Microsatellite typing reveals strong genetic structure of Schistosoma mansoni from localities in Kenya.

Genetic diversity and population structure of seven populations of Schistosoma mansoni sampled in Kenya were assessed using five microsatellite markers. The mean number of alleles per locus, expected heterozygosity in Hardy-Weinberg equilibrium and pairwise F(ST) values ranged from 5.2 to 10.7, 0.5-0.8 and 3.6-27.3%, respectively. These data reveal that S. mansoni populations in Kenyan have relatively high levels of genetic diversity and is significantly differentiated. Our data combined with information on biogeography support the hypothesis that the strong genetic structure in Kenyan schistosomes is as a result of limited gene flow and large population sizes. Resistance to anthelminthics has not been reported among the Kenyan schistosomes, we hypothesize that this is probably due to the very little gene flow among populations, thereby limiting opportunities for the spread of rare alleles that might confer resistance to the drugs.

A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy.

CV706 is a prostate-specific antigen (PSA)-selective, replication-competent adenovirus that has been shown to selectively kill human prostate cancer xenografts in preclinical models. To study the safety and activity of intraprostatic delivery of CV706, a Phase I dose-ranging study for the treatment of patients with locally recurrent prostate cancer after radiation therapy was conducted. Twenty patients in five groups were treated with between 1 x 10(11) and 1 x 10(13) viral particles delivered by a real-time, transrectal ultrasound-guided transperineal technique using a three-dimensional plan. The primary end point was the determination of treatment-related toxicity. Secondary objectives included evaluation of the antitumor activity of CV706 and monitoring for other correlates of antineoplastic action. In this study, CV706 was found to be safe and was not associated with irreversible grade 3 or any grade 4 toxicity. No grade >1 alterations in liver function tests associated with CV706 administration were observed. Posttreatment prostatic biopsies and detection of a delayed "peak" of circulating copies of virus provided evidence of intraprostatic replication of CV706. The study defined the timing of CV706 shedding into blood and urine as well as the appearance of circulating Ad5 neutralizing antibodies. Finally, this study documents the serum PSA response of treated patients and reveals a dose response showing that all five patients who achieved a > or =50% reduction in PSA were treated with the highest two doses of CV706. This study represents the first clinical translation of a prostate-specific, replication-restricted adenovirus for the treatment of prostate cancer. Taken together, this study documents that intraprostatic delivery of CV706 can be safely administered to patients, even at high doses, and the data also suggest that CV706 possesses enough clinical activity, as reflected by changes in serum PSA, to warrant additional clinical and laboratory investigation.

A neotropical snail host of Schistosoma mansoni introduced into Africa and consequences for the schistosomiasis transmission Biomphalaria tenagophila in Kinshasa (Democratic Republic of Congo).

Malacological surveys carried out in the early 1970s in water bodies of the Kinshasa area, Lower Zaire (Democratic Republic of Congo), showed the appearance of a Biomphalaria species which was identified as Biomphalaria camerunensis. In 1976, other surveys confirmed the presence of the species in several sites and showed numerous infected snails with Schistosoma mansoni, demonstrating for the first time an active transmission of the parasite responsible of the intestinal schistosomiasis in this area. The most recent malacological sampling was carried out by one of us in 1994 in Mangungu River and revealed the presence of apparently the same snail species. However, conchological, anatomical and molecular studies showed that this snail may be considered as an introduced neotropical species, B. tenagophila. To our knowledge, this is the second example of the introduction of a neotropical snail host of schistosomes into Africa.

Premenstrual mood disorder and psychiatric illness.

The results of several studies suggest that a special relationship exists between premenstrual syndromes and major psychiatric disorders, particularly affective illness. These studies in general have not employed prospective criteria to diagnose premenstrual syndrome. In this paper the authors report a significant difference in the lifetime history of psychiatric illness between women with prospectively confirmed menstrually related mood disorder and those without it.

Vascular malformation of the brainstem: report of a case with long duration and fluctuating course.

We studied a patient with a vascular malformation within the pons and medulla, affecting the cranial nerve nuclei, ascending and descending pathways, and cerebellar peduncles and adjoining structures. The symptoms had been present for more than 50 years. They were fluctuating in the beginning but later were progressive. The malformation probably had its origin during the first month of embryonic life.

An out-of-hospital birth center using university referral.

