Disruption of spermatogenesis in the liver fluke, Fasciola hepatica by two artemisinin derivatives, artemether and artesunate.

An in vivo study in the laboratory rat model has been carried out to monitor changes to the spermatogenic cells in the testis tubules of adult Fasciola hepatica following treatment with the artemisinins, artemether and artesunate. Rats infected with the triclabendazole (TCBZ)-resistant Sligo isolate were dosed orally with artemether at a concentration of 200 mg/kg and flukes recovered at 24, 48 and 72 h post treatment (pt). Rats infected with the TCBZ-resistant Oberon isolate were dosed orally with artesunate at a concentration of 200 mg/kg and flukes recovered 24, 48, 72 and 96 h pt. The flukes were processed for histological and transmission electron microscope (TEM) examination. Changes to the spermatogenic cells were evident at 24 h pt with artemether. The spermatogonial and spermatocyte cells contained abnormal mitochondria, there were fewer spermatids and spermatozoa in the tubules than normal, and a number of cells showed signs of apoptosis. There was a further decline in cell numbers at 48 h pt and the organization of the spermatocyte and spermatid rosettes was atypical. Sperm formation had become abnormal and those spermatozoa present possessed only a single axoneme. By 72 h pt, the testis tubules were vacuolated and filled with abnormal cells and cell debris. Only spermatogonial cells could be identified and there was widespread evidence of apoptosis in the cells. Distinct cellular changes following artesunate treatment did not become apparent until 48 h pt. The changes seen were similar to those described for artemether, but were generally less severe at matching time-periods. The fine structural changes occurring in the spermatogenic cells were compared to those observed in other cell types and fluke tissues and the overall information was collated to identify the cellular targets for artemisinin action and to establish the time-line for drug action.

Ultrastructural changes in the tegument and gut of adult Fasciola hepatica following in vivo treatment with artesunate.

An in vivo study in the laboratory rat model has been carried out to monitor changes to the tegument and gut of adult Fasciola hepatica following treatment with artesunate. Rats infected with the triclabendazole-resistant Oberon isolate were dosed orally with artesunate at a concentration of 200 mg/kg and flukes recovered 24, 48, 72 and 96 h post-treatment (pt). The flukes were processed for scanning and transmission electron microscope examination. Changes to the external surface were limited to swelling and blebbing of the interspinal tegument. There was one exception, a specimen recovered 72 h pt, which had completely lost the syncytium over the posterior region of the fluke. Internal changes to the tegumental syncytium and cell bodies were more severe and were apparent from 48 h pt onwards. Increased numbers of secretory bodies were present in the apical region of the syncytium, the basal infolds were swollen and sloughing of the apical plasma membrane was seen at 96 h pt. In the cell bodies, there was swelling and vesiculation of the cisternae of the granular endoplasmic reticulum (ger), swelling of the mitochondria and a decrease in secretory body production. Changes to the gastrodermal cells were evident from 24 h onwards. They comprised swelling and vesiculation of the ger cisternae, swelling and lysis of the mitochondria and accumulation of autophagic vacuoles and lipid droplets. The nuclei of the cells were karyopyknotic by 96 h pt. The gut was consistently more severely affected than the tegument at all time points pt, pointing to an oral route of uptake for artesunate. This study has provided information on the primary subcellular targets for drug action in the fluke.

Electron microscopical study to assess the in vitro effects of the synthetic trioxolane OZ78 against the liver fluke, Fasciola hepatica.

Adult Fasciola hepatica were incubated for 48 h in vitro in the synthetic peroxide, OZ78 at a concentration of 100 microg/ml and then prepared for scanning and transmission electron microscopy. There was limited disruption to the external fluke surface, with only slight swelling and blebbing of the interspinal tegument in the midbody and ventral tail regions. By contrast, significant disruption was observed to the ultrastructure of the tegument and subtegumental tissues. There was severe swelling of the basal infolds in the tegumental syncytium and the flooding spread internally to affect the subtegumental tissues. In the tegumental system, there was swelling of the cisternae of granular endoplasmic reticulum and of the mitochondria, with the latter showing signs of breaking down. Autophagic vacuoles and lipid droplets were present and the synthesis of tegumental secretory bodies was much reduced. The gastrodermal cells were severely affected, with swelling and degeneration of the mitochondria and the presence of autophagic vacuoles and lipid droplets. The granular endoplasmic reticulum was swollen and vesiculated and the cells contained few secretory bodies. Both the vitelline and testis follicles showed evidence of extensive cellular disruption and degeneration. This study confirms previous data indicating the potential flukicidal activity of OZ78.

