The Double Burden of COVID-19 and Dengue in Nepal: The challenges ahead.

Coronavirus disease 2019 (COVID-19) pandemic has caused significant impact on the health care system. As a consequence, diagnosis and treatment of vector borne diseases including dengue has been equally affected. Nepal is no exception to this, where COVID-19 cases is exponentially increased and all resources are concentrated on its prevention, control and management. Dengue, one of the major vector-borne diseases in Nepal, is apparently overlooked despite approaching the peak season of the disease. The aim of this paper is to describe the double burden of COVID-19 and dengue in Nepal, particularly highlighting the co-circulation and possible coinfections. This has posed higher risk of increased severity, more severe cases and deaths in Nepal. Moreover, potential misdiagnosis of these viral diseases may lead to delayed or, inappropriate treatment and poor allocation of resources.

Comparative study of microscopy and polymerase chain reaction for the diagnosis of suspected visceral leishmaniasis patients in Nepal.

BACKGROUND: Visceral leishmaniasis is potentially fatal protozoan diseases caused by Leishmania donovani. Nepal is an endemic region in which visceral leishmaniasis causes a major public health problem in the lowland areas that border the endemic areas of Bihar state in India. Accurate diagnosis to inform treatment is a first step in achieving the goal of visceral leishmaniasis elimination from South East Asian regions by 2020. OBJECTIVE: The objective of the present study was to compare between the Microcopy and polymerase chain reaction for diagnosis of visceral leishmaniasis. METHODS: In the present study, 236 bone marrow aspirations were collected from suspected visceral leishmaniasis patients in Janakpur Zonal Hospital, Dhanusa district, Terai region of Nepal in between 2003-2007. We evaluated bone marrow samples by microscopic examination with subsequent testing of the same sample by polymerase chain reaction and sequence analysis. RESULTS: Giemsa's solution stained bone marrow slides stored for over five years were used for polymerase chain reaction amplification. The result showed that 71% were polymerase chain reaction positive and 56% were microscopic positive. Out of 104 microscopic negative bone marrow samples, 15% of samples were positive by polymerase chain reaction. CONCLUSION: Polymerase chain reaction could make a very good option for diagnosis by using less or non-invasive material from visceral leishmaniasis patients in endemic areas of Nepal.

Trends of rotavirus in Nepal.

BACKGROUND: Rotavirus gastroenteritis is the major cause of morbidity and mortality in infants and young children worldwide. Safe and effective rotavirus vaccine is needed to have significant impact on severe rotavirus gastroenteritis. Currently, two live oral rotavirus vaccines have been licensed in many countries. Knowledge on distribution of human rotavirus of G and P types are essential before rotavirus vaccines are introduced in the target populations. OBJECTIVE: To observe the trends of rotavirus strains in children below five years of age, during the years, 2003-2005 in Nepal. METHODS: Stool specimen collected from children with acute diarrhea who were referred to observation unit or hospitalized in Kanti Children Hospital between 2003 and 2005 were examined. Meteorological data was obtained from Ministry of Environment, Nepal to examine the possibility on the impact of weather on rotavirus infection. RESULTS: Of 1250 stool specimens, 271(22%) were positive for rotavirus by Rotaclone ELISA. G1 was the most common serotype in the first year of study, and G2 in the following year. G12 serotype emerged and remained predominant in two consecutive years. In addition, G9 and G3 emerged in the second year of the study. Children less than three years of age were commonly affected. The records reveal that rotavirus infection is related to the climate, and is commonly seen in the dry season, peaking in January. CONCLUSIONS: Continued surveillance of different regions is needed to monitor the trend of rotavirus strains and to establish rotavirus disease burden, which will help policy makers to make a decision in introducing rotavirus vaccine in Nepal.

Rotavirus infection: an unrecognised disease in Nepal.

