Ficus exasperata Vahl leaves extract attenuates motor deficit in vanadium-induced parkinsonism mice.

Medicinal herbs have played significant roles in the treatment of various diseases in humans and animals. Sodium metavanadate is a potentially toxic environmental pollutant that induces oxidative damage, neurological disorder, Parkinsonism and Parkinson-like disease upon excessive exposure. This study is designed to investigate the impact of saponin fraction of Ficus exasperata Vahl leaf extract (at 50 and 100 mg/kg body weight for 14 days at different animal groupings) on vanadium treated mice. Animals were randomly grouped into five groups. Control (normal saline), NaVO3 (10 mg/kg for 7 days), withdrawal group, NaVO3+Vahl (low dose) and NaVO3+Vahl (high dose). The animals were screened for motor coordination using rotarod and PBTs and a post mortem study was conducted by quantitatively assessing the markers of oxidative stress such as lipid peroxidation, catalase, glutathione activities, and also through immunohistochemistry via glia fibrillary acidic protein, tyrosine hydroxylase and dopamine transporter to study the integrity of astrocytes and dopaminergic neurons of the substantia nigra (SNc). Vanadium-exposed group showed a decreased motor activity on the neurobehavioural tests as well as an increase in markers of oxidative stress. Saponin fraction of F. exasperata Vahl leaves extract produced a statistically significant motor improvement which may be due to high antioxidant activities of saponin, thereby providing an ameliorative effect on the histoarchitecture of the SNc. It can be inferred that the saponin fraction of F. exasperata Vahl leaves extract to possesses ameliorative, motor-enhancing and neurorestorative benefit on motor deficit in vanadium-induced parkinsonism mice.

Ficus exasperata Vahl leaves extract attenuates motor deficit in vanadium-induced parkinsonism mice / 대한해부학회지

Medicinal herbs have played significant roles in the treatment of various diseases in humans and animals. Sodium metavanadate is a potentially toxic environmental pollutant that induces oxidative damage, neurological disorder, Parkinsonism and Parkinson-like disease upon excessive exposure. This study is designed to investigate the impact of saponin fraction of Ficus exasperata Vahl leaf extract (at 50 and 100 mg/kg body weight for 14 days at different animal groupings) on vanadium treated mice. Animals were randomly grouped into five groups. Control (normal saline), NaVO3 (10 mg/kg for 7 days), withdrawal group, NaVO3+Vahl (low dose) and NaVO3+Vahl (high dose). The animals were screened for motor coordination using rotarod and PBTs and a post mortem study was conducted by quantitatively assessing the markers of oxidative stress such as lipid peroxidation, catalase, glutathione activities, and also through immunohistochemistry via glia fibrillary acidic protein, tyrosine hydroxylase and dopamine transporter to study the integrity of astrocytes and dopaminergic neurons of the substantia nigra (SNc). Vanadium-exposed group showed a decreased motor activity on the neurobehavioural tests as well as an increase in markers of oxidative stress. Saponin fraction of F. exasperata Vahl leaves extract produced a statistically significant motor improvement which may be due to high antioxidant activities of saponin, thereby providing an ameliorative effect on the histoarchitecture of the SNc. It can be inferred that the saponin fraction of F. exasperata Vahl leaves extract to possesses ameliorative, motor-enhancing and neurorestorative benefit on motor deficit in vanadium-induced parkinsonism mice.

Ficus exasperata Vahl leaves extract attenuates motor deficit in vanadium-induced parkinsonism mice / 대한해부학회지

Medicinal herbs have played significant roles in the treatment of various diseases in humans and animals. Sodium metavanadate is a potentially toxic environmental pollutant that induces oxidative damage, neurological disorder, Parkinsonism and Parkinson-like disease upon excessive exposure. This study is designed to investigate the impact of saponin fraction of Ficus exasperata Vahl leaf extract (at 50 and 100 mg/kg body weight for 14 days at different animal groupings) on vanadium treated mice. Animals were randomly grouped into five groups. Control (normal saline), NaVO3 (10 mg/kg for 7 days), withdrawal group, NaVO3+Vahl (low dose) and NaVO3+Vahl (high dose). The animals were screened for motor coordination using rotarod and PBTs and a post mortem study was conducted by quantitatively assessing the markers of oxidative stress such as lipid peroxidation, catalase, glutathione activities, and also through immunohistochemistry via glia fibrillary acidic protein, tyrosine hydroxylase and dopamine transporter to study the integrity of astrocytes and dopaminergic neurons of the substantia nigra (SNc). Vanadium-exposed group showed a decreased motor activity on the neurobehavioural tests as well as an increase in markers of oxidative stress. Saponin fraction of F. exasperata Vahl leaves extract produced a statistically significant motor improvement which may be due to high antioxidant activities of saponin, thereby providing an ameliorative effect on the histoarchitecture of the SNc. It can be inferred that the saponin fraction of F. exasperata Vahl leaves extract to possesses ameliorative, motor-enhancing and neurorestorative benefit on motor deficit in vanadium-induced parkinsonism mice.