Out-of-hospital birth centers are controversial. A retrospective chart review was performed for 150 consecutive patients who had their prenatal care at The Birthplace, a Seattle birth center with certified nurse-midwives licensed by the state of Washington. Seventy-two percent of the women were nulliparous. Antepartum or intrapartum hospital referral was necessary for 28% of the patients. An additional 17% of the patients would have been transferred if specific written criteria for transfer had been precisely followed. The cesarean section rate was 6% (9 of 150). Nonoptimal 1-minute Apgar scores of 6 or less were more common in nulliparas (20%) than in multiparas (3%) who delivered at The Birthplace (P less than .05). All 5-minute Apgar scores were 7 or more. Three infants had birth weights less than 2500 g. Noncompliance with the transfer criteria was associated with untoward outcome. Patients considering out-of-hospital delivery should be counseled that a high rate of hospital transfer is necessary to minimize risk.

Measurement of quality-of-life changes in patients with Alzheimer's disease.

A scale was developed that appears to be a reliable and sensitive indicator of differences and changes in the quality of life of patients with Alzheimer's disease (AD) as the disease progresses. The instrument was generated from interviews with spouses and/or caregivers of AD patients, and was designed to be completed easily by the caregiver. The bipolar analog scale was based on the daily behavior of AD patients and was developed in three steps involving interviews with caregivers (step I), testing of questionnaires, and validation of the instrument. At step II, four iterative trials, each with a different version of the questionnaire, were performed for validation. The final form of the Progressive Deterioration Scale (PDS) contained 27 quality-of-life factors and was cross-validated in a second, separate study. The Global Deterioration Scale (GDS) for cognitive function was used as the external criterion for the analysis of the quality-of-life scales. Statistical analysis indicates that the PDS provides a reliable, valid, and sensitive measure of changes in the quality of life as AD progresses. The PDS achieved 80% overall accuracy in discriminating non-AD elderly patients from patients in the early, middle, and late stages of AD. This scale may provide a useful means for clinical evaluation (phase III) of potential medications to alleviate the symptoms of AD.

Parasites of the deepwater sculpin, Myoxocephalus thompsoni (Cottidae), from Lake Michigan and Lake Huron.

A total of 190 deepwater sculpins, Myoxocephalus thompsoni, collected in 1995 from Michigan waters of Lake Michigan and Lake Huron was examined for parasites. Five parasite species occurred in sculpins from Lake Michigan with Echinorhynchus salmonis being most common. Six parasite species infected sculpins from Lake Huron, with Haplonema sp. the most common. Haplonema sp. is the only gravid helminth species reported from deepwater sculpins. Pleistophora sp. and Trichodina sp. infected sculpins from Lake Huron and Lake Michigan. Parasite species richness for sculpins at the 3 locations ranged from 5 to 6; mean values ranged from 1.18 to 1.39 for examined fish. The restricted diet of deepwater sculpin, which may be related to the depth of its habitat, appears to determine its helminth fauna. Deepwater sculpin may be an important transport host for E. salmonis, Cyathocephalus truncatus, and Eubothrium salvelini to lake trout and burbot that commonly feed on them.

Analysis of messages expressed by Echinostoma paraensei miracidia and sporocysts, obtained by random EST sequencing.

A lambdaZAP Express cDNA library was constructed with mRNA obtained from immature miracidia within eggs, hatched miracidia, and sporocysts of Echinostoma paraensei. This cDNA library was amplified and 213 expressed sequence tag (EST) sequences (averaging 466 nucleotides in length) were obtained. The mean percentage of unresolved bases within the EST sequences was 0.4%, ranging from 0 to 4.6%. The 213 ESTs represent 151 unique messages. BLAST (version 2.0.8) analysis disclosed that 64 unique E. paraensei messages (42.4%) had significant similarities (BLAST score < or =e-5), at deduced amino acid or nucleotide levels, with known sequences in the nonredundant GenBank databases or the dbEST database (NCBI). The remainder, 57.6% of the unique EST-encoded messages, scored nonsignificant hits. Most of the E. paraensei messages that could be assigned a cellular role based on sequence similarities were involved in gene/protein expression. Several ESTs scored highest similarities with sequences obtained from trematode species. A total of 22,560 nucleotides present in open reading frames from ESTs that aligned with known sequences was used to determine codon usage for E. paraensei. Analysis of a subset of eight ESTs that contained full-length open reading frames did not reveal a bias in codon usage. Also, EST sequences were found to contain 3' untranslated regions with an average length of 69.9 +/- 88.4 nucleotides (n = 46). The EST sequences were submitted to GenBank/dbEST, adding to the 51 available Echinostoma-derived sequences, to provide reference information for both phylogenetic analysis and study of general trematode biology.