Rotavirus is the most common cause of acute infectious gastroenteritis in young children and is associated with substantial morbidity and mortality worldwide, mostly in developing countries. The global rotavirus disease burden has prompted study on their basic research, molecular epidemiology and vaccine development. Little is known about rotavirus infection among health professionals in Nepal. This article summarises basic and clinical features, treatment and prevention, epidemiological pattern, challenges and recommendations of human rotavirus infections in Nepal.

Pregnancy outcomes of women with pruritus, normal bile salts and liver enzymes: a case control study.

BACKGROUND: Obstetric cholestasis (OC) is associated with increased maternal and perinatal complications. Nevertheless, data on pregnancy outcomes of women who experience pruritus on a transient basis, but have normal bile salts and liver function tests (LFT) is scarce. METHODS: The maternal and fetal outcomes of 144 women with pruritus but normal bile salts and LFTs were compared with the next delivered patient without itch who matched for age, ethnicity and parity. RESULTS: The study and control groups had similar mean gestational ages at delivery and birth weights (p>0.05, t test). However, women with pruritus were more likely to have meconium-stained liqor, abnormal intrapartum cardiotocography and postpartum hemorrhage (PPH) (p<0.05, Fisher's exact test). There appears to be a trend towards a higher rate of instrumental delivery (p=0.07) in the study compared to the control group, although this did not reach statistical significance. CONCLUSION: This study suggests that women who have transient pruritus with normal bile salts and liver biochemistry appear to have higher intrapartum and postpartum complications and require increased vigilance. In order to evaluate this finding, further prospective studies will be required.

Periodic rewetting enhances the viability of chondrocytes in human articular cartilage exposed to air.

Desiccation of articular cartilage during surgery is often unavoidable and may result in the death of chondrocytes, with subsequent joint degeneration. This study was undertaken to determine the extent of chondrocyte death caused by exposure to air and to ascertain whether regular rewetting of cartilage could decrease cell death. Macroscopically normal human cartilage was exposed to air for 0, 30, 60 or 120 minutes. Selected samples were wetted in lactated Ringer's solution for ten seconds every ten or 20 minutes. The viability of chondrocytes was measured after three days by Live/Dead staining. Chondrocyte death correlated with the length of exposure to air and the depth of the cartilage. Drying for 120 minutes caused extensive cell death mainly in the superficial 500 microm of cartilage. Rewetting every ten or 20 minutes significantly decreased cell death. The superficial zone is most susceptible to desiccation. Loss of superficial chondrocytes likely decreases the production of essential lubricating glycoproteins and contributes to subsequent degeneration. Frequent wetting of cartilage during arthrotomy is therefore essential.

MMP9-sensitive polymers mediate environmentally-responsive bivalirudin release and thrombin inhibition.

MMP9-responsive bivalirudin-HPMA copolymers were synthesized for direct, local administration in rat spinal cord contusion injury models. Polymer-conjugated bivalirudin peptides maintained activity while demonstrating enzyme-mediated release upon MMP9 exposure and prolonged release from hyaluronic acid/methylcellulose (HAMC) hydrogels compared to free bivalirudin peptide. Localized administration of bivalirudin copolymers in vivo at the site of rat spinal cord injury decreased cellular proliferation and astrogliosis, suggesting the bivalirudin copolymer and HAMC hydrogel system are a promising therapeutic intervention for reducing immediate inflammatory responses and long term scarring.

Intermittent on/off prostaglandin E2 and risedronate are equally anabolic as daily PGE2 alone treatment in cortical bone of ovariectomized rats.