Resection of the sciatic, peroneal, or tibial nerves: assessment of functional status.

BACKGROUND: Lower-extremity tumors are often treated by amputation rather than limb-sparing excision that sacrifices the sciatic nerve or a branch. This study assessed the functional outcome of major nerve sacrifice during limb-sparing resections for lower-extremity soft tissue sarcoma. METHODS: Patients who underwent division of the sciatic, tibial, or peroneal nerve(s) during limb-sparing sarcoma surgery (January 1982 through June 2000) were identified. Eleven surviving patients evaluated their pre- and postoperative functional status by self-administered questionnaire (six sciatic, two tibial, and three peroneal nerve divisions). RESULTS: Eighteen patients (10 male, 8 female; 14-84 years old) had nine primary and nine locally recurrent tumors. Tumors were high (16) or low grade (two). Five patients died of disease and two died of other causes. Median overall survival was 50 months. One of 11 reported increased pain. Eight had new phantom sensations with a median intensity of 4.5 (1 = least; 10 = most). All patients used an ankle brace to walk after a sciatic (four) or peroneal (one) division. Walking ability and distance after surgery was unchanged (nine), improved (one), and worsened (one). Standing improved in 7 of 11 patients. Proprioception in the affected extremity was retained in six. The median postoperative leg functional score was 8 (1 = worst; 10 = best). No patient developed foot ulcers. One patient underwent amputation for recurrence. All patients preferred their status over having an amputation. CONCLUSIONS: Objectively and subjectively, division of the major lower-extremity nerves causes acceptable functional deficits in most patients. Resection of affected sciatic nerve (branches) during limb-sparing tumor surgery is an excellent alternative to amputation.

A preliminary open label dose comparison using an antioxidant regimen to determine the effect on viral load and oxidative stress in men with HIV/AIDS.

OBJECTIVE: To investigate the effect of antioxidant supplementation on viral load and the antioxidant/reactive oxygen species system in people with HIV. DESIGN: Single centre, prospective, dose comparison study. SETTING: Outpatient clinic specializing in HIV care. SUBJECTS: Sixty-six participants were sequentially recruited by advertisement, and 48 subjects completed the study. INTERVENTIONS: A recommended dose antioxidant regimen (5,450 IU vitamin A as beta-carotene, 250 mg vitamin C, 100 IU vitamin E, 100 microg selenium, 50 mg coenzyme Q10) or a high-dose antioxidant regimen (21,800 IU vitamin A as beta-carotene, 1,000 mg vitamin C, 400 IU vitamin E, 200 microg selenium, 200 mg coenzyme Q10) for a 12 week period. RESULTS: Using repeated measures analysis of variance, the changes over treatment time were significant for selenium, glutathione, glutathione peroxidase and lipid peroxides (P < 0.03). Changes in allantoin, uric acid and viral load were not significant (P > 0.05). The main effects for group and the interaction effects were not significant for any of the parameters measured (P > or = 0.05). CONCLUSION: Antioxidant supplementation significantly improved some measures of oxidative defence. There was no benefit in using a high-dose supplement in this study.

A do-it-yourself membrane-activated auditory feedback device for weight bearing and gait training: a case report.

An augmented auditory feedback device comprised of a thin membrane switch mini-buzzer, and battery is described as a modification of a previously described feedback device. The membrane switch can be customized for the patient and is designed to fit inside a patient's shoe without altering the heel height. Its appeal lies in its simplicity of construction, low cost, and ease of implementation during a patient's training for weight bearing and gait. An ever-present source of information, it provides performance-relevant cues to both patient and clinician about the occurrence, duration, and location of a force component of motor performance. The report includes suggested applications of the device, instructions to construct it, and a case report in which the device was used to improve weight bearing and gait in a cognitively healthy person with spina bifida.

