Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle.

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.     

固相法合成心肌兴奋肽及其类似物

用Boc-和Tos-基团分别保护氨基和侧链胍基,以1%交联度聚苯乙烯二苯甲氨基树脂为载体,用DCC固相法合成肽,HF断裂肽树脂键和去除侧链保护基团,粗产物经高效液相层析纯化,合成了心肌兴奋肽Phe-Met-Arg-Phe-NH_2及其类似物Phe-Pro-Arg-Phe-NH_2,并观察了此二种肽对大鼠血压和心率的影响。     

Visual impairment following radial keratotomy. A cluster of cases

Thirteen patients who underwent radial keratotomy developed complications leading to visual impairment. Three eyes were legally blind. Two groups of complications were seen: those common to surgical procedures involving the eye--optic atrophy, infections, cataract and retinal detachment, and those unique to radial keratotomy--complete failure of the procedure, marked undercorrection, marked overcorrection, and induced astigmatism. Symptoms due to anisometropia were prominent in the latter group who considered themselves visually disabled by the surgery. Radial keratotomy, like all surgical procedures, is liable to complications that may lead to visual impairment, blindness, or loss of an eye.     

Diabetes mellitus associated with cystic fibrosis

The prevalence of overt diabetes mellitus and carbohydrate intolerance was studied in 448 patients with cystic fibrosis (CF). Insulin-dependent diabetes (IDDM) developed in 7.6% of patients (13 male and 21 female). Survival was significantly lower (P less than 0.01) in the IDDM-CF group, with fewer than 25% surviving to age 30 years, whereas nearly 60% of the nondiabetic CF population reached this age. A significant deterioration in CF clinical status, based on NIH score, became apparent 2 years before onset of overt IDDM (P less than 0.05 at 2 years prior, P less than 0.01 at IDDM diagnosis). Total glycosylated hemoglobin (HbA1) was significantly (P less than 0.001) higher for the total CF population (7.3% +/- 1.2%) than for the general non-CF population (6.5% +/- 0.7%), and in the IDDM-CF group (P less than 0.05) compared with normoglycemic CF control patients. Female patients had a higher mean HbA1 after 12 years of age than their male counterparts did (P less than 0.02). HBA1 did not predict the development of IDDM, but there was a weak inverse relationship between HbA1 and both NIH clinical score (r = -0.41, P less than 0.02) and standard pulmonary function tests (forced vital capacity, r = -0.25, P less than 0.01) in the general CF population. Therefore, impaired carbohydrate tolerance in CF is associated with progressive clinical deterioration.     

Preterm labor in twins and high-order multiples

Preterm labor (PTL) in a multiple gestation occurs frequently and is a common reason for preterm delivery (PTD). Management strategies for multiple gestations must be directed at early detection of PTL and effective strategies to delay or prevent PTD. Unlike singleton gestation where identification of patients at risk for PTL is often difficult, every multiple gestation is at risk for PTL, so all patients can be managed as being at risk. Although PTL is a significant cause of PTD, one must recognize that there are other reasons for delivery in multiple gestations. Clinicians must treat the whole patient and extend the pregnancy to the most advanced gestational age possible that is consistent with the best outcome.     

AN INACTIVE PRECURSOR OF STREPTOCOCCAL PROTEINASE

1. Streptococcal proteinase is derived from an inactive precursor found in culture filtrates of proteinase-producing streptococci. 2. The precursor can be converted into the proteinase by low concentrations of trypsin but not by chymotrypsin. 3. In cultures grown in suitable media the conversion of precursor to proteinase is effected autocatalytically. This reaction occurs under reducing conditions and is initiated by active proteinase present in low concentrations with the precursor. 4. The autocatalytic reaction is suppressed or retarded by conditions which decrease the activity of the proteinase, e.g. by growing cultures at 22°C. instead of at 37°C. or by growing them under markedly aerobic conditions. It is also retarded in the presence of casein.     

A retrospective study of physiotherapy management for patients with pneumonia requiring invasive ventilation in a single-center Australian ICU

Background:Pneumonia is a frequent diagnosis for patients admitted to Australian intensive care units (ICUs) for invasive ventilation. Physiotherapists in ICU provide interventions to enhance respiratory function and physical recovery.Objective:This retrospective cohort study aimed to describe physiotherapy management of adults with pneumonia who require invasive mechanical ventilation in a single Level 3 ICU in a quaternary teaching hospital.Methods:All adults admitted with a medical diagnosis of pneumonia requiring invasive mechanical ventilation over a two-year period were included. Demographic and clinical data, including APACHE II score, ventilator-free days (VFDs) to day 28, ICU length of stay (LOS), and type and frequency of physiotherapy episodes of care delivered in ICU, were collected from electronic medical records. Correlations between VFDs to day 28 and the frequency of physiotherapy interventions delivered per subject were examined using Spearman’s rho analysis.Results:From 208 records screened, 66 subjects with an ICU admission diagnosis of pneumonia, who required invasive mechanical ventilation, were included. Median (IQR) ICU LOS was 10 (5–17) days, and mortality rate was 15.2% (n=10). The cohort had a median of 20.5 (IQR 2–25) VFDs to day 28. Community-acquired pneumonia (66.7%, n=44) was the most frequent type of pneumonia diagnosis. There were 1110 episodes of physiotherapy care, with patients receiving a median of 13.5 (IQR 6.8–21.3) episodes during their ICU stay, with a median rate of 1.2 (IQR 1.0–1.6) episodes per day. Over 96.7% of patients with pneumonia received physiotherapy treatment during their ICU stay. Overall, physiotherapy treatments consisting only of respiratory techniques were most commonly provided (55.1%, n=612). Airway suctioning (92.4%, n=61), patient positioning (72.7%, n=48) or positioning advice to nurses (77.3%, n=51), and hyperinflation techniques (63.6%, n=42) were among the respiratory techniques most delivered.Conclusion:This study described the current intensive care physiotherapy management in a single center for adults with pneumonia who required invasive mechanical ventilation, demonstrating that respiratory physiotherapy interventions are often provided for this ICU patient cohort. Further research is warranted to determine the efficacy of respiratory physiotherapy interventions to justify their use for ICU patients with pneumonia receiving invasive mechanical ventilation.