In this study, we evaluated the rat cortical bone changes after a two-cycle, 60-day each (ON/OFF/ON/OFF) treatment with either prostaglandin E2 (OVX/c-PGE2) alone or in combination with risedronate (OVX/c-PGE2+Ris), in comparison with daily treatment with PGE2 for 240 days (OVX/PGE2-240d) in ovariectomized (OVX) rats. At the end of the study, we found that: (1) the overall effectiveness of the treatment on bone mass in the tibial shaft indicates the following ranking: OVX/PGE2-240d = OVX/c-PGE2+Ris > OVX/c-PGE2 > OVX/c-Ris > or = OVX = aging; (2) the same bone mass and architecture were produced in the OVX/PGE2-240d and the OVX/c-PGE2+Ris groups, but the histomorphometric profiles differed in that the former exhibited a higher bone turnover and index of resorption; (3) OVX/c-PGE2+Ris treatment prevented endocortical bone loss and minimized trabecular bone loss during the OFF periods; and (4) the OVX/c-PGE2 alone treatment resulted in the accumulation of less total bone than OVX/PGE2-240d and OVX/c-PGE2+Ris because it could not maintain most of the new subendocortical and marrow trabecular bone generated earlier. In summary, both continuous daily PGE2 and two cycles ON/OFF combined PGE2 and Ris treatments result in more bone mass than two cycles ON/OFF PGE2 alone and Ris alone in estrogen-deficient rats. This study showed that the anabolic effects of PGE2 can be induced and maintained either by continuous administration or by cyclical PGE2+Ris.

Parathyroid hormone and mechanical usage have a synergistic effect in rat tibial diaphyseal cortical bone.

Previous reports showed that bone mass and architecture only partially recovered by remobilization (RM) after immobilization (IM)-induced osteopenia, and that parathyroid hormone (PTH) had an anabolic effect on the skeleton. The aim of this study was to determine whether low doses of PTH could restore IM-induced cortical bone loss and whether a combination of PTH plus loading (RM) treatment would be more effective than the PTH in unloaded (IM) limbs. One hundred and sixty 6-month-old rats were divided into aging and IM groups. The right hindlimb of the rat was immobilized by elastic bandage for 18 weeks, and then groups of rats were either kept IM or RM and treated with 30 microgram or 80 microgram of hPTH(1-38)/kg/day for 2, 10, and 20 weeks. Fluorescent-labeled, undecalcified cross-sections of right tibial shafts were studied. We found that RM for 20 weeks after 18 weeks of IM only partially recovered IM-induced muscle weight loss and PTH had no effect on muscle weight in either IM or RM limbs; that RM for 20 weeks after 18 weeks of IM partially restored some minimal cortical width by stimulating periosteal and endocortical bone formation and decreasing endocortical resorption; that PTH treatment of IM limbs completely restored IM-induced cortical bone loss and added extra bone by stimulating bone formation indices on all bone surfaces and depressing bone resorption on endocortical surface; that PTH treatment of RM limbs produced similar anabolic effects as in IM limbs with 30 microgram/kg/day dose but the 80 microgram/kg/day dose-treated limbs had a higher periosteal bone formation rate, which created a larger cross-sectional area, more cortical bone area, and a thicker cortex than the same dose treated IM limbs; and that PTH 80 microgram/kg/day treatment produced more anabolic effect than the 30 microgram/kg/day in both IM and RM limbs. We concluded that reloading the hindlimb by RM after long-term IM could not recover the cortical bone mass. PTH at employed doses was able to completely restore IM-induced cortical bone loss, and this effect was independent of mechanical stimulation. However, when PTH was combined with mechanical loading (RM), a synergistic anabolic effect on periosteal bone formation occurred which increased the cross sectional area that can increase bone strength.

Bone anabolic effects of basic fibroblast growth factor in ovariectomized rats.

