Candida keratitis and endopthalmitis after corneal transplantation; two case reports, a novel regimen and literature overview of therapeutic options.

PURPOSE: To evaluate treatment options for candida keratitis and endopthalmitis after corneal transplantation. METHODS: Case reports and literature review. RESULTS: Two patients with keratitis due to Candida glabrata/parapsilosis after corneal transplantation were successfully treated with a combination of topical voriconazole, intracameral voriconazole and amphotericin B, and systemic treatment with flucytosine. CONCLUSIONS: Natamycine and voriconazole topically are preferred therapeutic options for the treatment of fungal keratitis. Systemic flucytosine is a useful alternative additive, particularly for countries where natamycine is not registered as a pharmaceutical agent.

"Compensated hyperosmolarity" of cerebrospinal fluid and the development of hydrocephalus.

Acute osmolar loading of cerebrospinal fluid within one lateral ventricle of dogs was examined as a cause of water extraction from the bloodstream and an increase in intracranial pressure. We have shown that a certain amount of (3)H2O from the bloodstream enters osmotically loaded cerebrospinal fluid significantly faster, hence causing a significant increase in intracranial pressure. The noted phenomenon in which intracranial pressure still significantly increases, but in which the hyperosmolarity of the cerebrospinal fluid is no longer present, was named "compensated hyperosmolarity". In the case of the sub-chronic application of hyperosmolar solutions into cat ventricles, we observed an increase in cerebrospinal fluid volume and a more pronounced development of hydrocephalus in the area of application, but without significant increase in intracranial pressure and without blockage of cerebrospinal fluid pathways. These results support the newly proposed hypothesis of cerebrospinal fluid hydrodynamics and the ability to develop new strategies for the treatment of cerebrospinal fluid-related diseases.

POMT1-associated walker-warburg syndrome: a disorder of dendritic development of neocortical neurons.

We have analyzed the morphology and dendritic development of neocortical neurons in a 2.5-month-old infant with Walker-Warburg syndrome homozygotic for a novel POMT1 gene mutation, by Golgi methods. We found that pyramidal neurons frequently displayed abnormal (oblique, horizontal, or inverted) orientation. A novel finding of this study is that members of the same population of pyramidal neurons display different stages of development of their dendritic arborizations: some neurons had poorly developed dendrites and thus resembled pyramidal neurons of the late fetal cortex; for some neurons, the level of differentiation corresponded to that in the newborn cortex; finally, some neurons had quite elaborate dendritic trees as expected for the cortex of 2.5-month-old infant. In addition, apical dendrites of many pyramidal neurons were conspiciously bent to one side, irrespective to the general orientation of the pyramidal neuron. These findings suggest that Walker-Warburg lissencephaly is characterized by two hitherto unnoticed pathogenetic changes in the cerebral cortex: (a) heterochronic decoupling of dendritic maturation within the same neuronal population (with some members significantly lagging behind the normal maturational schedule) and (b) anisotropically distorted shaping of dendritic trees, probably caused by patchy displacement of molecular guidance cues for dendrites in the malformed cortex.

Clinical importance of somatosensory evoked potentials in early diagnosis of syringomyelia.

We report a rare case of syringomyelia, the development of which was monitored by somatosensory evoked potentials. The evoked potentials recorded over an eight months' period of time were correlated with the incidence of syringomyelia. Changes of the evoked response latency and amplitude were dtected. The evoked potential change and the sensation deficit indicated a pathological process. High-resolution MRI revealed syringomyelia in the cervical and the thoracic segments of the spinal cord. Somatosensory evoked potentials represent a sensitive diagnostic method recording changes in the biopotentials. Potential changes require localisation of a possible process and high-resolution MRI. Evoked potentials enable to monitor both, the disease development, but also the healing process (Fig. 3, Ref 11).

Spinal contribution to CSF pressure lowering effect of mannitol in cats.

OBJECTIVES: After application of hyperosmolar mannitol the cerebrospinal (CSF) pressure is usually lowered within 30 min but this effect cannot be explained either by changes in intracranial blood volume and flow or by changes in brain volume. We assume that this effect of mannitol my be consequence of CSF volume decrease primarily in the spinal CSF due to high compliance of the spinal dura. METHODS: To explore such a possibility we planned to separate spinal and cerebral CSF. In chloralose anaesthetized cats dorsal laminectomy of C2 vertebrae was performed and a plastic semi ring was positioned extradurally separating cranial and spinal CSF. CSF pressures were recorded via cannulas positioned in lateral ventricle and lumbar subarachnoid space at L3 vertebrae, respectively. RESULTS: After intravenous bolus of 20% mannitol (0.5 or 1.0 g/kg/ 3 min) in control animals without cervical stenosis, the fall of both ventricular and lumbar CSF pressures was equal over time. At 15 min after mannitol application in cats with cervical stenosis an slight increase of ventricular and a fall of lumbar CSF pressures were observed, while at 30 min a gradient of these pressures of 5.5 and 7 cm H2O at lower and higher dose of mannitol, respectively, were registered. However, after removal of cervical stenosis these gradients disappeared. CONCLUSION: The observed changes of CSF pressures in spinal and intracranial space indicate that spinal subarachnoid space contributes a great deal to overall fall of CSF pressure and volume in the early period after mannitol application probably due to high compliance of the spinal dura.

S-Adenosylhomocysteine hydrolase deficiency: a second patient, the younger brother of the index patient, and outcomes during therapy.

S-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.

Doppler visualization of ureteric jets in unilateral hydronephrosis in children and adolescents.

