize native or applied P. In this study we compared biological activity in soil of a long-term farming systems comparison field trial in vertisols under a subtropical (semi-arid) environment. Soil samples were collected from plots under 7 years of organic and conventional management at five different time points in soybean (Glycine max) -wheat (Triticum aestivum) crop sequence including the crop growth stages of reproductive significance. Upon analysis of various soil biological properties such as dehydrogenase, ß-glucosidase, acid and alkaline phosphatase activities, microbial respiration, substrate induced respiration, soil microbial biomass carbon, organically managed soils were found to be biologically more active particularly at R2 stage in soybean and panicle initiation stage in wheat. We also determined the synergies between these biological parameters by using the methodology of principle component analysis. At all sampling points, P availability in organic and conventional systems was comparable. Our findings clearly indicate that owing to higher biological activity, organic systems possess equal capabilities of supplying P for crop growth as are conventional systems with inputs of mineral P fertilizers.

Finger doses for staff handling radiopharmaceuticals in nuclear medicine.

UNLABELLED: Radiation doses to the fingers of occupational workers handling 99mTc-labeled compounds and 131I for diagnostic and therapeutic procedures in nuclear medicine were measured by thermoluminescence dosimetry. METHODS: The doses were measured at the base of the ring finger and the index finger of both hands in 2 groups of workers. Group 1 (7 workers) handled 99mTc-labeled radiopharmaceuticals, and group 2 (6 workers) handled 131I for diagnosis and therapy. Radiation doses to the fingertips of 3 workers also were measured. Two were from group 1, and 1 was from group 2. RESULTS: The doses to the base of the fingers for the radiopharmacy staff and physicians from group 1 were observed to be 17+/-7.5 (mean+/-SD) and 13.4+/-6.5 microSv/GBq, respectively. Similarly, the dose to the base of the fingers for the 3 physicians in group 2 was estimated to be 82.0+/-13.8 microSv/GBq. Finger doses for the technologists in both groups could not be calculated per unit of activity because they did not handle the radiopharmaceuticals directly. Their doses were reported in millisieverts that accumulated in 1 wk. The doses to the fingertips of the radiopharmacy worker and the physician in group 1 were 74.3+/-19.8 and 53.5+/-21.9 microSv/GBq, respectively. The dose to the fingertips of the physician in group 2 was 469.9+/-267 microSv/GBq. CONCLUSION: The radiation doses to the fingers of nuclear medicine staff at our center were measured. The maximum expected annual dose to the extremities appeared to be less than the annual limit (500 mSv/y), except for a physician who handled large quantities of 131I for treatment. Because all of these workers are on rotation and do not constantly handle radioactivity throughout the year, the doses to the base of the fingers or the fingertips should not exceed the prescribed annual limit of 500 mSv.

Polymer functionalized nanocomposites for metals removal from water and wastewater: An overview.

Pollution by metal and metalloid ions is one of the most widespread environmental concerns. They are non-biodegradable, and, generally, present high water solubility facilitating their environmental mobilisation interacting with abiotic and biotic components such as adsorption onto natural colloids or even accumulation by living organisms, thus, threatening human health and ecosystems. Therefore, there is a high demand for effective removal treatments of heavy metals, making the application of adsorption materials such as polymer-functionalized nanocomposites (PFNCs), increasingly attractive. PFNCs retain the inherent remarkable surface properties of nanoparticles, while the polymeric support materials provide high stability and processability. These nanoparticle-matrix materials are of great interest for metals and metalloids removal thanks to the functional groups of the polymeric matrixes that provide specific bindings to target pollutants. This review discusses PFNCs synthesis, characterization and performance in adsorption processes as well as the potential environmental risks and perspectives.

Cholecystokinin-8 increases Fos-like immunoreactivity in the brainstem and myenteric neurons of rats through CCK1 receptors.

To examine the role of cholecystokinin1 receptor (CCK1) in the activation of brainstem and myenteric neurons by CCK, we compared the ability of exogenous CCK-8 to induce Fos-like immunoreactivity (Fos-LI) in these neurons in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, lacking CCK1 receptors, and Long-Evans Tokushima Otsuka (LETO) controls. Five groups (n=4 rats per group) of OLETF rats, and five LETO control groups, were injected intraperitoneally (IP) with 5, 10, 20, and 40 microg/kg CCK-8 or saline. Forty-micrometer brainstem sections containing the area postrema, nucleus of the solitary tract, and the dorsal motor nucleus of the vagus, and myenteric neurons of the duodenum, jejunum, and ileum underwent a diaminobenzidine reaction enhanced with nickel to reveal Fos-LI. CCK-8 did not increase Fos-LI in any of the tested neurons in the OLETF rats. CCK-8 increased Fos-LI in the brainstem of the LETO rats in a dose dependent manner. In the LETO rats only 40 microg/kg CCK-8 increased Fos-LI in the myenteric plexus of the jejunum. This study demonstrates that CCK-8 activates the brainstem and myenteric neurons through the CCK1 receptor.

Chemical sympathectomy attenuates myenteric but not dorsal vagal complex Fos-like immunoreactivity induced by cholecystokinin-8 in the rat.