Adult triclabendazole-resistant Fasciola hepatica: morphological changes in the tegument and gut following in vivo treatment with artemether in the rat model.

A study has been carried out to determine the morphological changes to the adult liver fluke, Fasciola hepatica after treatment in vivo with artemether. Rats were infected with the triclabendazole-resistant Sligo isolate of F. hepatica, dosed orally with artemether at a concentration of 200 mg/kg and flukes recovered at 24, 48 and 72 h post-treatment (p.t.). Surface changes were monitored by scanning electron microscopy and fine structural changes to the tegument and gut by transmission electron microscopy. Twenty-four hours p.t., the external surface showed minor disruption, in the form of mild swelling of the tegument. The tegumental syncytium and sub-tegumental tissues appeared relatively normal. Forty-eight and seventy-two hours p.t., disruption to the tegumental system increased, with isolated patches of surface blebbing and reduced production of secretory bodies by the tegumental cells being the main changes seen. The gastrodermal cells showed a relatively normal morphology 24 h p.t. By 48 h, large numbers of autophagic vacuoles and lipid droplets were present. Autophagy increased in magnitude by 72 h p.t. and substantial disruption to the granular endoplasmic reticulum was observed. Results from this study show that flukes treated in vivo with artemether display progressive and time-dependent alterations to the tegument and gut. Disruption to the gut was consistently and substantially more severe than that to the tegument, suggesting that an oral route of uptake for this compound predominates. This is the first study providing ultrastructural information on the effect of an artemisinin compound against liver fluke.

A comparative study on the impact of two artemisinin derivatives, artemether and artesunate, on the female reproductive system of Fasciola hepatica.

An in vivo study in the laboratory rat model has been carried out to monitor changes to the female reproductive system in adult Fasciola hepatica following treatment with the artemisinins, artemether and artesunate. Rats infected with the triclabendazole (TCBZ)-resistant Sligo isolate were dosed orally with artemether at a concentration of 200mg/kg and flukes recovered at 24, 48 and 72 h post-treatment (pt). Rats infected with the TCBZ-resistant Oberon isolate were dosed orally with artesunate at a concentration of 200mg/kg and flukes recovered 24, 48, 72 and 96 h pt. The flukes were processed for histological and transmission electron microscope (TEM) examination of the uterus, Mehlis' gland, ovary and vitellaria. After treatment with artemether, egg production had become abnormal by 72 h pt, with free vitelline cells and masses of shell protein material within the uterus; spermatozoa were absent. The Mehlis' gland and ovary retained a normal morphology over the 3-day period. A change in the cell population in the vitelline follicles was seen at 48 h pt, with a decline in the number of immature cells. This became more marked by 72 h and the follicles became progressively vacuolated over the 3-day period. At the TEM level, there were changes in the immature vitelline cells at 24h pt, as evidenced by a decrease in shell protein production and the presence of lipid droplets and abnormal mitochondria. Spaces in the follicles separated the cells from each other. The changes became progressively more severe with time, so that, by 72 h pt, the follicles were very disrupted, containing cells in the advanced stages of apoptotic breakdown. In extreme cases, the follicles were scarcely recognisable and had become filled with cellular debris. Fine structural changes to the vitelline cells induced by artesunate treatment were similar to those described for artemether, but generally occurred more quickly and were greater; this was particularly true of the swelling of the ger cisternae. Overall, the results have shown that artemisinin treatment has a severe impact on egg production by TCBZ-resistant flukes, an effect that is mediated by disruption of the vitelline cells.