Hematozoa of hatch-year common mergansers from Michigan.

Fifty-five hatch-year common mergansers (Mergus merganser) were sampled for hematozoa from Douglas Lake (Michigan, USA) on 17 July 1995. Forty-one (75%) were infected with hematozoa. Haemoproteus greineri and Leucocytozoon simondi were common, infecting 28 (51%) and 26 (47%) common mergansers, respectively. Plasmodium circumflexum infected two (4%) birds. The common merganser is a new host record for H. greineri and P. circumflexum. Intensity data indicate possible negative interspecific interaction between H. greineri and L. simondi.

Somatostatin-receptor imaging of medullary thyroid carcinoma.

In-111 pentetreotide scintigraphy of 10 patients with residual or metastatic medullary thyroid carcinoma is described. Six patients had sporadic tumor and 4 had MEN IIB. Foci of increased tracer uptake were observed in 9 patients: in the thyroid bed (4 patients), the mediastinum (3 patients.), the shoulder area and left lower abdomen (1 patient), and the left upper abdomen (1 patient). The 10th patient had no abnormal uptake. CT confirmed 2 mediastinal lesions and 2 out of 3 thyroid masses, but did not detect the thyroid remnants or the lesions in the shoulder area and abdomen. Lung lesions < or = 1 cm in diameter and ill-defined liver foci (2 patients) were seen on CT, but not on scintigraphy. Small liver metastases not demonstrated on CT or on scintigraphy were identified at surgery in a MEN IIB patient. Elevated urinary epinephrine was found in 2 out of 4 MEN IIB patients. In one, tracer uptake in the left adrenal corresponded to a mass on CT, to pathological uptake of MIBG and DMSA, and to a tumor removed at surgery. The second patient had peritoneal spread of malignant pheochromocytoma (at surgery), but negative CT and only a single focus in the left lower abdomen on scintigraphy. Somatostatin-receptor imaging is useful for the detection of residual and recurrent medullary thyroid carcinoma, and may identify pheochromocytoma in MEN IIB patients.

CNS manifestations of diabetes mellitus.

The neurologic manifestations most frequently described in association with diabetes are caused by involvement of the peripheral nerves and nerve roots. Whether there is also a specific central nervous system involvement has not been well documented. Pseudotabes diabetica and diabetic amyotrophy probably can be explained on the basis of severe neuropathy or radiculopathy. According to fairly recent studies, however, both myelopathy and encephalopathy may be part of the diabetic process. In the cases of myelopathy, there are degeneration of the long tracts and areas of demyelination with gliosis, as well as microinfarcts. In the cases of encephalopathy, there are degeneration of ganglion cells and nerve fibers in the cerebrum, brain stem, and cerebellum; cell loss, demyelination and gliosis; and infarction secondary to severe angiopathy.

In vivo regulation of CrkII and CrkL proto-oncogenes in the uterus by insulin-like growth factor-I. Differential effects on tyrosine phosphorylation and association with paxillin.

Changes in CrkII and CrkL phosphorylation are associated with insulin-like growth factor receptor activation in cultured cells. We examined whether similar changes also occur following administration of recombinant human insulin-like growth factor-I to the intact animal. In female rats starved overnight, CrkL phosphorylation was significantly increased 12 min after insulin-like growth factor-I administration. Tyrosine phosphorylation of CrkII was not detectable in either control or treated animals. Paxillin, a 65-70-kDa phosphoprotein containing high affinity binding sites common for the Src homology 2 (SH2) domains of CrkII and CrkL, was observed in both CrkII and CrkL immunoprecipitates. Insulin-like growth factor-I treatment stimulated the association of CrkII with paxillin. In contrast, the same treatment resulted in the dissociation of the CrkL-paxillin complex. Similar effects of insulin-like growth factor-I treatment on the association of CrkL with tyrosine phosphorylated paxillin were observed in fibroblasts overexpressing CrkL. This study demonstrates that the activation of the insulin-like growth factor-I receptor induces changes in the tyrosine phosphorylation and protein-protein interactions of the Crk proteins in vivo. The different responses of CrkL and CrkII to insulin-like growth factor-I receptor activation suggest distinct roles for these two adapter proteins in signal transduction.