Herbal-drug therapy interactions: a focus on dementia.

Older people with dementia are often prescribed numerous medications. Use of herbal therapies in addition to these conventional drug therapies may lead to interactions that result in an adverse drug event. We have conducted a systematic review to identify all studies that examined interactions between herbal and conventional drug therapies (i.e. prescription or over-the-counter). Using a MEDLINE search of English-language studies published between 1980 and 2000, we limited our search to those herbal therapies most likely to be used for the treatment of dementia (memory loss and decreased concentration) and related symptoms. We identified 28 articles that describe interactions between these herbal (i.e. St. John's wort, ginkgo biloba, kava, valerian, and ginseng) and conventional drug therapies. Of these articles, 11 examined St. John's wort, four examined ginkgo biloba, five examined kava, one examined valerian, and seven examined ginseng. We identified a series of potential interactions between herbal and conventional drug therapy that place older people at risk for an adverse drug event. Health care professionals need to be aware of these potential interactions.

Effects of contextual processing on visual conditional associative learning in schizophrenia.

BACKGROUND: We adapted visual conditional associative learning paradigms to assess the contextual processing deficit model of schizophrenic cognitive impairment proposed by J.D. Cohen and D. Servan-Schreiber in 1992. In this task subjects learn the associations between four sets of stimuli through the use of feedback. We administered two experimental conditional associative learning conditions: in one, the eight stimuli used to make four pairs were all different; in the other, the pairs were made from different combinations of four identical stimuli, requiring the use of contextual information to mediate correct performance. Two additional associative learning tasks were administered where subjects generated the stimulus pairings or observed the experimenter form the pairs, eliminating the need to learn from feedback. METHODS: We tested 37 patients with schizophrenia and 20 healthy control subjects in each conditional associative learning task condition. RESULTS: Patients demonstrated significant impairments on all four conditional associative learning tasks. The demand to process contextual information did not differentially impact patient performance. Patients were better able to learn associations if they generated or observed the pairings rather than utilized feedback to guide learning. CONCLUSIONS: Patients with schizophrenia demonstrate pronounced deficits in the ability to utilize feedback to guide learning. We found no evidence of an additional deficit in processing of contextual information.

Effect of the intensity of transcutaneous acupoint electrical stimulation on the postoperative analgesic requirement.

Given the inherent side effects associated with both opioid and nonopioid analgesic drugs, a nonpharmacologic therapy that could decrease the need for analgesic medication would be valuable. We designed a sham-controlled study to assess the effect of the intensity of transcutaneous acupoint electrical stimulation (TAES) on postoperative patient-controlled analgesia (PCA) requirement for hydromorphone (HM), the incidence of opioid-related side effects, and the recovery profile after lower abdominal surgery. One hundred one healthy consenting women undergoing lower abdominal procedures with a standardized general anesthetic technique were randomly assigned to one of four postoperative analgesic treatment regimens: Group I (n = 26) PCA only; Group II (n = 25), PCA + sham-TAES (no electrical stimulation); Group III (n = 25), PCA + low-TAES (4-5 mA of electrical stimulation); Group IV (n = 25), PCA + high-TAES (9-12 mA of electrical stimulation). The PCA device was programmed to deliver HM, 0.2-0.4 mg intravenously boluses "on demand," with a minimum lockout interval of 10 min. The TAES skin electrodes were placed at the Hegu acupoint on the nondominant hand and on both sides of the surgical incision. The TAES frequency was set in the dense-and-disperse mode, alternating at 2 Hz and 100 Hz every 3 s, with stimulation of the hand and incision alternated every 6 s. The patients in Groups II-IV were instructed to use TAES every 2 h for 30 min while awake. After discontinuation of PCA, oral pain medications were administered on demand. The postoperative PCA-HM requirement, pain scores, opioid-related side effects, and requirements for antiemetic and antipruritic medication were recorded. High-TAES decreased the HM requirement by 65% and reduced the duration of PCA therapy, as well as the incidence of nausea, dizziness, and pruritus. Low-TAES produced a 34% decrease in the HM requirement compared with only 23% in the "sham" TAES group. We conclude that high-TAES produced a significant decrease in the PCA opioid requirement and opioid-related side effects after low intraabdominal surgery.