The purpose of this study was to characterize the bone anabolic effects of basic fibroblast growth factor (bFGF) in ovariectomized (OVX) rats. Female Sprague Dawley rats were subjected to ovariectomy or sham surgery at 3 months of age and maintained untreated for 2 months post surgery. Groups of OVX rats were then treated iv with bFGF at doses of 100 or 200 microg/kg day for 7 or 14 days. Another group of OVX rats and a group of sham-operated control rats were treated iv with vehicle alone for 14 days. Certain groups of bFGF-treated OVX rats were killed at 7 or 14 days after withdrawal of treatment. The right tibiae were processed undecalcified for quantitative bone histomorphometry. Vehicle-treated OVX rats were characterized by decreased cancellous bone volume associated with increased bone turnover. Treatment of OVX rats with bFGF strongly stimulated bone formation, as indicated by marked increases of at least a factor of 10 in osteoblast surface, osteoid surface, and osteoid volume. Furthermore, new osteoid spicules were observed within the marrow cavity of these animals. Osteoclast surface was markedly decreased in bFGF-treated OVX rats, but this finding may be secondary to the extensive osteoid surface. The strongest bone anabolic effects occurred in OVX rats treated with the higher dose of bFGF for 14 days, but these animals exhibited a bone mineralization defect, as evidenced by abundant osteoid and a lack of double fluorochrome labeling, despite markedly increased osteoblast surface. However, the newly-formed osteoid rapidly calcified after withdrawal of bFGF treatment. The data indicate that bFGF not only stimulates bone formation on pre-existing bone surfaces but also induces de novo formation of bone spicules within the marrow cavity, which results in partial restoration of lost cancellous bone mass in osteopenic OVX rats after only 14 days of treatment with the growth factor. These findings suggest that bFGF merits consideration for development as a potential treatment for patients with severe osteopenia who are unresponsive to conventional osteoporosis therapies.

NG108-15 cells express neuregulin that induces AChR alpha-subunit synthesis in cultured myotubes.

A cholinergic neuroblastoma x glioma hybrid cell line NG108-15 is able to form functional synapses, and contains both AChR-aggregating and AChR-inducing activities when cocultured with myotubes. Several lines of evidence indicate that the AChR-inducing activity of NG108-15 cells is derived from neuregulin. The conditioned medium of cultured NG108-15 cells induced the expression of AChR alpha-subunit as well as the tyrosine phosphorylation of erbB-3 receptor. NG108-15 cells expressed neuregulin with a protein of approximately 100 kDa in size and transcripts of approximately 6.8 kbp, approximately 2.6 kbp and approximately 1.8 kbp; mRNAs encoding beta1 and alpha2 isoforms of neuregulin were revealed. NG108-15 cells were induced to differentiate by chemicals, and the chemical-induced differentiation of NG108-15 cells increased the level of neuregulin mRNA expression approximately 3-fold while the expression of a housekeeping gene remained relatively unchanged. The activity of neuregulin in the conditioned medium of NG108-15 cells was reduced by treating the medium with heparin and anti-neuregulin antibody. In addition, NG108-15 cells were transfected with antisense neuregulin cDNA and its expression of neuregulin was reduced, while its neuregulin-induced tyrosine phosphorylation activity was markedly decreased. This is the first direct demonstration that the NG108-15 cell-induced AChR upregulation on cultured myotubes is mediated by neuron-derived neuregulin.

Cerebellar granule cells express a specific isoform of agrin that lacks the acetylcholine receptor aggregating activity.

Agrin is a synapse-organizing molecule that mediates nerve-induced aggregation of acetylcholine receptors and other postsynaptic components at the developing and regenerating vertebrate neuromuscular junctions. Several lines of evidence indicate that agrin might play a similar role in directing the organization of postsynaptic specifications of neuron-neuron synapse formation. Here we used immunological methods and polymerase chain reaction to identify the expression of agrin protein and alternatively spliced mRNA isoforms in the culture of rat granule cells. Anti-agrin polyclonal antibody labeled the cultured granule cells and it detected a protein of over 200 kDa in size from the lysate of the cultured cells. Analysis by polymerase chain reaction showed that the granule cells in culture expressed predominantly the B0 isoform of agrin mRNA. When granule cells were co-cultured with primary chick myotubes, there was no detectable effect on the aggregation of acetylcholine receptors on the surface of the myotubes. These results show that the cerebellar granule cells, similar to motor neurons in vitro, express and secrete agrin but it lacks the acetylcholine receptor aggregating activity.

The EGF-like domain of chick acetylcholine receptor-inducing activity (ARIA) contains its full biological activity.