Evaluation of tremor and efficacy of oral procaterol in adult patients with asthma.

Tremor, the most common side effect of ordinary doses of beta 2-agonists, was evaluated in a quantitative manner and compared to improvement in pulmonary function in respect to time of onset, duration, peak effect, and tachyphylaxis with procaterol in adults. Forty-five adult patients with reversible obstructive airway disease were studied during administration of three different dosages of procaterol, 25 micrograms escalating to 100 micrograms, and 100 micrograms twice daily. Tremor was quantitatively evaluated with a Grass model accelerometer. The patients were evaluated during 8 hours approximately every 2 weeks for 8 weeks. Daily diaries of symptoms and side effects were also maintained. The study demonstrated no direct relationship between tremor and pulmonary function as far as time of onset, peak effect, or duration. Although tachyphylaxis was demonstrated, much of the tolerance developed to the tremor was explained by an increase in baseline tremor. Procaterol was demonstrated to be an effective bronchodilator, and tolerance to tremor was demonstrated to develop with time but is highly variable. There was not a direct relationship between tremor and pulmonary function, indicating possible differences between lung and peripheral muscle beta 2-receptors. It appeared that the best way to minimize the problem of tremor is to begin with a lower dose and increase the dose gradually during a period of weeks.

Pharmacokinetics, central nervous system uptake, and lipid solubility of propranolol, acebutolol, and sotalol.

The relation of in vitro lipophilicity, based on octanol:buffer partition ratio and on reverse-phase liquid chromatographic retention, to in vivo pharmacokinetics and central nervous system entry was evaluated for the beta-blockers propranolol, acebutolol, and sotalol. Anesthetized cats received single intravenous doses, following which plasma kinetics, cerebrospinal fluid (CSF) kinetics and brain tissue uptake were determined over the next 4 h. Propranolol, by far the most lipophilic beta-blocker in vitro, had the highest in vivo metabolic clearance and volume of distribution (Vd), the most rapid entry into CSF, and the highest brain:plasma uptake ratio (38.0). Sotalol, the most hydrophilic drug in vitro, had the lowest in vivo clearance and Vd, the slowest CSF entry, and the lowest brain:plasma ratio (0.52). Acebutolol had slightly greater in vitro lipophilicity than sotalol, intermediate values of in vivo plasma kinetics and CSF entry rate, and a slightly greater brain:plasma uptake ratio (0.71). Thus, differences among beta-blockers in lipid solubility are associated with predictable differences in plasma kinetics, and rate of entry into CSF. Furthermore, the relative extent of entry into brain is lower for hydrophilic as opposed to lipophilic beta-blockers.

High prevalence of cervical dysplasia in STD clinic patients warrants routine cytologic screening.

The results of routine cervical cytology screening at a Planned Parenthood Center (PPC) clinic were compared to those at a nearby sexually transmitted diseases (STD) clinic in Seattle. Cervical cytologic findings were consistent with cervical intraepithelial neoplasia (CIN), grades 1 (mild dysplasia), 2 (moderate dysplasia), or 3 (severe dysplasia to carcinoma in situ) in 502 (5.9 per cent) of 8,504 PPC patients and 87 (11.4 per cent) of 764 STD patients (p = .001). This rate for STD patients is five times that reported for the general population. Sixty-three PPC patients and 31 STD patients with screening smears consistent with CIN 1 or 2 underwent further prospective study by us, including repeated cytologic and colposcopic examinations. Thirty-seven (59 per cent) of 63 PPC patients and 26 (84 per cent) of 31 STD patients (p = .02) had at least on additional smear or colposcopy consistent with CIN and were advised to undergo cervical biopsy. Among those who underwent recommended biopsy, CIN was confirmed histologically in 15 (50 per cent) of 30 PPC patients and 11 (61 per cent) of 18 STD patients. Thus, the proportion of patients who had screening cytologic findings consistent with CIN, the proportion with persistent cytologic or colposcopic findings consistent with CIN on retesting, and the proportion of those biopsied who had histologically confirmed CIN, all were higher for STD than for PPC patients. There is a serious need for cytologic screening in STD clinics throughout the nation.