Vagotomy and capsaicin treatment attenuate dorsal vagal complex (DVC) but not myenteric Fos-like immunoreactivity (Fos-LI) induced by cholecystokinin-8 (CCK-8). The goal of this experiment is to test the role of the sympathetic nervous system in the pathway by which CCK-8 increases myenteric Fos-LI. Adult male Sprague-Dawley rats were pretreated with guanethidine sulfate (40 mg/kg daily for 5 weeks) or vehicle intraperitoneally (IP), and injected with CCK-8 (40 microg/kg) or saline IP. Fos-LI was then quantified in the DVC and the myenteric neurons of the duodenum and jejunum using a diaminobenzidine reaction. Guanethidine pretreatment attenuated myenteric but not DVC Fos-LI induced by CCK-8. These findings demonstrate that sympathetic neurons play a role in mediating the myenteric Fos-LI response to CCK. They also suggest differential mediation of myenteric and DVC responses to CCK.

Cholecystokinin-8 increases Fos-like immunoreactivity in myenteric neurons of the duodenum and jejunum more after intraperitoneal than after intravenous injection.

The objective of this study was to measure the relative efficacy and potency of cholecystokinin-8 (CCK-8) given by intraperitoneal (i.p.) and intravenous (i.v.) injection to stimulate Fos-like immunoreactivity (Fos-LI) in neurons of the myenteric plexus in the duodenum and jejunum. The subjects for his experiment were 40 male Sprague-Dawley rats divided into eight treatment groups (n=5 rats per treatment). Four groups of rats were injected with 5, 10, and 40 microg/kg sulfated CCK-8 and saline (control) i.p., and the remaining groups with the same treatments i.v. We then detected Fos-LI, a marker for neuronal activation, in the myenteric plexus of the duodenum and jejunum, in response to the previous doses and routes. All of the CCK-8 doses administered by both routes increased Fos-LI in the myenteric plexus of the duodenum and jejunum significantly more than saline did. Although both routes were efficacious in increasing Fos-LI, CCK-8 i.p. was significantly more potent than CCK-8 i.v. These data provide immunohistochemical evidence that i.p. administration of CCK-8 is a more potent stimulant of Fos-LI in the neurons of the myenteric plexus of the duodenum and jejunum than i.v. injection.

Effects of cholecystokinin-receptor antagonists on Fos-like immunoreactivity stimulated by sulfated cholecystokinin-8 in neurons of the myenteric plexus and hindbrain of rats.

OBJECTIVE: To evaluate the role of cholecystokinin (CCK)-receptor antagonists in the activation of enteric and hindbrain neurons by sulfated CCK-8. ANIMALS: 81 male Sprague-Dawley rats. PROCEDURE: Rats were allocated to 10 groups (5 to 22 rats/group). Each rat received 2 IP injections (15 minutes between injections). The first injection consisted of a specific CCK2-receptor (CCK2R) antagonist (L365,260; 150, 500, or 1,000 microg/kg), a specific CCK1-receptor (CCK1R) antagonist (devazepide; 150 microg/kg), or 1% dimethyl sulfoxide (DMSO [ie, vehicle]), and the second injection consisted of sulfated CCK-8 (10 microg/kg) or saline (0.9% NaCl) solution. Rats were anesthetized and perfused with 500 mL of Krebs saline solution, and the myenteric plexuses of the duodenum and jejunum were collected. Rats were then perfused with 500 mL of phosphate-buffered 4% formaldehyde solution; rats were then euthanatized, and the hindbrain of each was harvested. Tissues were stained by use of a diaminobenzidine reaction enhanced with nickel to reveal Fos-like immunoreactivity (Fos-LI), a marker of neuronal activation, in the aforementioned neurons. RESULTS: Sulfated CCK-8 significantly increased Fos-LI in the myenteric and hindbrain neurons, compared with values for the DMSO injections. All dosages of L365,260 failed to attenuate this increase; however, injection of devazepide attenuated the increase in Fos-LI. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of the results of this study reveals that sulfated CCK-8 activates myenteric and hindbrain neurons of rats primarily through CCK1 R. It provides evidence that CCK2R are lacking or not functional in the gastrointestinal tract of rats.

Hsp90 regulates the phosphorylation and activity of serum- and glucocorticoid-regulated kinase-1.

SGK-1 (serum- and glucocorticoid-regulated kinase-1), a member of the AGC protein kinase family, plays an important role in regulating ion channel expression and contributes to malignant epithelial cell proliferation and survival. SGK-1 activity is regulated on three levels: transcriptional induction following a variety of environmental and intracellular stresses, proteasomal degradation, and phosphorylation. Here we report that phosphoinositide 3-kinase (PI3K)-dependent phosphorylation of SGK-1 requires formation of a complex between SGK-1 and heat-shock protein 90 (Hsp90). Inactivation of Hsp90 by geldanamycin led to decreased SGK-1 phosphorylation independently of increased proteasomal protein degradation, and inhibition of PI3K activity by LY294002 appeared to eliminate SGK-1 phosphorylation at the same residues as those affected by geldanamycin treatment. Interestingly, geldanamycin-targeted phosphorylation sites were not limited to the known conserved PI3K-dependent sites Thr-256 and Ser-422 in SGK-1 but included additional unknown PI3K-dependent residues. Inhibition of Hsp90 also resulted in a complete loss of SGK-1 kinase activity, suggesting that Hsp90 activity is essential for regulating the PI3K/SGK-1 pathway.