Sinus histiocytosis presenting as an epibulbar mass. A clinicopathologic case report.

Sinus histiocytosis is a well-recognized condition that mainly affects children in the first decade of life. Although this usually benign disease often features massive cervical lymphadenopathy, numerous extranodal sites of involvement can be seen. We describe a new presenting manifestation for sinus histiocytosis. A 13-month-old infant developed a rapidly growing unilateral epibulbar tumor that involved the cornea. A complete physical examination revealed only mild inguinal lymphadenopathy. A diagnosis of sinus histiocytosis was made by histologic examination of the lesion after surgical excision.

Elevated levels of peripheral serum creatine phosphokinase with strangulated small bowel obstruction.

Experimental arterial bowel infarction can cause elevations in levels of peripheral serum creatine phosphokinase (CPK), lactic dehydrogenase (LDH), and their isoenzymes. To test whether these changes would occur in strangulated small bowel infarctions, 18 dogs were placed under general anesthesia and randomized to one of three categories: laparotomy alone, simple mechanical small bowel obstruction, or strangulated small bowel infarction induced by incarcerating bowel in a surgically created ventral hernia. Serum samples were drawn for 48 hours postoperatively. Total CPK and LDH activity were determined by automated spectrophotometry; isoenzyme levels were determined by agarose gel electrophoresis. Levels of peripheral serum CPK and each of its isoenzymes became significantly elevated in the dogs with strangulated infarction. Such elevations did not occur with LDH. The findings suggest that changes in peripheral serum CPK could prove helpful in evaluating bowel viability in cases of intestinal obstruction.

Inherited patterned lentiginosis in blacks.

We present 10 patients with autosomal dominant transmission of a pigmentary pattern characterized by facial, lip, extremity, buttock, and palmoplantar small, discrete hyperpigmented macules. None of the patients had lesions of the oral mucosa or internal organ system abnormalities. These patients' pigmentary pattern can resemble the ones seen in other lentiginosis syndromes. Those most closely mimicked--the Peutz-Jeghers syndrome, the centrofacial lentiginosis syndrome, and Carney's syndrome--all have associated internal abnormalities. We believe the pattern of pigmentation in these 10 black patients is distinct.

Autosomal recessive pericentral pigmentary retinopathy.

A brother and sister, born to consanguineous parents, had pigmentary retinopathy in a pericentral distribution. The retinopathy was noted in infancy when the siblings were examined for strabismus. The optic disks, maculae, and retinal vessels were normal. There was mild reduction in amplitude of both scotopic and photopic electroretinographic responses. Both patients had moderate hyperopic astigmatism and esotropia. The fundus and visual acuity remained unchanged over periods of nine and 13 years in the brother and sister, respectively. Results of ocular examinations on the father, mother, and an older sister were normal. These findings support an autosomal recessive mode of inheritance in this family with pericentral pigmentary retinopathy.

Infantile glaucoma in Down's syndrome (trisomy 21).

We examined five patients with Down's syndrome and bilateral infantile glaucoma. In the first few months of life four patients had large cloudy corneas, breaks in Descemet's membrane, increased intraocular pressure, photophobia, and tearing. In one patient the diagnosis was delayed until 3 1/2 years of age because of concomitant nasolacrimal duct obstruction. Two patients developed cataracts and retinal detachment and have undergone multiple surgical procedures. The clinical course in these two older patients suggests that coexistence of congenital glaucoma, severe myopia, and cataracts in patients with trisomy 21 strongly predisposes for the development of retinal detachment and poor visual outcome.

Who receives Ryan White CARE Act services? A demographic comparison of CARE act clients and the general AIDS population.

This study examines the extent to which health and social service providers funded by the Ryan White Comprehensive AIDS Resources Emergency (CARE) Act serve women, minorities, and other vulnerable populations emphasized by the legislation. Demographic characteristics of AIDS-diagnosed clients served by CARE Act-funded providers in four metropolitan areas and two states are compared with Centers for Disease Control and Prevention estimates of AIDS prevalence. Clients of CARE Act-funded providers tend to reflect the demographics of local HIV/AIDS epidemics. Where differences exist, CARE Act clients are more likely to be women and minorities and less likely to be injecting drug users. CARE Act-funded providers are effectively reaching most medically underserved populations.

