Donepezil in more advanced Alzheimer's disease.

OBJECTIVE: Donepezil is currently approved for treatment of patients with mild to moderate Alzheimer's disease (AD). However, since cholinergic activity declines as AD progresses, increasing acetylcholine levels would be expected to provide benefits in severe AD. The primary objective of this article is to review the recent data demonstrating that patients with advanced AD can benefit from treatment with the cholinesterase inhibitor donepezil. DATA SOURCES: A MEDLINE (PubMed) literature search was performed using the key words "donepezil" and "advanced AD." STUDY SELECTION: The search yielded 13 articles, which were then further screened for the criterion: randomized, double-blind, placebo-controlled clinical study. DATA EXTRACTION AND SYNTHESIS: Two studies were found that met these specific study criteria. In the first study, donepezil-treated patients with moderate to severe AD showed significant improvements in cognition and behavior, with preservation of activities of daily living compared with placebo-treated patients. Similar improvements in donepezil-treated patients were seen in the second study involving 27 nursing homes. In this study of older patients, donepezil treatment significantly improved cognition, function, and agitated and aggressive behaviors. Safety and tolerability findings of these two studies are further assessed. Considerations for drug therapy as well as a case study are presented to illustrate the benefits of donepezil treatment in patients with advanced AD. CONCLUSION: . The decision to continue treating severe AD patients with donepezil is an opportunity for consultant pharmacists to decrease the burden of caregivers and to maximize a patient's quality of life for as long as possible.

The nucleoprotein of Pichinde virus expressed by a vaccinia-Pichinde virus recombinant partially protects hamsters from lethal virus challenge.

Syrian hamsters, strain MHA/Lak, are susceptible to intraperitoneal infection with Pichinde virus and die from an overwhelming viremia. We have studied the ability of a vaccinia-Pichinde recombinant virus expressing amino acids 51-561 of the viral nucleoprotein (VVNP51-561) to protect from lethal Pichinde virus infection. Priming with VVNP51-561 significantly delayed mortality and increased final survival outcome after challenge with 2 x 10(3) pfu of Pichinde virus. This protection was not complete compared to priming with Pichinde virus in the footpad, which was not lethal and provided 100% protection. At a higher challenge dose of Pichinde virus, 2 x 10(4) pfu, immunization with VVNP51-561 delayed mortality but did not increase final survival. The partial protection correlated with an early but not late reduction in infectious virus in serum, kidney and liver, and infectious centers in the spleen. Thus the immune response generated by VVNP51-561 could initially control the infection, effectively reducing the virus inoculum. As the infection proceeded, virus replication could not be limited resulting in death in some hamsters. The partial protection did not appear to be mediated by anti-viral antibodies since these were not detected in the serum of VVNP56-561-immunized hamsters. This finding appears to support the hypothesis that in many arenavirus infections cellular immunity is central to viral clearance and protection from reinfection.

Construction and preliminary characterization of a nondefective herpes simplex virus recombinant bearing the genome of human papillomavirus type 16.

Studies of the molecular biology of human papillomavirus type 16 have been limited by the lack of a tissue culture system that is fully permissive for virus replication; as a result, high-titre stocks of infectious virus are not readily available. Therefore, studies of viral gene expression have relied on analysis of transformed or tumour cell lines harbouring latent or integrated viral genomes, or on the behaviour of transfected reporter gene constructs. To provide a method of efficiently delivering papillomavirus information into the nuclei of mammalian cells, we constructed a herpes simplex virus type 1 recombinant bearing the entire human papillomavirus type 16 genome. The resulting recombinant was capable of lytic replication and induced the accumulation of papillomavirus mRNAs initiated from the p97 early promoter during infection of Vero cells. This and other herpes simplex - papillomavirus recombinants should facilitate molecular analysis of the life cycle of human papillomavirus type 16.

[Human papilloma virus infections in adult women in Panama]. / Infección por el virus del papiloma humano en la mujer adulta de Panamá.

This study shows that 10% of Panamanian women are infected with VPH. This incidence of premalign and malign infection is one of the highest in the world. It is necessary that panamanian women be educated to participate in the program of the early detection of the disease to control the incidence of cancer in the uterine cervix.

