Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships.

Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.     

Primary cranial vault lymphoma mimicking meningioma

Primary lymphomas of the cranial vault are rare; only six patients have been described in the literature. We report a 75-year-old woman who was admitted to our hospital after a focal seizure. CT showed a homogeneous mass which, on contrast enhancement, was similar to a meningioma. The tumour was excised and found to be a centroblastic, centrocytic non-Hodgkin's lymphoma. Treatment was completed with radiotherapy and chemotherapy.     

Attempted rapid elbow flexion movements in patients with athetosis.

Voluntary rapid elbow flexion movements were studied in 14 patients with athetosis on the basis of cerebral palsy. When the movement was attempted with one arm, other muscles inappropriate for the task, such as muscles in the opposite limb, were also activated. EMG activity of the biceps and triceps was analysed in detail, and the patterns seen in the different patients were divided into six groups: (1) The normal "ballistic" triphasic pattern, with bursts of normal duration, alternating in biceps and triceps, but the triceps might be activated first, causing the limb to extend rather than flex, (2) The triphasic pattern, with bursts of long duration, (3) Repetitive cycles of the triphasic pattern with particularly long antagonist bursts, apparently limiting the movement in each cycle, (4) Long bursts synchronous in agonist and antagonist muscles, (5) Continuous activity of the agonist, with reduction in activity of the antagonist, (6) Failure to be able to do the task. The pathophysiology of athetosis is that voluntary movement is characterised by excessive muscular activity, most prominently in inappropriate muscles, both extraneous to the task and directly antagonistic.     

Dermatosis among the Xavánte from the Pimentel Barbosa Indian Reservation, Mato Grosso, (Brazil)

The authors present the results of a dermatological survey conducted among the Xavánte Indians from the Pimentel Barbosa Reservation, state of Mato Grosso, Brazil Scabies, pediculosis, and pioderma were the most frequent diseases, clearly related to poor hygiene. The finding of perleche indicates the presence of nutritional deficiency. Endemic pemphigus foliaceus (fogo selvagem) was the most serious dermatological affection found in this population.     

Pressure ulcers: critical considerations in prevention and management

Pressure ulcer development is a serious problem occurring predominately among elderly persons, who are confined to bed or chair. Factors associated with pressure ulcer development include: cerebrovascular accident, impaired nutritional intake, fecal incontinence, lymphocytopenia and a high comorbidity score. Implementation of preventative measures, such as: in-depth assessment for mobility, a pressure relieving device combined with adequate repositioning, thorough evaluation for nutritional status and urinary incontinence, significantly reduce pressure ulcer incidence. If the pressure ulcer is a partial thickness (Stage II) wound, the causative factors are probably friction and/or moisture. If the ulcer is full thickness (Stage III, IV) it is secondary to pressure and/or shearing forces. The development of wound infection is the most common complication. Osteomyelitis is not an uncommon occurrence and must be initially ruled out in all full thickness pressure ulcers. Surgical debridement of necrotic tissue is necessary prior to further treatment and /or assessments. Cultures and antibiotic therapy are indicated only upon evidence of infection (erythema, edema, cellulitis, osteomyelitis, leukocytosis, bandemia or fever). Topical pharmacologic agents may be used to prevent or treat infection but must be carefully controlled to avoid such adverse effects as toxicity to the wound, allergic reaction and development of resistant pathogens. Proper use of occlusive dressings increase patient comfort, enhance healing, decrease the possibility of infection, save time and reduce costs. A patient presenting an ulcer which fails to improve, or due to its size will take a great deal of time to heal, should be evaluated for surgical closure.     

Microfluorometry of nuclear acridine orange metachromasia in lymphocytes of thymus, spleen, and blood of AKR and random-bred mice.

Lymphocyte chromatin lability to acid hyrolysis was studied using acridine orange fluorescence metachromasia in a high-lymphocytic-leukemia-susceptibility strain (AKR) and random-bred mice (ICR). Comparisons were made of blood, thymus, and spleen lymphocytes between random-bred, "normal" AKR, and leukemic AKR animals. The leukemic mice were in the stages of the disease characterized by enlarged thymus and spleen but preceding massive elevation of blood lymphocytes. The ranges of the mean chromatin acid lability overlapped and were nearly identical in peripheral blood lymphocytes. However, thymic and splenic lymphocytes showed a marked rise in mean chromatic acid lability in the leukemic animals. The ranges of the mean values of this parameter were also found to be far greater in the lymphopoietic organs of normal AKR than in the random-bred mice. The data indicate that anatomically normal AKR animals of an age in which they are highly susceptible to spontaneous lymphocytic leukemia may contain a greater number of lymphoblasts in both the spleen and the thymus than do comparable random-bred mice. The implications of these findings are discussed in relation to strain differences and the concept of thymic origin of lymphocytic leukemia in mice.