Primary care of the HIV-seropositive chemically dependent patient.

Persons with chemical dependency problems account for a large and growing number of cases of HIV/AIDS in the United States. This group poses unique challenges as providers address their medical and psychosocial needs. Although much of the care of substance-using HIV patients is the same as that of non-substance-using patients, differences do exist. Treatment of the underlying chemical dependency is a cornerstone of caring for these patients.

Health care of the gay male patient.

A significant number of men presenting to any primary care physician are gay or have had sexual encounters with members of their own sex. It is important, therefore, that the physician be familiar with particular medical care issues commonly encountered in this population and that she or he also be aware of psychosocial issues that impact on the gay patient's well-being and on the physician's ability to provide competent primary care.

Palliative medicine and HIV/AIDS.

This article provides an introduction to the field of palliative medicine as it applies to the care of HIV/AIDS. Issues of pain management, end-of-life care, ethics, and bereavement are discussed with the intention of providing the primary care physician additional resources in the provision of care to patients with HIV/AIDS.

The spectrum in the morphology of the so-called "morning glory disc anomaly".

Eight cases illustrating the different configurations of the morning glory disc anomaly are presented. The spectrum of the appearance is due to variability in excavation of the disc, amount of glial tissue and hyaloid system remnants in the center of the disc, and degree of peripapillary pigmentary changes. There is no correlation between optic disc configuration and visual acuity. This anomaly should be suspected in infants presenting with unilateral retinal detachment.

Accommodation deficiency in healthy young individuals.

Ten patients, ages 10 to 19, with accommodation insufficiency are reported. All patients were in good health and asymptomatic, except for asthenopia during near visual activities. Each patient's amplitude of accommodation was measured and found to be considerably below the minimal normal for their respective ages (an average of 6 diopters). Only three patients had associated convergence insufficiency. No etiology for the diminished accommodation was suggested by history or could be identified by careful examination. All patients were successfully managed optically with bifocals or reading glasses, although three required the addition of base-in prisms for the near exodeviation. Near vision testing and determination of the near point of accommodation should be part of the pediatric ophthalmologic examination in all patients with complaints referable to their reading and visual performance at near.

A unique epibulbar osseous choristoma.

The case of a 14-year-old girl found to have a unique epibulbar osseous choristoma attached to the sheath of the superior rectus muscle is recorded. The bony mass was palpable through the upper lid and by computerized tomography, it appeared densely calcified and noncystic. There was no ptosis or abnormality in ocular motility preoperatively or postoperatively.

The ocular manifestations of congenital infection: a study of the early effect and long-term outcome of maternally transmitted rubella and toxoplasmosis.

