Identification of 32 novel mutations in the factor VIII gene in Indian patients with hemophilia A

Seventy-five unrelated hemophilia A patients from India were analyzed for factor VIII gene defects. Intron 22 inversion was identified in 22 patients and intron 1 inversion in 2 patients. In the remaining 51 patients without inversions screening the FVIII gene by denaturing high performance liquid chromatography (DHPLC) revealed 42 different mutations in 44 unrelated subjects. These included 14 missense, 7 nonsense, 9 splice site, 8 deletional, 3 insertional mutations and one indel mutation. Of these, 32 were novel gene alterations. The hotspots included intron 22 inversion, CpG and adenine runs.     

Subdiuretic dose of furosemide enhances albuterol effects in asthmatic mice rather than bumetanide

Background

One of the loop diuretics, furosemide, was found useful in bronchial asthma. It enhanced anti-asthmatic effects of albuterol. The underlying mechanism is still unclear.

Improved Survival with Anti-VEGF Therapy in the Treatment of Unresectable Appendiceal Epithelial Neoplasms

Annals of Surgical Oncology - Currently, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are accepted treatments for surgically resectable appendiceal epithelial neoplasms....     

Anticonvulsant activities of nutmeg oil of Myristica fragrans

The purpose of this study was to investigate the anticonvulsant activity of the volatile oil of nutmeg, the dried seed kernel of Myristica fragrans Houtt, using well‐established animal seizure models and to evaluate its potential for acute toxicity and acute neurotoxicity. The volatile oil of nutmeg (nutmeg oil) was tested for its effects in maximal electroshock, subcutaneous pentylenetetrazole, strychnine and bicuculline seizure tests. All the experiments were performed at the time of peak effect of nutmeg oil. Nutmeg oil showed a rapid onset of action and short duration of anticonvulsant effect. It was found to possess significant anticonvulsant activity against electroshock‐induced hind limb tonic extension. It exhibited dose dependent anticonvulsant activity against pentylenetetrazole‐induced tonic seizures. It delayed the onset of hind limb tonic extensor jerks induced by strychnine. It was anticonvulsant at lower doses, whereas weak proconvulsant at a higher dose against pentylenetetrazole and bicuculline induced clonic seizures. Nutmeg oil was found to possess wide therapeutic margin, as it did not induce motor impairment when tested up to 600 µL/kg in the inverted screen acute neurotoxicity test. Furthermore, the LD₅₀ (2150 µL/kg) value was much higher than its anticonvulsant doses (50–300 µL/kg). The results indicate that nutmeg oil may be effective against grand mal and partial seizures, as it prevents seizure spread in a set of established animal models. Slight potentiation of clonic seizure activity limits its use for the treatment of myoclonic and absence seizures. Copyright © 2008 John Wiley & Sons, Ltd.     

5-phenylthioacyclouridine: a potent and specific inhibitor of uridine phosphorylase

5-Phenylthioacyclouridine (PTAU or 1-[(2-hydroxyethoxy)methyl]-5-phenylthiouracil) was synthesized as a highly specific and potent inhibitor of uridine phosphorylase (UrdPase, EC 2.4.2.3). PTAU has inhibition constant (K(is)) values of 248 and 353 nM towards UrdPase from mouse and human livers, respectively. PTAU was neither an inhibitor nor a substrate for thymidine phosphorylase (EC 2.4.2.4), uridine-cytidine kinase (EC 2. 7.1.48), thymidine kinase (EC 2.7.1.21), dihydrouracil dehydrogenase (EC 1.3.1.2), orotate phosphoribosyltransferase (EC 2.4.2.10), or orotidine 5'-monophosphate decarboxylase (EC 4.1.2.23), the enzymes that could utilize the substrate (uridine or thymidine) or products (uracil or thymine) of UrdPase. Different isomers of 5-tolylthiouracil also were synthesized and tested as inhibitors of UrdPase. The meta-substituted isomer was 3- to 4-fold more potent as an inhibitor of UrdPase than the para- or ortho-substituted isomers. These data indicate that the hydrophobic pocket in the active site of UrdPase adjacent to the 5-position of the pyrimidine ring can accommodate the meta-substituted 5-phenyluracils better than the other isomers, leading to improved inhibition. Therefore, it is anticipated that the potency of PTAU can be increased further by the addition of certain hydrophobic groups at the meta position of the phenyl ring. PTAU has potential usefulness in the therapy of cancer and AIDS as well as other pathological and physiological disorders that can be remedied by the administration of uridine.     

