- Email: [email protected]
Transmission of zidovudine-resistant AIDS virus report
418 Cyclin levels during Cl progression
in mammalian
cells.
The proliferation of eukaryotic cells is primarily regulated by a decision that occurs during the GI-phase of the cell-cycle - to remain in the cell-cycle and divide or to withdraw from the cell-cycle and adopt an alternative cell fate. In budding yeast. cdc2 + gene product, in combination with a Cl-cyclin. plays a pivotal role in this decision. Related kinases, cyclin-dependent kinases (CDK). are also supposed to be required for progression through the Gl-phase in higher eukaryotes. It was, however, obscure that CDK and Cl-cyclins play a role during the Gl-phase of mammalian cells although candidate Gl-cyclins of mammals were isolated. The role of cyclins in controlling Gl progression in mammalian fibroblasts was tested by construction of fibroblasts that constitutively overexpress a candidate G I -cyclin of mammals. human cyclin E. This was found to shorten the duration of Gl, decrease cell size and diminish the serum requirement for the transition from G- to S- phase. Our observations support the facts that i) CDK is required for Gl-progression in fibroblasts. ii) cyclin levels can be rate-limiting for G I -progression in fibroblasts, and iii) cyclin synthesis may be the target of physiological signals that control cell proliferation. M Okrsubo ( I ) Fred Hutchinson Cancer Rcscarch Center, Seattle. WA 98 1043092. USA
Malaria
prophilaxis
with metloquine.
Longitudinal studies of malaria prophylaxis in Peace Corps volunteers in Africa have demonstrated that a weekly dose of 250 mg base mefloquine was 94% more effective than a weekly dose of 300 mg base chloroquine (95% CI 86% to 97%) and 86% more effective than chloroquine plus a daily dose of 200 mg proguanil (95% .CI 67% to 94%). No serious adverse reactions were observed. Mild adverse events were equally frequent in mefloquine users and in chloroquine users, and the frequency of these events declined with increased duration of prophylaxis. Mefloquine is an effective and well-tolerated drug for prophylaxis of malaria by short-term and long-term travellers. The absence of effective and well-tolerated drugs in the 1980s to prevent malaria resulted in varying recommendations for travel to malarious areas. resulting in confusion for the medical profession and short-term travellers and expatriates. Because mefloquine is highly effective against chloroquine-resistant falciparum malaria in Africa and is well tolerated, the recommendations for malaria prophylaxis for shortterm travellers and expatriate residents can now be simplified. Mefloquine is the drug of choice for malaria prevention in Africa. If mefloquine cannot be tolerated, a daily dose of 100 mg doxicycline is an effective alternative drug. If neither mefloquine nor doxycycline can be tolerated, chloroquine (with or without proguanil) may (I)
Science
(1993)
259,
1908
be recommended: however. travellers using these drugs must be advised of chloroquinc‘s limited effectiveness and therefore how to mu~agc febrile illness. HO Lohcl (2) Ccnlcra Cur Disease Conlrol. Atlanta. GA 30333. USA
Transmission
of zidovudine-resistant
AIDS virus report.
The first report documenting transmission of a zidovudine-resistant strain of human immunodeficiency virus type I (HIVI ) appeared in an April issue of N El@ J Met/. The patient. a previously healthy homosexual male, developed a sev’ere form of primary HIV-I infection. the clinical syndrome that sometimes appears in patients shortly after they are infected with HIV. Because the patient was very sick. he was treated with zidovudine for three months. laboratory tests showed that the virus obtained before the patient received his first dose of zidovudine was resistant to the drug i/r 13ir,n. and contained a characteristic mutation that has been shown only among zidovudine-resistant viruses. The virus obtained three months later was also a mutant resistant to zidovudine. Because one of the patient’s sexual partners was receiving zidovudine (and this could have been harboring a high percentage of resistant HIV-l variants). these findings suggest that the patient acquired a zidovudineresistant virus. This report shows that horizontal transmission of a zidovudine-resistant strain of HIV-I is possible. This may have a bearing on the clinical approach to persons newly infected with HIV-I, who could have acquired a resistant strain of the virus. HH Balfour (3) University of Minnesota. Minneapolis. MN 55455-0392. USA
Pregnancy
after age 50.
The age at which the uterus no longer provides a receptive environment for embryo implantation and development remains unknown. We assessed whether menopausal women between the ages of 50 and 59 years could be prepared for pregnancy with oocyte donation. All potential recipients underwent extensive screening to ensure that they were in excellent physical, reproductive, and psychological health before enrollment. Of I8 patients initially screened (mean [SD] age 52.2 years [2.5]), I4 couples were entered into the study. Oocytes were donated by fertile women (28.1 [2.7] years) who provided gametes after pituitary down regulation with leuprolide acetate and routine ovarian hyperstimulation by human menopausal gonadotropin. Twenty-two donor follicle aspirations resulted in 21 embryo transfers to I4 recipients. Pregnancies were established in nine women, one pregnancy ended in a pre-clinical loss. The ratio of clinical pregnancies per (2) (3)
Lcrrrcer (1993) 341, 848 N Et@ J Med (1993) 328,
II63
in mammalian
cells.