Acetylcholine receptor-inducing activity (ARIA) is a glycoprotein initially purified from chick brain based on its ability to increase the synthesis of acetylcholine receptor (AChR) on cultured myotubes. cDNA encoding ARIA contains different domains and the functions of each domain in ARIA activity are not known. We used molecular genetic methods to construct a chimeric fusion protein, designated ARIA(S136-K205)-Fc, that contained the leader sequence, the EGF-like domain of chick ARIA (S136 to K205) and the Fc region of human immunoglobulin. The ARIA(S136-K205)-Fc cDNA was transfected into HEK 293 cells and stable cell lines secreting soluble ARIA(S136-K205)-Fc were obtained. The secreted ARIA(S136-K205)-Fc has a molecular mass of approximately 60 kDa and can be purified by protein G chromatography. The purified ARIA(S136-K205)-Fc retained its full biological activity of chick ARIA that included: (i) induction of tyrosine phosphorylation of erbB 3 receptor in C2C12 myotubes; and (ii) approximately 12-fold stimulation of AChR alpha-subunit mRNA synthesis when applied onto cultured chick myotubes. This Fc-tagged ARIA could be rapidly purified and provides a very useful ligand for identifying its true receptor(s) on muscle cell surface.

Self-assembling nucleic acid delivery vehicles via linear, water-soluble, cyclodextrin-containing polymers.

Non-viral (synthetic) nucleic acid delivery systems have the potential to provide for the practical application of nucleic acid-based therapeutics. We have designed and prepared a tunable, non-viral nucleic acid delivery system that self-assembles with nucleic acids and centers around a new class of polymeric materials; namely, linear, water-soluble cyclodextrin-containing polymers. The relationships between polymer structure and gene delivery are illustrated, and the roles of the cyclodextrin moieties for minimizing toxicity and forming inclusion complexes in the self-assembly processes are highlighted. This vehicle is the first example of a polymer-based gene delivery system formed entirely by self-assembly.

Anabolic effects of basic fibroblast growth factor in the tibial diaphysis of ovariectomized rats.

The purpose of this study was to determine the effects of basic fibroblast growth factor (bFGF) on cortical bone in ovariectomized (ovx) rats. Female Sprague-Dawley rats were subjected to sham surgery or ovariectomy at 3 months of age and maintained untreated for 2 months after surgery. Polyurethane catheters were then inserted in the jugular veins of all rats for daily intravenous treatments with vehicle or bFGF at doses of 100 or 200 microg/kg for 7 or 14 days. Other groups of ovx rats were killed at 7 or 14 days after withdrawal of treatment with the higher dose of bFGF. Quantitative bone histomorphometry was performed in undecalcified cross sections of the tibial diaphysis. Cortical bone area was nearly the same in vehicle-treated control and ovx rats, but a small, statistically significant increase in this structural variable was observed in ovx rats treated with both doses of bFGF. This small increase in cortical bone area was maintained at 7 days after withdrawal of bFGF treatment. Fluorochrome-based analyses of periosteal and endocortical bone formation were inconclusive due to an inhibitory effect of bFGF on bone mineralization. However, a marked increase in fluorescent bone area was observed within the marrow cavity of bFGF-treated OVX rats during the withdrawal period. The results indicate that treatment of OVX rats with bFGF for only 7 to 14 days augments cortical bone mass and induces formation of bone spicules within the marrow cavity of the tibial diaphysis. These bone anabolic effects of the growth factor support its consideration as a potential osteoporosis therapy.

Effects of age, estrogen depletion, and parathyroid hormone treatment on vertebral cancellous wall width in female rats.