PURPOSE: To study the spectrum of adverse ocular effects which result from maternally transmitted rubella and toxoplasma infection; further, to record the long-term visual and neurodevelopmental outcomes of these 2 major causes of fetal infection. STUDY DESIGN AND PATIENTS: A series of 55 patients with congenital infection have been studied prospectively on a long-term basis. The study group included a cohort of 34 cases with congenital rubella syndrome demonstrated by virus isolation, and 21 cases with a clinical diagnosis of congenital toxoplasmosis and serologic confirmation. All patients had specific disease-related ocular defects. Rubella patients were first identified during or following the last major rubella epidemic in 1963-1964, and some have been followed serially since that time. A separate study group of representative toxoplasmosis patients presented for examination and diagnosis at varying time periods between 1967 and 1991. OBSERVATIONS AND RESULTS: This study confirms that a broad spectrum of fetal injury may result from intrauterine infection and that both persistent and delayed-onset effects may continue or occur as late as 30 years after original infection. Many factors contribute to the varied outcome of prenatal infection, the 2 most important being the presence of maternal immunity during early gestation and the stage of gestation during which fetal exposure occurs in a nonimmune mother. RUBELLA: As a criteria of inclusion, all 34 rubella patients in this study exhibited one or more ocular defects at the time of birth or in the immediate neonatal period. Cataracts were present in 29 (85%) of the 34, of which 21 (63%) were bilateral. Microphthalmia, the next most frequent defect, was present in 28 (82%) of the 34 infants and was bilateral in 22 (65%). Glaucoma was recorded in 11 cases (29%) and presented either as a transient occurrence with early cloudy cornea in microphthalmic eyes (4 patients), as the infantile type with progressive buphthalmos (1 patient), or as a later-onset, aphakic glaucoma many months or years following cataract aspiration in 11 eyes of 6 patients. Rubella retinopathy was present in the majority of patients, although an accurate estimate of its incidence or laterality was not possible because of the frequency of cataracts and nystagmus and the difficulty in obtaining adequate fundus examination. TOXOPLASMOSIS: Twenty-one patients with congenital toxoplasmosis have been examined and followed for varying time periods, 7 for 20 years or more. The major reason for initial examination was parental awareness of an ocular deviation. Twelve children (57%) presented between the ages of 3 months and 4 years with an initial diagnosis of strabismus, 9 of whom had minor complaints or were diagnosed as part of routine examinations. All cases in this study have had evidence of retinochoroiditis, the primary ocular pathology of congenital toxoplasmosis. Two patients had chronic and recurrent inflammation with progressive vitreal traction bands, retinal detachments, and bilateral blindness. Macular lesions were always associated with central vision loss; however, over a period of years visual acuity gradually improved in several patients. Individuals with more severe ocular involvement were also afflicted with the most extensive central nervous system deficits, which occurred following exposure during the earliest weeks of gestation. CONCLUSIONS: Although congenital infection due to rubella virus has been almost completely eradicated in the United States, the long-term survivors from the prevaccination period continue to experience major complications from their early ocular and cerebral defects. They may be afflicted by the persistence of virus in their affected organs and the development of late manifestations of their congenital infection. Congenital toxoplasmosis continues to be the source of major defects for 3,000 to 4,100 infants in the United States each year; the spectrum of defects is wide and may vary from blindness and severe mental retardation to minor retinochoroidal lesions of little consequence. Effective solutions for either the prevention or treatment of congenital toxoplasmosis have not been developed in this country but are under intensive and continuing investigation.

Atypical cases of sinus histiocytosis (Rosai-Dorfman disease) with ophthalmological manifestations.

Sinus histiocytosis with massive lymphadenopathy is a non-neoplastic disease of unknown cause observed mainly in children with markedly enlarged cervical or other lymph nodes. We have reported two very atypical cases with extranodal manifestations that required ophthalmological consultation. Neither patient had significant lymphadenopathy. One patient, who had tumors of all four eyelids as well as lesions of the nose and larynx, was 68 years old when first examined, and 70 at the time of his last surgical procedure. The other patient, a 13-month-old child, had a unique corneoscleral lesion as his only clinical manifestation. The excised tissues obtained from the eyelids and larynx in case 1 and from the corneoscleral lesion in case 2 revealed characteristic histopathologic features of sinus histiocytosis (Rosai-Dorfman disease), including strongly positive immunoperoxidase staining for S-100 protein in the cytoplasm of most of the histiocytes.

Strabismus in childhood.

We have discussed what constitutes a normal visual and ocular system in children and the inherent mechanisms that help each person develop and maintain normal visual function. This ideal status should include good visual acuity in each eye, straight eyes, and the development of fusion. Strabismus represents an obstacle to obtaining these goals and may be caused by poor vision, refractive errors, or anatomic, structural, or innervational abnormalities. Each of these conditions is treatable and correctable when discovered early. With early identification, proper treatment can be instituted and the patient can have the opportunity to develop optimal vision with fusion and depth perception -- a lifetime benefit. Several other types of strabismus respond poorly to the use of glasses, prisms, exercises, or medications and can be effectively treated only by surgical methods. Most divergent and vertical deviations fall into this group, as do ocular deviations associated with paretic or structurally abnormal muscles.