Intraoperative autologous blood donation preserves red cell mass but does not decrease postoperative bleeding.

BACKGROUND: Postoperative bleeding and transfusion remain a source of morbidity and cost after open heart operations. The benefit of the acute removal and reinfusion of fresh autologous blood around the time of cardiopulmonary bypass-a technique known as intraoperative autologous donation (IAD)-has not been universally accepted. We sought to more clearly evaluate the effects of IAD on allogeneic transfusion and postoperative bleeding by removing, preserving, and reinfusing a calculated maximum volume of fresh autologous whole blood. METHODS: Ninety patients undergoing coronary artery bypass grafting or valvular operations were prospectively randomized to either have (IAD group) or not have (control group) calculated maximum volume IAD performed. Treatment was otherwise identical. Transfusion guidelines were uniformly applied to all patients. RESULTS: An average volume of 1,540 +/- 302 mL of fresh autologous blood was removed and reinfused in the IAD group. Postoperative hematocrits were significantly greater at 12 and 24 hours postoperatively in the IAD group versus the control group despite a significant decrease in both the percentage of patients in whom allogeneic red blood cells were transfused (17% versus 52%; p < 0.01) and the number of red blood cell units transfused per patient per group (0.28 +/- 0.66 and 1.14 +/- 1.19 units; p < 0.01). Conversely, chest tube output, incidence of excessive postoperative bleeding, postoperative prothrombin time, and platelet and coagulation factor transfusion requirement did not differ between groups. CONCLUSIONS: These results indicate that intraoperative autologous donation serves to preserve red blood cell mass. Its routine use in eligible patients is therefore justified. However, the removal and reinfusion of an individually calculated maximum volume of fresh autologous blood had no effect on postoperative bleeding or platelet and coagulation factor transfusion requirement. This lack of hemostatic effect belies the beliefs of many about the primary action of IAD, helps to delineate the optimal way in which to perform IAD, and carries implications regarding the use of allogeneic platelet and coagulation factors for the treatment of early postoperative bleeding.

Ex vivo activated memory T-lymphocytes as adoptive cellular therapy of human soft-tissue sarcoma targets with potentiation by cis-diamminedichloroplatinum(II).

Autolymphocyte therapy (ALT) is tumor-specific, adoptive cellular therapy of neoplastic disease using nonspecific ex vivo activation of autologous peripheral blood lymphocytes (PBL), which are composed primarily of memory T-cells (ALT-cells) and are active in patients with metastatic renal cell carcinoma and melanoma. Ex vivo pretreatment of tumor target cells with certain chemotherapeutic agents can enhance susceptibility to lysis by antitumor lymphocytes. To determine if cis-diamminedichloroplatinum(II) (CDDP) enhances ex vivo antitumor cytotoxicity of ALT-cells and if this lysis is mediated by T- and/or NK-cells and is human leukocyte antigen (HLA)-restricted, human soft tissue sarcoma (STS) target cells were derived from primary and metastatic surgical specimens and were incubated with and without CDDP. ALT-cells were prepared from autologous PBL obtained prior to surgery. Primary (PSTS) and metastatic (MSTS) target cells from each group were labelled with chromium 51 (51Cr) and used as targets for ALT-cells, CD45-depleted ALT-cells, CD56 (NK)-depleted ALT-cells, and PBL in a standard (4-hour) and delayed (18-hour) 51Cr release assay. Interferon-gamma (IFN-gamma) release was measured as an indication of antitumor effect and recognition by the noncytolytic lymphocytes in ALT-cells. Primary tumor target cells incubated in CDDP showed enhanced lysis as measured by the 51Cr release assay compared to non-CDDP-treated controls. Metastatic tumor target cells showed less lysis than the primary targets, although this was enhanced by pretreating metastatic tumor targets with CDDP. Lysis of all tumor targets was significantly greater when ALT-cells were used as the effector cells rather than PBL. Depletion of memory T-cells abrogated ex vivo lysis. Depletion of NK cells (CD56+) affected ex vivo lysis of autologous targets during the 4-hour but not the 18-hour assay. Ex vivo ALT-cell lysis and IFN-gamma release against only the autologous tumor targets confirmed tumor-specificity in one patient. Restriction of ALT-cell lysis and IFN-gamma release against HLA-A2+ autologous and one allogeneic HLA-A2+ STS tumor target, but not other non-STS targets, was demonstrated in another patient. These data suggest that CDDP may help render STS susceptible to tumor-specific, immune-mediated attack and that the combination of ALT and CDDP may lead to effective tumor-specific chemoimmunotherapy in patients with metastatic STS.