The main goal of this study was to determine whether vertebral cancellous wall width changes with age and parathyroid hormone (PTH) treatment in rats. Female Sprague-Dawley rats were subjected to sham surgery or ovariectomy at 3 months of age. One month after surgery, ovariectomized (ovx) rats were injected subcutaneously (s.c.) 5 days/week for 6 weeks with vehicle or human parathyroid hormone [hPTH (1-34)] at a dose of 80 microg/kg body weight. Sham-operated control rats were injected s.c. with vehicle alone. All rats from this first study were 5.5 months of age at the time of killing. In the second study, control and ovx rats were subjected to the same treatments for a 10-week period beginning at one year after surgery. These animals were 17.5 months of age at the end of the study. The first lumbar vertebra was collected from each rat and processed undecalcified for measurements of cancellous wall width. At 5.5 months of age, control and ovx rats had nearly identical mean values for vertebral cancellous wall width, but this remodeling variable was significantly increased in PTH-treated ovx rats. At 17.5 months of age, wall width in control and ovx rats decreased significantly compared with wall width in the younger rats. PTH treatment of aged ovx rats induced a significant increase in vertebral cancellous wall width when compared with vehicle treatment of aged ovx rats. These results, which are consistent with findings in humans, indicate that vertebral cancellous wall width decreases with age in intact female rats and in ovx rats, but increases in ovx rats in response to PTH treatment. Furthermore, the results add to the growing body of evidence that substantial cancellous bone remodeling occurs in the vertebral bodies of rats.

Decreased bone anabolic effect of basic fibroblast growth factor at fatty marrow sites in ovariectomized rats.

The purpose of the study was to compare the bone anabolic effects of basic fibroblast growth factor (bFGF) at hematopoietic (red) and fatty (yellow) marrow sites in ovariectomized (ovx) rats. Female Sprague Dawley rats were subjected to ovariectomy or sham surgery at 3 months of age and maintained untreated for 2 months after surgery. Three groups of ovx rats were then injected intravenously with bFGF for 14 days at a dose of 200 microg/kg body weight. One group of bFGF-treated OVX rats was killed at the end of the treatment period, whereas the other two groups were killed at 7 or 14 days after withdrawal of bFGF treatment. Another group of ovx rats and a group of sham-operated control rats were treated intravenously with vehicle alone for 14 days. The proximal tibia and first lumbar vertebra, bone sites with hematopoietic marrow, as well as the distal tibia and caudal vertebra, bone sites with primarily fatty marrow, were processed undecalcified for quantitative bone histomorphometry. At the hematopoietic marrow sites, bFGF treatment induced a marked accumulation of osteoid, which calcified during the withdrawal period to result in a significant increase in cancellous bone volume. Osteoblast and osteoid surfaces were increased by at least a factor of 10 at these sites in bFGF-treated ovx rats before declining rapidly during the withdrawal period. In contrast, osteoid volume was negligible in the fatty marrow sites of bFGF-treated ovx rats. Although these animals exhibited a nonsignificant trend for increased cancellous bone volume in the fatty distal tibia during the withdrawal period, no such trend was observed in the fatty caudal vertebra. Indices of bone formation (osteoblast and osteoid surfaces) were significantly increased by bFGF treatment in the fatty distal tibia, which retained some small pockets of hematopoietic cells, but not to the same great extent as in the skeletal sites with hematopoietic marrow. Furthermore, not even a trend for increased osteoblast and osteoid surfaces was observed in the fatty caudal vertebra of bFGF-treated ovx rats. These findings indicate that bFGF is a strong bone anabolic agent at skeletal sites with hematopoietic marrow, but the stimulatory effects of the growth factor on bone formation are greatly attenuated at fatty marrow sites.

Transforming growth factor-beta administration modifies cyclosporine A-induced bone loss.