OBJECTIVE: to evaluate Doppler visualization of ureteric jets in the assessment of unilateral kidney collecting system dilatation in children and adolescents. METHODS AND PATIENTS: color Doppler ultrasonography was performed in 27 patients with hydronephrosis (11 female, 16 male, age range 3-21 years, mean age 10.5+/-4.4). Nine had acute obstruction due to ureteral calculus, seven had obstructive hydronephrosis due to uretero-pelvic junction (UPJ) stenosis, and 11 had non-obstructive hydronephrosis. Doppler was also performed in 32 healthy children (15 boys and 17 girls, age 2-17 years, mean age 7.8+/-3.9), who represented the control group. RESULTS: in the control group jets were visible in 57 out of 64 ureteric units (89%). The mean frequency of jets in healthy children was 4.1 jets per min. In all children with hydronephrosis, jets were visible in 25 out of 27 normal ureteric units (92.6%), and their mean frequency was 4.5 jets per min. In children with acute unilateral colic, ureteric jets were completely absent in eight of nine patients (89%). In children with obstructive hydronephrosis, due to UPJ stenosis, jets were absent in five out of seven patients (71.4%), and in children with non-obstructive hydronephrosis jets were absent in three out of eleven patients (27.3%). When jets are visible, their frequencies are much lower on the obstructed side as compared with normal side, while in cases of nonobstructive dilatation frequency of jets is similar on both sides. CONCLUSION: absence of jets in patients with acute obstruction due to ureteral calculus, strongly correlates with high-grade obstruction. In children with UPJ stenosis, presence of ureteric jet does not exclude significant obstruction, but the frequency of jets on the obstructed side is much lower as compared with the unaffected side. When there is absence of jet from the dilated side or significant asymmetry in jet frequency, hydronephrosis is likely to be obstructive.

Ketoconazole inhibits acetaminophen-induced hepatotoxicity in mice.

OBJECTIVE: To investigate the effect of ketoconazole on acetaminophen (AAP)-induced hepatotoxicity in mice. MATERIALS AND METHODS: Mice were given AAP intragastrically (300 mg/kg) and treated with ketoconazole (100 mg/kg intraperitoneally) or saline either 30 min before or 2-3 h after AAP administration. Mortality was recorded for 48 h, during which all mice given saline either died or recovered fully. Serum alanine and aspartate transaminase levels were determined 24 h after administration of AAP. Prostaglandin E2, thromboxane A2 and leukotriene C4 production was determined 6 h after AAP administration in the supernatants from the short-term culture of liver fragments by radioimmunoassay. RESULTS: Ketoconazole significantly decreased mortality and transaminase levels when given to mice either 30 min before or 2 h after AAP. Liver fragments from mice with AAP hepatitis produced greater quantities of prostaglandin E2, thromboxane A2 and leukotriene C4 than fragments from normal liver. Pretreatment of mice with ketoconazole or its addition to liver fragments ex vivo further increased the production of prostaglandin E2 and reduced the production of thromboxane A2. The effect of ketoconazole on leukotriene C4 synthesis was different in vivo (synthesis stimulation) from in vitro (synthesis inhibition). CONCLUSION: The protective effect of ketoconazole in AAP hepatitis is most probably mediated by modulation of eicosanoid synthesis by liver cells.

Long-term risk of breast cancer in women with fibroadenoma.

BACKGROUND: Fibroadenomas are benign breast tumors that are commonly diagnosed in young women and are associated with a slight increase in the risk of breast cancer. These lesions vary considerably in their histologic characteristics. We assessed the correlation between the histologic features of fibroadenomas and the risk of subsequent breast cancer. METHODS: We conducted a retrospective cohort study of a consecutive series of patients with fibroadenoma diagnosed between 1950 and 1968. Follow-up data were obtained for 1835 patients (90 percent of those eligible). Fibroadenomas with cysts, sclerosing adenosis, epithelial calcifications, or papillary apocrine changes were classified as complex. The rate of subsequent breast cancer among the patients was compared with the rates in two control groups, women listed in the Connecticut Tumor Registry and women chosen from among the patients' sisters-in-law. RESULTS: The risk of invasive breast cancer was 2.17 times higher among the patients with fibroadenoma than among the controls (95 percent confidence interval, 1.5 to 3.2). The relative risk increased to 3.10 among patients with complex fibroadenomas (95 percent confidence interval, 1.9 to 5.1) and remained elevated for decades after diagnosis. Patients with benign proliferative disease in the parenchyma adjacent to the fibroadenoma had a relative risk of 3.88 (95 percent confidence interval, 2.1 to 7.3). Patients with a family history of breast cancer in whom complex fibroadenoma was diagnosed had a relative risk of 3.72, as compared with controls with a family history (95 percent confidence interval, 1.4 to 10). Two thirds of the patients had noncomplex fibroadenomas and no family history of breast cancer and did not have an increased risk. CONCLUSIONS: Fibroadenoma is a long-term risk factor for breast cancer. The risk is increased in women with complex fibroadenomas, proliferative disease, or a family history of breast cancer.

Atypical hyperplastic lesions of the female breast. A long-term follow-up study.

A total of 10,542 breast biopsy specimens obtained between 1950 and 1968 were studied. Examples of atypical "ductal" (ADH) and atypical lobular hyperplasia (ALH), defined as having only some features of carcinoma in situ (CIS), were diagnosed in 3.6% of these specimens. In the same series, CIS was diagnosed in 1.7% of biopsy specimens excluding those with invasive cancer. The subsequent risk of invasive breast carcinoma after ALH or ADH was 4-5 times that of the general population. Follow-up was 90% successful and extended 17 years after biopsy. History of breast cancer in a mother, sister, or daughter doubled the risk of subsequent invasive carcinoma development (to 8 times for ALH and 10 times for ADH). The authors conclude that among the epithelial hyperplastic lesions of the human breast, a minority may be recognized by their resemblance to CIS which have a clinically significant elevation of subsequent breast cancer risk. This risk is one-half that of CIS.