Infección por el virus del papiloma humano en la mujer adulta de Panamá / Human papilloma virus infections in adult women in Panama

This study shows that 10% of Panamanian women are infected with VPH. This incidence of premalign and malign infection is one of the highest in the world. It is necessary that panamanian women be educated to participate in the program of the early detection of the disease to control the incidence of cancer in the uterine cervix

PCR-detected genital papillomavirus infection: prevalence and association with risk factors for cervical cancer.

In an investigation conducted in student health clinic patients, the polymerase chain reaction was used to detect human papillomavirus (HPV) DNA, thereby allowing measurement of the prevalence of HPV infection and study of the association between HPV infection and risk factors for cervical cancer. Of 159 women eligible to participate, 105 (66%) provided a specimen of cervical cells for HPV typing, and also answered an interviewer-administered questionnaire which sought information on risk factors for cervical cancer. Nucleic acid extracted from cervical cells was screened with primers for HPV types 6, 11, 16, 18, 33 and with an HPV Consensus primer. Overall, the prevalence of HPV infection was 18.1%, while for HPV-6/11 it was 2.9% and for HPV-16/18 it was 10.5%. There were statistically significant increases in risk of HPV infection with a history of ever having smoked cigarettes (overall, and for HPV-16 alone) and with a history of usually having sexual intercourse during menstrual periods (overall, but not for HPV-16), and these associations were independent of the effects of age at first sexual intercourse and number of sexual partners. The latter 2 variables, as well as the total number of occasions of sexual intercourse, a history of anal intercourse, and a history of ever having used oral contraceptives, were not associated with statistically significant alterations in risk of HPV infection.

Nucleotide and amino acid sequence variation in the L1 and E7 open reading frames of human papillomavirus type 6 and type 16.

Human papillomavirus (HPV) type 6 and type 16 DNA sequence variants were found by partially sequencing the L1 and E7 open reading frames, using templates generated with the polymerase chain reaction. Identical variants were found in patients from widely separated locations, such as the United States, the Philippines, and India. The same sequence variants of HPV 16 were found in women with invasive cervical carcinoma and in women with no evidence of disease. Variation in the predicted amino acid sequences of the HPV 16 L1 and E7 proteins was found. A single nucleotide change at position 6433 was found in about 50% of the HPV 16 DNAs, resulting in a change in predicted amino acid sequence from threonine to alanine at the equivalent position in the L1 protein. Predicted amino acid changes were found in the HPV 16 E7 proteins at amino acid positions 28, 29, and 47. Variation at these positions could affect known properties of the E7 protein, including binding to the retinoblastoma protein.

Herpes simplex virus type 2: a possible interaction with human papillomavirus types 16/18 in the development of invasive cervical cancer.

A case-control study of 766 histologically confirmed incident cases of invasive cervical cancer and 1,532 hospital and community controls was conducted in Latin America to evaluate the etiologic role of herpes simplex virus type 2 (HSV-2) and to examine whether HSV-2 interacts with other risk factors. In addition to a personal interview, all subjects were asked to donate blood samples and cervical swabs for assessment of exposure to HSV-2 and human papillomaviruses (HPVs) respectively. Ninety-eight percent of cases and 91% of controls agreed to the interview and blood collection. Women testing positive for HSV-2 antibodies were found to have a 60% increased risk of cervical cancer compared with seronegative women (95% CI = 1.3, 1.9). Control for education, sexual and reproductive behavior, prior Pap-smear screening, smoking, oral contraceptive use, HPV-6/11 DNA, or HPV-16/18 DNA detection did not materially affect this estimate. No effect modification of HSV-2 by age, HPV-6/11 DNA, pregnancies, oral contraceptive use or cigarette smoking was observed. However, a significant interaction was detected between HSV-2 and HPV-16/18. Compared with women testing negative to both virus types, those positive for HSV-2 alone had a RR of 1.2 (95% CI = 0.9, 1.6), those positive for HPV-16/18 DNA alone had a RR of 4.3 (95% CI = 3.0, 6.0), and those positive for both viruses had a RR of 8.8 (95% CI = 5.9, 13.0). These findings corroborate recent laboratory evidence of a possible biological interaction between HSV-2 and HPV-16/18 in the development of cervical cancer. Further confirmatory studies are needed, given concerns with potential misclassification of exposure by the laboratory assays utilized.

