Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.     

Possible Neuroprotective Effects of l-Carnitine on White-Matter Microstructural Damage and Cognitive Decline in Hemodialysis Patients

Although l-carnitine alleviated white-matter lesions in an experimental study, the treatment effects of l-carnitine on white-matter microstructural damage and cognitive decline in hemodialysis patients are unknown. Using novel diffusion magnetic resonance imaging (dMRI) techniques, white-matter microstructural changes together with cognitive decline in hemodialysis patients and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent dMRI and laboratory and neuropsychological tests, which were compared across seven patients each in two groups according to duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment (NSTLC), and (2) long-term l-carnitine treatment (LTLC). Ten age- and sex-matched controls were enrolled. Compared to controls, microstructural disorders of white matter were widely detected on dMRI of patients. An autopsy study of one patient in the NSTLC group showed rarefaction of myelinated fibers in white matter. With LTLC, microstructural damage on dMRI was alleviated along with lower levels of high-sensitivity C-reactive protein and substantial increases in carnitine levels. The LTLC group showed better achievement on trail making test A, which was correlated with amelioration of disorders in some white-matter tracts. Novel dMRI tractography detected abnormalities of white-matter tracts after hemodialysis. Long-term treatment with l-carnitine might alleviate white-matter microstructural damage and cognitive impairment in hemodialysis patients.     

Clinical and immunopathological evaluation of epidermolysis bullosa acquisita

Background. Epidermolysis bullosa acquisita (EBA) is a subepidermal blistering disease with IgG antibodies against collagen VII. The disease is heterogeneous and can lead to significant morbidity. Aim. To characterize the clinical and laboratory profile of patients with EBA from Sao Paulo, Brazil. Methods. In total, 12 patients (mean age 24 years) were analysed for cutaneous and mucosal involvement, laboratory data and response to treatment. Results. Mucosal involvement occurred in 11 of the 12 patients (eyes in 4/12, nose in 4/9, pharynx–larynx in 5/9 and oesophagus in 4/10; 3 patients did not undergo nasopharyngeal examination and 2 paediatric patients did not undergo endoscopy). Using direct immunofluorescence, different patterns of deposits were found at the basement membrane zone: IgG (12/12), IgA (6/12), IgM (4/12), C3 (11/12). Indirect immunofluorescence (IIF) was positive in 6 of 12 patients, and IIF on salt‐split skin detected dermal deposition in 10 of 12 patients. Antinuclear antibodies were found in 3 of 12 patients, but none of them fulfilled the criteria for systemic lupus erythematosus. After treatment, total remission was achieved in three patients and partial remission in five (three were maintained on minimal treatment, one on the full treatment and one was able to come off treatment). Two patients were lost to follow‐up and the remaining two had disease flares. Complications were mainly mucosal (oesophageal stenosis, laryngeal synechia, symblephara and trichiasis). Conclusions. Mucosal involvement in EBA is a determining factor for disease morbidity. Complete evaluation of the patient, focusing on both cutaneous and extracutaneous sites is essential, as EBA may evolve to refractory disease, severely compromising its outcome.     

Clonazepam in the treatment of prolonged depression.

BACKGROUND: The purpose of this paper was to examine the optimal adjunctive dose of clonazepam for the treatment of prolonged depression. METHODS: Sixty nine patients with prolonged depression were enrolled in an open trial over a 4 week period during which clonazepam was added to their medication. RESULTS: A daily dose of 3.0 mg clonazepam as augmentation was significantly more effective than doses of 1.5 mg and below. Most of the improved patients showed a rapid onset of action within 2 weeks, and side effects were not severe. CONCLUSION: A daily dose of at least 3.0 mg clonazepam as augmentation of ongoing antidepressant treatment should be considered in prolonged depressive patients with suboptimal improvement. LIMITATIONS: The effect on clonazepam alone on prolonged depression was not established, and its effect of on severe depression is unknown. High dose treatment was not carried out in this study.     

Discrimination of multiple primary lung cancers from intrapulmonary metastasis based on the expression of four cancer‐related proteins

BACKGROUND:

Because distinguishing between multiple primary lung cancers and intrapulmonary metastasis is often difficult when the tumor histology is same, the feasibility of analyzing differential protein expression profiles to distinguish multiple primary lung cancers from intrapulmonary metastasis was evaluated.

METHODS:

This study enrolled 50 patients, with multiple primary lung cancers demonstrating the same histology, who underwent surgery between April 1994 and March 2006 and 20 patients who were diagnosed to have intrapulmonary metastasis during the same period. Thirty patients with lymph‐node metastasis were selected for comparison purposes. The sum value of the differences in the expression ratio of 4 proteins (p53, p16, p27, and c‐erbB2) was evaluated in immunohistochemically stained specimens among multiple primary lung cancers and intrapulmonary metastasis.

RESULTS:

None of the 30 patients with lymph‐node metastasis showed a sum value of the differences between primary tumor and lymph‐node metastasis in the 4 protein expression ratios >90. Therefore, when the difference between 2 tumors exceeded 90, the 2 tumors were considered to be different from each other, ie, multiple primary lung cancers. Forty‐one of 50 (82%) patients who were clinically diagnosed to have multiple primary lung cancers showed a sum value of the differences in their protein expression ratios >90, 4 of 20 (20%) patients who were clinically diagnosed to have intrapulmonary metastasis showed a sum value >90. Among the patients who were clinically diagnosed to have multiple primary lung cancers and intrapulmonary metastasis, the 5‐year survival of 70 patients who had a sum value of the differences in their 4 protein expression ratios, either >90 (newly classified multiple primary lung cancers) and ≤90 (newly classified intrapulmonary metastasis), were 81.1% and 40.2%, respectively (P = .002).

CONCLUSIONS:

The profile of protein expression in cancer‐related genes is, thus, considered to be a useful tool for distinguishing multiple primary lung cancers from intrapulmonary metastasis and for determining the appropriate biological staging of lung cancer. Cancer 2009. © 2009 American Cancer Society.     

Rebleeding from intracranial dissecting aneurysm in the vertebral artery

We describe two patients with rebleeding from intracranial vertebral artery dissecting aneurysms during the acute stage. One patient had excellent results after emergency surgery. A review of recent reports including 60 patients with this disorder revealed a rebleeding rate of 30%, mostly during the acute stage. This suggests that a ruptured dissecting aneurysm in the vertebral artery is at risk for rebleeding during the acute stage, similar to a saccular aneurysm in the same location.