Cytoplasmic tail deletion of T cell receptor (TCR) beta-chain results in its surface expression as glycosylphosphatidylinositol-anchored polypeptide on mature T cells in the absence of TCR-alpha.

Surface expression of the T cell antigen receptor (TCR) in mature T cells requires the association of a variable heterodimer (alpha.beta or gamma.delta) with six invariant CD3 polypeptides (gamma, delta, epsilon-epsilon, zeta-zeta, or zeta-eta). We described here that deletion of the cytoplasmic tail polypeptide sequence (Lys-Lys-Lys-Asn-Ser) of TCR beta-chain (beta CT) results in expression of the truncated beta-chain on the surface of a mature T cell hybridoma line, in the absence of TCR-alpha, as a glycophosphatidylinositol (GPI)-anchored monomeric polypeptide. The GPI-anchored TCR-beta CT is not associated with CD3-epsilon and is incapable of conventional signal transduction. Association with TCR-alpha prevents beta CT from GPI-linkage formation. The alpha beta CT heterodimer binds the CD3 polypeptides, and the resultant TCR alpha beta CT/CD3 complex is capable of signal transduction. Our data show that a signal sequence for GPI-linkage formation is present in TCR-beta, and this alternative membrane anchoring mechanism can be utilized by beta-chain polypeptide lacking the CT sequence. We conclude therefore that in the absence of TCR-alpha expression, the beta-chain CT sequence plays an essential function in hindering GPI-linkage formation, thereby preventing escape of incompletely assembled TCR beta-chain to the cell surface of mature T cells.

Autolymphocyte therapy--I. In vivo tumour-specific adoptive cellular therapy of murine melanoma and carcinoma using ex vivo activated memory T-lymphocytes.

Autolymphocyte therapy (ALT) is tumour-specific adoptive cellular therapy of neoplastic disease based upon non-specific ex vivo activation of autologous peripheral blood lymphocytes (PBL), using the supernatant derived from a previously prepared one-way mixed lymphocyte culture (MLC). To determine the requirement for tumour antigen during the activation process, splenocytes from C57BL/6J healthy syngeneic mice (HSM) and tumour-bearing mice (TBM) were activated ex vivo using a MLC-supernatant (MLCS). Ex vivo activation was performed both in the presence (HSM splenocytes) and absence (TBM splenocytes) of a 3M KC1 syngeneic tumour-antigen (STA) extract prepared from Lewis lung (3LL) carcinoma, B16 melanoma, or normal lung. Immunophenotyping of splenocytes pre- and post-activation by MLCS plus STA or MLCS only revealed expansion of activated CD44+ (memory) T-cells. Ex vivo tumour-specific cytotoxicity was demonstrated using MLCS-activated (TBM) or MLCS + STA-activated (HSM) splenocytes against 3LL or B16 target cells. CD44+ T-cells (ALT-cells) were then infused into synegeneic 3LL and B16 TBM. Significant antitumour activity was detected in 3LL and B16 TBM receiving cells from normal mice that were activated with MLCS in the presence of 3LL or B16 STA, respectively, and in 3LL and B16 TBM receiving splenocytes from 3LL-TBM and B16-TBM, respectively, activated by MLCS alone. Infusions of 3LL-derived or B16-derived ALT-cells into HSM provided specific immunity on tumour challenge. No antitumour activity was seen in 3LL and B16 TBM receiving fresh TBM splenocytes, ALT-cells derived from HSM which were activated ex vivo using MLCS without antigen, normal lung tissue as antigen, or using MLCS-activated splenocytes without STA derived from reciprocal TBM. Ex vivo depletion of CD44+ cells or Thy-1.2+ T-cells abrogated all antitumour activity in TBM and in HSM challenged with tumour. Depletion of NK-1.1+ natural killer (NK)-cells had no effect on antitumour efficacy. These data suggest that tumour-specific adoptive cellular therapy is possible using ex vivo activated HSM splenocytes with STA, or TBM splenocytes activated ex vivo without STA, and that these antitumour effects are dependent on CD44+ memory T-cells.