Characterization of Pichinde virus infection of cells of the monocytic lineage.

To establish a model of viral infection of monocytes, we examined infection of human cells and cell lines of the monocytic series with the arenavirus Pichinde virus. We demonstrate for the first time that human peripheral blood monocytes are susceptible to Pichinde virus infection, as shown by immunoprecipatation of virus-specific polypeptides from infected cells, immunofluorescence analyses, and quantitation of virus production from infected cells. The human promyelocytic leukemia cell line HL60 did not support Pichinde virus replication, even if cells were induced with the phorbol ester phorbol myristate acetate (PMA) to differentiate to monocytes. However, the human promonocytic leukemia cell line THP-1 did support Pichinde virus replication. Replication depended on exposure of the cells to PMA. We examined the nature of the effect of PMA in the induction of THP-1 cells to support Pichinde virus replication. We found that 5 min of exposure of THP-1 cells to PMA is sufficient to support virus growth and that PMA-treated THP-1 cells remain susceptible to infection up to 4 days after the initial PMA treatment. We also showed that infection of PMA-treated THP-1 cells is mediated through protein kinase C (PKC). H7, a PKC inhibitor, was able to block both PMA-induced differentiation and Pichinde virus infection of THP-1 cells. The synthetic diacylglycerol and PKC agonist, diC8, was able to stimulate THP-1 cells to support virus growth, albeit to lower levels than PMA. Dactinomycin abrogated the ability of virus to replicate and suggested a requirement for host cell transcription. The PMA effect did not appear to relate to receptor modulation. These results suggest that PMA-induced susceptibility to Pichinde virus infection occurs at a point later than the initial binding and penetration stages and that infection depends on the activation or differentiation state of the cell.

Transitional cell carcinoma of the renal pelvis with ovarian metastasis.

This article describes the first reported case of a primary transitional cell carcinoma of the renal pelvis metastatic to the ovary. The clinical presentation in our patient was similar to that of a primary ovarian carcinoma. The differential diagnosis of a primary or metastatic transitional cell carcinoma in the ovary is important and has therapeutic as well as prognostic implications.

Human papillomavirus types 16 and 33, herpes simplex virus type 2 and other risk factors for cervical cancer in Sichuan Province, China.

Cancer of the cervix is relatively common in China, but has been investigated epidemiologically in only a few studies. In the hospital-based case-control study reported here, we investigated the role of various lifestyle and dietary factors, as well as infection with human papillomavirus (HPV) types 16 and 33 and herpes simplex virus type 2 in the aetiology of invasive cervical cancer. The study was conducted in Sichuan province, and involved 101 cases with histologically-confirmed cervical cancer recruited from the gynaecological oncology clinic of the West China University Hospital, and 146 controls recruited from patients attending the gynaecology clinic of the same hospital. Risk of cervical cancer was greatly increased in association with infection with HPV 16/33, the adjusted odds ratio for those with evidence of infection being 32.9 (95% CI 7.7-141.1). In contrast, infection with HSV 2 was not associated with a significantly altered risk of cervical cancer. Indices of sexual history and of dietary habits also showed no association with risk of cervical cancer, while good personal and genital hygiene were associated with markedly reduced risk. Although the results of this study are consistent with a causal role for HPV in the aetiology of cervical cancer, bias or increased viral expression following malignant transformation cannot be excluded as explanations for the strong positive association.

Occurrence of IgA and IgG antibodies to select peptides representing human papillomavirus type 16 among cervical cancer cases and controls.