The analgesic,anti-inflammatory and calcium antagonist potential of<Emphasis Type="Italic">Tanacetum artemisioides</Emphasis>

Several species of the genus Tanacetum are traditionally used in a variety of health conditions including pain, inflammation, respiratory and gastrointestinal disorders. In the current investigation, we evaluated the plant extract of T. artemisioides and some of its pure compounds (flavonoids) for analgesic, anti-inflammatory and calcium antagonist effects in various in-vivo and in vitro studies. Using the actetic acid induced writhing test, intraperitoneal (i.p) administration of the plant extract (25-50 mg/kg) and its flavonoid compounds TA-1 and TA-2 (1-5 mg/kg ) exhibited significant analgesic actvity. The maximum analgesic effect observed with the crude extract of the plant was 71% at 50 mg/kg, while that of compounds TA-1 and TA-2 (5 mg/kg i.p) was 75 and 47%, respectively. The plant extract and its pure compounds caused inhbition of formalin induced paw licking in mice predominatly in the second phase of the test. Diclofenac sodium, a standard reference compound, showed a simlar effect in these chemical induced pain models. In the carrgeenan induced rat paw edema assay, the plant extract (50-200 mg/kg i.p) demonstrated significant (P< 0.01) anti-inflammatory activity which was comparable to that obtained with diclofenac sodium and indomethacin. In isolated rabbit jejunum preprations the plant extract showed an atropine sensitive dose-dependent (0.10-1.0 mg/mL) spasmogenic activity followed by a spasmolytic effect at the next higher doses (3-5 mg/mL). The crude extract of the plant also inhibited the high K+-induced contractions, indicating a calcium channel blocking (CCB) activity, which was further confirmed when the plant extract caused a rightward shift in the Ca++ concentration response curves in the isolated rabbit jejunum preparations, similar to that seen with verapamil. The flavonoid compounds isolated from the plant were devoid of any activity in the isolated tissue preparations. These results indicate that the plant extract of T. artemisioides possesses analgesic, anti-inflammatory and CCB activities. The flavonoid compounds of the plant may have a role in its observed analgesic and antiinflammatory activities, while the CCB activity of the plant may be attributed to some other chemical constituents present. Moreover the findings support the traditional reputation of the genus Tanacetum for its therapeutic benefits in pain and inflammatory conditions.     

Use of Intron 1 and 22 inversions and linkage analysis in carrier detection of hemophilia A in Indians

BACKGROUND: Hemophilia A is an X-linked recessively inherited bleeding disorder characterized by deficiency of procoagulant factor VIII (FVIII). METHODS: Sixty unrelated hemophilia A patients and their family members have undergone tests for carrier detection by linkage analysis using the polymorphic markers Bcl I, Xba I and Intron 13 or 22 VNTRs. In families of sporadic hemophiliacs, the carrier status of female subjects was ascertained by linkage analysis along with FVIII:C/VWD Ag estimation. RESULTS: Of the 33 families with positive family history, the defective X chromosome was tracked in 28 mothers. The carrier status of females from hemophilia A families with positive family history, ascertained by linkage analysis and Intron 22 and 1 inversion, was made out in 85% cases. FVIII:C/VWF Ag ratio was evaluated in 36 females from 9 sporadic hemophilic families. Using the FVIII:C/VWF Ag ratio along with linkage analysis, carrier status was determined in 9 (25%) of the 36 females studied. Using Intron 22 inversion along with linkage analysis and FVIII:C/VWF Ag estimation, the informativity in female subjects from families of sporadic hemophiliacs increased from 25% to 52%. CONCLUSION: In the West, linkage analysis with Bcl I, Xba I and Intron 13 or 22 VNTR markers and inversion 22 offers a good tool for carrier detection of hemophilia A in India.