Thyrotoxicosis and renal tubular acidosis presenting as hypokalaemic paralysis

We report a case of oesophageal disease as the first manifestation in a patient with CREST syndrome. A 46-year-old man with achalasia-like syndrome developed CREST syndrome 4 years later. A pneumatic dilatation of the cardia was performed. After pneumatic dilatation the dysphagia and regurgitation disappeared but the patient developed reflux oesophagitis. Four years after diagnosis of oesophageal disease he presented with a clinical picture of CREST syndrome. An acute ileus and constipation developed later. After receiving medical therapy with omeprazole and cisapride the patient is free of oesophageal symptoms and bowel movements are normal. Oesophageal disease is common in patients with limited and diffuse scleroderma, but to our knowledge achalasia-like syndrome has not been previously described as the first manifestation of the systemic disease.     

CD56+ NK lymphomas: clinicopathological features and prognosis

Dosing regimen is an important determinant of both drug cost and patient compliance. This retrospective analysis evaluated dosing regimens and drug acquisition costs for 101 patients identified from medical records in a large metropolitan hospital as having hypertension and/or benign prostatic hyperplasia and receiving alpha-blocker therapy with either doxazosin or terazosin. Although once-daily administration is generally recommended for both drugs, 25 (38%) of 66 patients receiving terazosin were treated twice daily compared with 6 (17%) of 35 patients treated twice daily with doxazosin. This difference was statistically significant. The average (mean +/- SD) daily treatment cost per patient for all individuals receiving terazosin during the period of the record review was $1.68 +/- 0.60. For patients treated with doxazosin, the average was $0.96 +/- 0.65-a highly statistically significant result. If all 66 patients receiving terazosin had been converted to doxazosin at the beginning of the study, annual savings would have been $17,345.00. These results demonstrate the importance of reviewing actual dosing regimens. The fact that doxazosin could be administered to a significantly higher percentage of patients once daily rather than twice daily substantially decreased its cost relative to terazosin. A once-daily treatment regimen may also enhance patient compliance, thereby improving the chances of therapeutic success.     

The intestinal epithelial stem cell: the mucosal governor

All epithelial cells in the small and large intestine are thought to originate from stem cells located towards the base of the crypts of Lieberkühn. To-date, there are no specific intestinal stem cell markers, hence stem cell properties can only be inferred. A range of experimental techniques have been employed including cell position mapping, radiation regeneration (clonogenic) assays, chimeric and transgenic mice. This review discusses the implications of experiments performed using these techniques in order to deduce the number, location and functional properties of stem cells. Stem cell homeostasis is maintained by cell proliferation and death 'through apoptosis'. The various growth and matrix factors and genes which may control these processes, and be important for stem cell function, are discussed along with their carcinogenic and clinical implications.     

CD72-mediated B cell activation involves recruitment of CD19 and activation of phosphatidylinositol 3-kinase

Occupancy of the B cell glycoprotein, CD72 results in syk-independent activation of phospholipase-C gamma and calcium mobilization. The cytoplasmic tail of CD72 does not contain an immunoreceptor tyrosine-based activation motif to directly transduce signals into the B lymphocyte. Hence, we investigated whether other coreceptors such as CD19 and its associated phosphatidylinositol 3-kinase (PI 3-K) were involved in CD72 signaling. Two specific inhibitors of PI 3-K inhibited CD72-stimulated B cell proliferation in a dose-dependent manner. Activation of B lymphocytes via CD72 resulted in recruitment and activation of PI 3-K, which was mediated by CD19. Accordingly, CD72 ligation induced CD19 tyrosine phosphorylation. Thus, lipid products generated as a result of PI 3-K activation may have an important function in CD72-mediated B lymphocyte activation. The kinetics of CD19 tyrosine phosphorylation induced by CD72 ligation were strikingly different from those seen following B cell antigen receptor (BCR) stimulation. A transient increase in the tyrosine phosphorylation of the complement receptors, CD21 and CD35 was observed in BCR- but not CD72-stimulated cells. Co-cross-linking of CD72 and CD19 failed to induce syk tyrosine phosphorylation suggesting that even under these conditions, CD72 signaling was independent of syk activation. A transient and stimulation-dependent physical association between CD19 and CD72 was observed in CD72-ligated cells. These observations suggest a mechanism by which CD72 can recruit CD19 and influence activation of CD19-associated PI 3-K, which appears to be critical for CD72-mediated B cell activation.     