We used an enzyme-linked immunosorbent assay to test sera from 186 cases of invasive cervical cancer and 172 age-matched controls for IgG and IgA antibodies to an human papillomavirus 16 E7 peptide and to peptide 245, representing an epitope in E2. Cases had significantly higher mean absorbance values than controls for both immunoglobulin isotypes to E7 and elevated mean values for IgG to peptide 245. Since absorbances were not normally distributed we analyzed cervical cancer risk for seropositive and seronegative women. Of the traditional cervical cancer risk factors, cigarette smoking, educational level, number of pregnancies, time interval since last Papanicolaou smear, and age at first intercourse influenced the distribution of seropositivity to some of the viral antigens. Adjusting for these variables, the odds ratios of cervical cancer associated with IgG to E7 was 5.28 [95% confidence (95% CI) = 2.4-11.6] and that with IgA to E7 was 2.67 (95% CI = 1.3-5.3). IgG to peptide 245 was less strongly associated, odds ratio 1.68 (95% CI = 1.2-3.3), and IgA to peptide 245 was not significantly associated with disease. These findings suggest that antibodies to E7 are markers for invasive cervical cancer. However, seropositivity correlated poorly with clinical state, survival, or the presence of human papillomavirus DNA in the cancer tissue.

Fatal sepsis following intravesical bacillus Calmette-Guerin administration for bladder cancer.

Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer. Complications from bacillus Calmette-Guerin therapy are usually minor but serious and even fatal reactions can occur. Five recent cases illustrate the gravity of bacillus Calmette-Guerin sepsis. One man with severe debility and the organic brain syndrome died acutely with a fever of 40 C. Two men had frank sepsis that progressed to multiorgan failure and death. Sepsis progressed despite the use of isoniazid, rifampin and streptomycin. Two men who had equally progressive sepsis with intravesical bacillus Calmette-Guerin survived with the use of cycloserine for the first 72 hours of treatment. Triple antituberculous antibiotics, including cycloserine, may be lifesaving. Sepsis resulted from intravenous absorption through inflamed or disrupted urothelium. Bacillus Calmette-Guerin treatment should not be administered in the presence of severe cystitis or after grossly traumatic catheterization.

[The risk factors of invasive carcinoma of the cervix uteri in Latin America]. / Factores de riesgo de carcinoma invasor del cuello uterino en América Latina.

A study of 759 patients with invasive cervical cancer, 1,430 controls, and 689 sexual partners of the participants who declared that they were monogamous was conducted in Colombia, Costa Rica, Mexico, and Panama from January 1986 to June 1987, to evaluate the risk factors associated with this neoplasm. The principal risk factors identified were: initiation of sexual relations by the woman at an early age, number of stable sexual partners (relationships of more than three months' duration), number of liveborn children, presence of DNA from human papilloma virus (HPV) types 16 or 18, history of venereal disease, lack of exposure to early detection programs, deprived socioeconomic conditions, and number of sexual partners of the partners of the monogamous women. Smoking increased the risk in those women who were shown to have DNA from HPV types 16 or 18. Fifty percent of the patients and 29% of the controls said they had never had a cytological examination (Papanicolaou test). No association was observed between the presence of HPV and sexual behavior. The study showed the need for further research on the possible mechanisms involved in carcinogenesis and infection. The common denominators of the risk factors mentioned are underdevelopment and poverty, which affect broad sectors of these populations. Mass detection programs targeting high-risk groups can reduce the high incidence of cervical cancer in Latin America.

Association of oral contraceptive use and human papillomaviruses in invasive cervical cancers.

In a study of 197 cases of histologically confirmed invasive cervical cancer, 61% of biopsies were positive for human papillomavirus (HPV) DNA by Southern or dot-blot hybridization. An association between detection of HPV DNA and oral contraceptive use was observed when HPV-positive and -negative cases were compared. Women reporting recent or long-term (greater than 4 yrs) oral contraceptive use were at 2.3 and 2.9-fold increased risks of HPV positivity, respectively. An increased risk of HPV positivity was also associated with formal education and with urban residence, while long-term smoking was negatively associated with HPV detection. A non-significant trend of increasing risk of HPV positivity with increasing number of sexual partners of the women and of the male partners of monogamous women was observed. Detection of HPV DNA was not associated with other cervical cancer risk factors examined, including age at first coitus, number of pregnancies, and Pap smear screening history. Our findings suggest either an interaction between HPV infection and oral contraceptive use in the genesis of cervical cancer or an increased expression of HPV genome in neoplasms of oral contraceptive users. These observations also support a multifactorial model of cervical cancer causation.