Erythropoietin in cardiac surgery.

Erythropoietin is the primary growth factor for red blood cells. A glycoprotein hormone synthesized by the kidneys, erythropoietin serves to increase red blood cell production in response to tissue hypoxia. It exerts its effect by increasing the numbers of erythroid progenitor cells in the bone marrow, and by increasing the rate at which their development is accomplished. With the introduction of recombinant erythropoietin in 1987, an important pharmacological agent became available for the manipulation of erythropoiesis. While used primarily for the treatment of the anemia of renal failure, recombinant erythropoietin has also shown usefulness in treating other types of anemias in which the endogenous erythropoietin response is insufficient. Perioperative use of the drug grew as a natural extension of this, and erythropoietin has been applied to correct preoperative anemia, augment autologous blood donation, and improve postoperative red cell recovery. Analysis of these perioperative clinical studies reveals success in these areas, but it also reveals that closer attention to the physiology of the natural response, and to the pharmacology of the recombinant product, might significantly improve results. Such an improvement in efficacy is both desirable and necessary when use of the drug is viewed in the setting of today's changing health care environment. By optimizing dosing schedules and targeting the drug to those most at risk for red cell transfusion, recombinant erythropoietin will likely become an important tool in efforts to achieve the elusive goal of bloodless cardiac surgery.

Phototoxicity of tin protoporphyrin, tin mesoporphyrin, and tin diiododeuteroporphyrin under neonatal phototherapy conditions.

Tin metalloporphyrins are being considered as therapeutic agents for neonatal hyperbilirubinemia, and it is possible that concurrent exposure to phototherapy will occur during their use. Euthymic hairless guinea pigs, Crl:IAF(HA)BR, were given daily intraperitoneal injections of tin protoporphyrin (SnPP), tin mesoporphyrin (SnMP), or tin diiododeuteroporphyrin (SnI2DP) for 3 successive days. They were concurrently exposed to ambient light or two different kinds of phototherapy light under conditions similar to that found in neonatal intensive care units. Phototherapy light exposure was for a continuous period of approximately 72 hours following the first injection of metalloporphyrin. The presence or absence of phototoxicity under these conditions was determined by observations for an erythematous response on the back and ears of the guinea pigs. The dosages used were 0.75, 3.75, and 7.5 mg/kg per day of SnPP, 0.075, 0.375, and 0.75 mg/kg per day of SnMP, and 0.9, 4.5, and 9.0 mg/kg per day of SnI2DP. These dosages for each drug were approximately 1 times, 5 times, and 10 times, respectively, the maximum anticipated clinical dosage. At equal multiples of the clinical dosages, SnI2DP was less phototoxic than SnPP, and SnMP was the least phototoxic of the three compounds. SnPP was marginally phototoxic at the lowest dosage. SnMP was phototoxic only at the highest dosage under phototherapy light emitting ultraviolet A irradiation, but when phototherapy light not emitting ultraviolet A irradiation was used, SnMP was not phototoxic. In all cases, the phototoxic response was reversible when the drug and phototherapy treatment were discontinued.

The prevalence of the Wernicke-Korsakoff syndrome in Sydney, Australia: a prospective necropsy study.

In a prospective necropsy study, the prevalence of the Wernicke-Korsakoff syndrome (WKS) in Sydney, Australia was 2.1% of adults over the age of 15 years. The population studied encompassed a wide spectrum of socio-economic and cultural backgrounds. Abuse of alcohol appeared to be the major predisposing factor to the development of the WKS in cases which were adequately documented. This high prevalence rate is in line with other clinical and pathological Australian studies and provides additional support for the idea of prevention of the WKS by the use of thiamin supplements in the Australian diet in flour, bread and perhaps alcoholic beverages.

In vivo synergy of vitamin K3 and methotrexate in tumor-bearing animals.

In vivo synergy was demonstrated with vitamin K3 (menadione) and methotrexate in rats bearing the Walker 256 im carcinosarcoma, without concomitant increase in toxicity. Synergy is defined as a combined antitumor effect which exceeds the sum of the individual antitumor effects. It is suggested that such synergy, extended to human neoplasms, may significantly increase the effectiveness of methotrexate as a chemotherapeutic agent.