Cyclosporine A (CsA), a potent immunosuppressant used in transplantation, induces increased formation with excess resorption in the rat with resultant osteopenia. These findings are confirmed in the human model. Transforming growth factor-beta (TGF-beta) is reported to be involved in the coupling of bone formation with resorption and in vivo and in vitro stimulates osteoblasts, and in vitro inhibits osteoclasts. CsA stimulates secretion of TGF-beta1 in humans, which, while improving immunosuppression, may also contribute to renal toxicity. This study was performed determine whether exogenously administered TGF-beta would modify the bone effects of CsA. Male Sprague-Dawley rats, 6 months of age, were randomized to receive: TGF-beta and CsA vehicle (group A); TGF-beta 5 microg/kg three times per week and CsA vehicle (group B); TGF-beta vehicle and CsA 10 mg/kg (group C); or TGF-beta 5 microg/kg three times per week and CsA 10 mg/kg (group D). These were compared with control over 28 days. CsA, but not TGF-beta, increased serum 1,25(OH)(2)D levels throughout the study. CsA increased osteocalcin (BGP), but TGF-beta negated this effect. Histomorphometry confirmed the known effects of CsA, whereas TGF-beta alone had no effect. However, in combination, TGF-beta blocked CsA's effect and increased osteoblast recruitment and activity, as reflected by increased percent mineralizing surface, percent osteoid perimeter, bone formation rate (bone volume referent), and activation frequency. Thus, it appears as if TGF-beta administration may have potential in modulating the deleterious bone effects of CsA.

Specific bone-protective effects of metabolites/derivatives of tamoxifen and clomiphene in ovariectomized rats.

In the ovariectomized (ovx) rat, the nonsteroidal antiestrogens, clomiphene (CLO) and tamoxifen (TAM), at dose levels that prevent development of osteopenia to a degree approaching that of 17beta-estradiol are, in contrast to 17beta-estradiol, only weakly uterotrophic. Metabolites of CLO and TAM might contribute differentially to these effects. Thus, we have evaluated bone protective and uterine effects in ovx rats of two such metabolites: 4-hydroxy CLO, produced by p-hydroxylation of CLO; and 4HTA, produced from TAM by stepwise replacement of its dimethylaminoethyl side chain with an acetic acid moiety, accompanied by p-hydroxylation. Also reported are effects of D4HTA, the dihydrodesethyl derivative of 4HTA previously characterized as a full estrogen mimetic in vitro. Administration of 4-hydroxy CLO (2.5 mg/kg subcutaneously) 5 days/week for 5 weeks to 3-month-old ovx rats resulted in complete prevention of bone loss and suppression of bone turnover to levels comparable to those of intact controls and to those of ovx animals similarly receiving 17beta-estradiol (10 microg/kg). However, uterine weight in animals receiving 4-hydroxy CLO was 64% less than that in 17beta-estradiol-treated animals. Although 4HTA (3.7 mg/kg s.c.) had a modest uterotrophic effect, it did not prevent bone loss associated with ovariectomy. In contrast, D4HTA (3.6 mg/kg s.c.) partially reduced bone turnover indicators and cancellous bone loss in a manner similar in many ways to that observed in TAM-treated ovx animals, but it had no uterotrophic effect. These results suggest that, although 4HTA does not contribute to the bone-protective effect of TAM, 4-hydroxy CLO might augment that of CLO.

Mycophenolate mofetil: a promising new immunosuppressant that does not cause bone loss in the rat.

BACKGROUND: Posttransplantation bone disease is a well-described phenomenon; among its etiology is immunosuppressant-induced bone disease. Mycophenolate mofetil (MMF) has emerged as a promising new immunosuppressant. Our study was designed to investigate the effect of MMF on in vivo bone mineral metabolism. METHODS: Twenty-four 6-month-old male Sprague-Dawley rats were randomized into two groups to receive either MMF vehicle daily for 28 days or 30 mg/kg MMF daily for 28 days. The serum was assayed for osteocalcin and 1,25-dihydroxy vitamin D3. Subsequent to double-labeling, the right tibiae were removed on day 28 for histomorphometry. RESULTS: MMF suppressed bone gla protein (osteocalcin) levels on days 14 and 28 (P < 0.05). Except for percentage osteoid perimeter, there was no difference in bone histomorphometry between the two groups. CONCLUSION: In this relatively short-term study, MMF did not cause osteopenia in the rat model, but the suppressed bone gla protein merits further study.