PIP: 197 cases of invasive cervical cancer were biopsied and tested for presence of human papilloma virus (HPV) DNA, and virus-positive and - negative cases were compared as to oral contraceptive use and other risk factors. These cases were all histologically confirmed invasive cervical cancers seen in the Panamanian National Oncology Institute ascertained from July 1985-June 1987. HPV DNA was identified by Southern or dot-blot hybridization, using probes for HPV-16, -18 and - 33. 61% of the cases were considered positive for at least 1 of the tests. Women reporting oral contraceptive use within the last year, or long-term (44 years) use, were 2.3 and 2.9-fold more likely to he HPV- positive than were non-users. Increased risk of HPV was also associated with urban residence and some, rather than no, formal education. Smoking was negatively associated with HPV. A non-significant trend was evident for multiple sexual partners of the women, or for monogamous women, of her partner. HPV was not linked with other cervical cancer risk factors, such as age at 1st coitus, parity, or Pap screen history. The possibility of an interaction between HPV infection and oral contraceptive use in the genesis of cervical cancer, or an increased expression of HPV genome in neoplasms of oral contraceptive users, was discussed, suggesting a multifactorial model of cervical cancer causation.

Oral contraceptive use and risk of invasive cervical cancer.

A case-control study of 759 invasive cervical cancer patients and 1430 controls in Panama, Costa Rica, Colombia and Mexico enabled an evaluation of risk in relation to oral contraceptive use. Overall use was associated with a 21% nonsignificant elevation in risk, with some further increases in risk for more extensive durations of use. Although risks were similar for recent and non-recent users (RRs = 1.3 versus 1.2), recent long-term users were at highest risk (RR for 5+ years use = 1.7, 95% Cl 1.1-2.6). Relationships were similar for women with and without a recent Pap smear, arguing against detection bias. There was little evidence that other risk factors, including smoking and detection of human papillomaviruses (HPV), altered the effects of oral contraceptives. The risk associated with oral contraceptives was significantly increased for adenocarcinomas (RR = 2.2), whereas for squamous cell tumours the effect was minimal (RR = 1.1). These results provide some support for an adverse effect of oral contraceptives on cervical cancer risk, although possibly limited only to a subpopulation of cases.

Human papillomavirus and cervical intraepithelial neoplasia in women who subsequently had invasive cancer.

In a retrospective case-control study biopsy specimens of cervical intraepithelial neoplasia (CIN) lesions from 47 women in whom invasive cancer subsequently developed (cases) and from 94 control subjects in whom CIN was diagnosed within 6 months of the diagnosis for the matched case subject but invasive disease did not develop were tested for human papillomavirus (HPV) DNA with tissue in-situ hybridization. There were no significant differences in the frequency of detection of HPV DNA between the two groups. In a cross-sectional survey the prevalence of HPV DNA was found to be 11% in specimens without CIN, 27% in those with CIN I, 49% in those with CIN II and 56% in those with CIN III. The positivity rates for HPV 16/33 DNA increased with the severity of CIN, but this was not observed for HPV 6/11 and 18 DNA. A comparison of the results of the case-control and cross-sectional studies suggested that the younger cohort of women had higher prevalence rates of HPV DNA than the older cohort.

Sexual behavior, venereal diseases, hygiene practices, and invasive cervical cancer in a high-risk population.

A case-control study of 759 women with invasive cervical cancer and 1430 controls in four Latin American countries evaluated risk in relation to sexual behavior, histories of specific venereal diseases, and hygiene practices. Early age at first sexual intercourse and increasing number of sexual partners were associated with significantly increased risks even after adjustment for their mutual effects. Risk increased to a twofold excess among women reporting first intercourse at 14 to 15 years of age compared with 20+ years. The number of steady sexual partners was a more important predictor of risk than the number of nonsteady partners, particularly before age 30, possibly reflecting the need for prolonged or repeated exposures to a transmissible agent, or different methods of protection against sexually transmitted diseases or pregnancy. Reported frequency of intercourse was not generally associated with risk, except among women reporting increased frequencies before 20 years of age. Histories of gonorrhea or crab lice were associated with increased risk, but histories of other venereal diseases were not significant predictors. No consistently increased risks were detected for women reporting specific hygiene or douching habits, except the practice of washing the genitalia infrequently during menstruation. These results provide support for a period of increased susceptibility to carcinogens during adolescence, and suggest that this may be an important determinant of the high incidence of cervical cancer in Latin America.