The proliferation of eukaryotic cells is primarily regulated by a decision that occurs during the GI-phase of the cell-cycle - to remain in the cell-cycle and divide or to withdraw from the cell-cycle and adopt an alternative cell fate. In budding yeast. cdc2 + gene product, in combination with a Cl-cyclin. plays a pivotal role in this decision. Related kinases, cyclin-dependent kinases (CDK). are also supposed to be required for progression through the Gl-phase in higher eukaryotes. It was, however, obscure that CDK and Cl-cyclins play a role during the Gl-phase of mammalian cells although candidate Gl-cyclins of mammals were isolated. The role of cyclins in controlling Gl progression in mammalian fibroblasts was tested by construction of fibroblasts that constitutively overexpress a candidate G I -cyclin of mammals. human cyclin E. This was found to shorten the duration of Gl, decrease cell size and diminish the serum requirement for the transition from G- to S- phase. Our observations support the facts that i) CDK is required for Gl-progression in fibroblasts. ii) cyclin levels can be rate-limiting for G I -progression in fibroblasts, and iii) cyclin synthesis may be the target of physiological signals that control cell proliferation. M Okrsubo ( I ) Fred Hutchinson Cancer Rcscarch Center, Seattle. WA 98 1043092. USA
Malaria
prophilaxis
with metloquine.
Longitudinal studies of malaria prophylaxis in Peace Corps volunteers in Africa have demonstrated that a weekly dose of 250 mg base mefloquine was 94% more effective than a weekly dose of 300 mg base chloroquine (95% CI 86% to 97%) and 86% more effective than chloroquine plus a daily dose of 200 mg proguanil (95% .CI 67% to 94%). No serious adverse reactions were observed. Mild adverse events were equally frequent in mefloquine users and in chloroquine users, and the frequency of these events declined with increased duration of prophylaxis. Mefloquine is an effective and well-tolerated drug for prophylaxis of malaria by short-term and long-term travellers. The absence of effective and well-tolerated drugs in the 1980s to prevent malaria resulted in varying recommendations for travel to malarious areas. resulting in confusion for the medical profession and short-term travellers and expatriates. Because mefloquine is highly effective against chloroquine-resistant falciparum malaria in Africa and is well tolerated, the recommendations for malaria prophylaxis for shortterm travellers and expatriate residents can now be simplified. Mefloquine is the drug of choice for malaria prevention in Africa. If mefloquine cannot be tolerated, a daily dose of 100 mg doxicycline is an effective alternative drug. If neither mefloquine nor doxycycline can be tolerated, chloroquine (with or without proguanil) may (I)
Science
(1993)
259,
1908
be recommended: however. travellers using these drugs must be advised of chloroquinc‘s limited effectiveness and therefore how to mu~agc febrile illness. HO Lohcl (2) Ccnlcra Cur Disease Conlrol. Atlanta. GA 30333. USA
Transmission
of zidovudine-resistant
AIDS virus report.
The first report documenting transmission of a zidovudine-resistant strain of human immunodeficiency virus type I (HIVI ) appeared in an April issue of N El@ J Met/. The patient. a previously healthy homosexual male, developed a sev’ere form of primary HIV-I infection. the clinical syndrome that sometimes appears in patients shortly after they are infected with HIV. Because the patient was very sick. he was treated with zidovudine for three months. laboratory tests showed that the virus obtained before the patient received his first dose of zidovudine was resistant to the drug i/r 13ir,n. and contained a characteristic mutation that has been shown only among zidovudine-resistant viruses. The virus obtained three months later was also a mutant resistant to zidovudine. Because one of the patient’s sexual partners was receiving zidovudine (and this could have been harboring a high percentage of resistant HIV-l variants). these findings suggest that the patient acquired a zidovudineresistant virus. This report shows that horizontal transmission of a zidovudine-resistant strain of HIV-I is possible. This may have a bearing on the clinical approach to persons newly infected with HIV-I, who could have acquired a resistant strain of the virus. HH Balfour (3) University of Minnesota. Minneapolis. MN 55455-0392. USA
Pregnancy
after age 50.
The age at which the uterus no longer provides a receptive environment for embryo implantation and development remains unknown. We assessed whether menopausal women between the ages of 50 and 59 years could be prepared for pregnancy with oocyte donation. All potential recipients underwent extensive screening to ensure that they were in excellent physical, reproductive, and psychological health before enrollment. Of I8 patients initially screened (mean [SD] age 52.2 years [2.5]), I4 couples were entered into the study. Oocytes were donated by fertile women (28.1 [2.7] years) who provided gametes after pituitary down regulation with leuprolide acetate and routine ovarian hyperstimulation by human menopausal gonadotropin. Twenty-two donor follicle aspirations resulted in 21 embryo transfers to I4 recipients. Pregnancies were established in nine women, one pregnancy ended in a pre-clinical loss. The ratio of clinical pregnancies per (2) (3)
Lcrrrcer (1993) 341, 848 N Et@ J Med (1993) 328,
II63