Rapid ganciclovir susceptibility assay using flow cytometry for human cytomegalovirus clinical isolates

Rapid, quantitative, and objective determination of the susceptibilities of human cytomegalovirus (HCMV) clinical isolates to ganciclovir has been assessed by an assay that uses a fluorochrome-labeled monoclonal antibody to an HCMV immediate-early antigen and flow cytometry. Analysis of the ganciclovir susceptibilities of 25 phenotypically characterized clinical isolates by flow cytometry demonstrated that the 50% inhibitory concentrations (IC50s) of ganciclovir for 19 of the isolates were between 1.14 and 6.66 microM, with a mean of 4.32 microM (+/-1.93) (sensitive; IC50 less than 7 microM), the IC50s for 2 isolates were 8.48 and 9.79 microM (partially resistant), and the IC50s for 4 isolates were greater than 96 microM (resistant). Comparative analysis of the drug susceptibilities of these clinical isolates by the plaque reduction assay gave IC50s of less than 6 microM, with a mean of 2.88 microM (+/-1.40) for the 19 drug-sensitive isolates, IC50s of 6 to 8 microM for the partially resistant isolates, and IC50s of greater than 12 microM for the four resistant clinical isolates. Comparison of the IC50s for the drug-susceptible and partially resistant clinical isolates obtained by the flow cytometry assay with the IC50s obtained by the plaque reduction assay showed an acceptable correlation (r2 = 0.473; P = 0.001), suggesting that the flow cytometry assay could substitute for the more labor-intensive, subjective, and time-consuming plaque reduction assay.     

Gamma-linolenic acid (GLA) is cytotoxic to 36B10 malignant rat astrocytoma cells but not to 'normal' rat astrocytes

This study compares the effect of gamma-linolenic acid (GLA) and its precursor linoleic acid (LA) on survival of 36B10 malignant rat astrocytoma cells and 'normal' rat astrocytes. GLA was cytotoxic to 36B10 cells but not to astrocytes. By contrast, LA supplementation did not affect the survival of either cell types. There were minor differences in the uptake, distribution and use of radiolabelled GLA and LA by the 36B10 cells and astrocytes. GLA and LA supplementation increased the total polyunsaturated fatty acid (PUFA) content of the cells indicating increased oxidative potential. However, elevated levels of 8-isoprostane, an indicator of increased oxidative stress, were only observed in the GLA supplemented 36B10 cells. Addition of the antioxidant trolox to GLA-enriched 36B10 cells blocked the cytotoxic effect. Further, GLA enhanced the radiation sensitivity of the astrocytoma cells but not the astrocytes; trolox blocked the GLA-mediated increase in astrocytoma cell radiosensitivity. LA did not affect the radiation response of either cell type. While cyclo-oxygenase inhibitors did not affect GLA cytotoxicity, they blocked the enhanced radiation response of GLA-supplemented cells. The lipoxygenase inhibitor NDGA did not affect the toxicity produced by GLA. Thus, GLA is toxic to the neoplastic astrocytoma cells but not to normal astrocytes.     

Conserved regulatory element involved in the early onset of Hoxb6 gene expression

When administered before training to 23-day-old Long-Evans rats, scopolamine hydrobromide significantly impaired both contextual and auditory-cue fear conditioning in a dose-dependent manner. Methylscopolamine which does not cross the blood-brain barrier, however, had no effect on either form of conditioned fear. Scopolamine administered up to 3 h after training also impaired both forms of fear conditioning when administered following a single pairing of the auditory cue and shock. When rats received three pairings, however, a posttraining treatment with scopolamine only impaired contextual fear conditioning. These results suggest that central cholinergic systems are involved in the posttrial processes that establish the memory trace for the conditioning experience.     

Occupational injuries among older workers with visual, auditory, and other impairments. A validation study

This study aims to validate a previously defined model of the risk of occupational injuries among older workers with visual, auditory, or other impairments. That model was based upon the Health and Retirement Study (HRS). The previous logistic regression model was recalculated using data from the 1994 National Health Interview Survey (NHIS). The parameter estimates for impaired hearing (.181 in NHIS, 1.55 in HRS), impaired vision (2.42 in NHIS, 1.48 in HRS), and self-employment (0.22 in NHIS, 0.49 in HRS) were in same direction and of roughly the same magnitude. The previously defined model was confirmed using NHIS data. The data suggest that as the workforce ages, more attention must be paid to the accommodation of disabilities in the workplace, especially sensory impairments-poor vision and hearing.     

Ocular neuromyotonia: clinical features, physiological mechanisms, and response to therapy

Ocular neuromyotonia (ONM) is a rare disorder characterized by episodic diplopia, occurring either spontaneously or following sustained eccentric gaze. Most patients have had prior radiation therapy to the sellar and parasellar region. ONM is thought to reflect impaired muscle relaxation due to inappropriate discharges from oculomotor, trochlear, or abducens neurons or axons with unstable cell membranes. Patients with ONM often benefit from membrane stabilizing agents such as carbamazepine. Here we describe a 71-year-old man, with no history of radiation therapy, who for 18 months had had transient episodic diplopia that occurred after down gaze. Clinical examination indicated ONM in muscles supplied by the right oculomotor nerve. Binocular scleral search coil eye movement recordings revealed a defect not only of muscle relaxation but also of maximal muscle contraction. The patient was treated with carbamazepine 200 mg per day with complete resolution of his symptoms. ONM may be more common than previously recognized, and patients with unexplained transient episodic diplopia should be specifically tested for diplopia and ocular misalignment following sustained eccentric gaze.