Study on Control of pH-Modulation Crystallization Utilizing Concept of Dissociation Equilibrium.

Crystallization by pH adjustment, as a type of reaction crystallization, is a solid-liquid separation method widely used in the area of pharmaceutical and pharmaceutical intermediate manufacturing. On the other hand, 3-alkenyl cephem compound is a typical zwitterionic pharmaceutical intermediate that possesses both an amino group and a carboxylic acid group. Such structure affords three main pH regions in solution and results in difficulties using crystallization by pH adjustment for isolation. As a consequence, 3-alkenyl cephem compound is usually crystallized at the point away from the solubility curve, causing unrestricted nucleation and flocculation behavior for the deposited particles which is difficult to filtrate. In this study, the pKa of 3-alkenyl cephem compound was intensively investigated to inhibit the nucleation. An optimal pH level point was also sought to make monodisperse particles. In particular, during crystallization by pH-modulation operation, the key point was identified to be the number of primary particles aggregated in the secondary particles. It was revealed that the increment number of primary particles led to the generation of larger monodisperse particles. This investigation, combined with solid-liquid equilibrium, enabled the acquisition of target species with good operability for filtration process. This present investigation becomes the prosperity in the zwitterion compound production that it has hardships to crystallize and filtrate.

[Laparoscopic adrenalectomy for isolated metastasis of adrenal glands].

OBJECTIVES: The treatment of adrenal metastases using laparoscopic surgery still remains a matter of considerable controversy. The aim of this study is to present our experience of laparoscopic adrenalectomy for isolated adrenal metastasis. METHODS: From June 2004 to June 2011, 5 adults (4 males/1 female) with isolated metastases to the adrenal glands underwent laparoscopic adrenalectomy. These patients included 3 cases of lung carcinoma, a case of hepatocellular carcinoma, and a case of renal cell carcinoma. The median patient age was 69 (range 61 to 72), and the median tumor size was 3.5 cm (range 2.5 to 7.0). RESULTS: Laparoscopic adrenalectomies were performed without any complications using transperitoneal and retroperitoneal approaches. The median operative time was 142 minutes (range 126 to 174), and the estimated blood loss was 38 ml (range 25 to 158). The resection margins were free in all cases. A patient with lung cancer has been treated with adjuvant chemotherapy, otherwise, 4 patients have not. Regarding the oncological outcome, 3 of 5 patients were alive without any recurrence at a median follow-up of 14 months. About the rest two cases, one was alive with lung metastasis occurred at 15 months later, the other was died of the cancer at 14 months later. CONCLUSIONS: Laparoscopic adrenalectomy for isolated adrenal metastasis is thought to be feasible. However, the indication of the surgery must be determined depending on tumor size, cancer characteristics, risk factors and so on. Additionally, the operative procedures such as approaches must be discussed sufficiently.

Investigation of Operation Strategy Based on Solution pH for Improving the Crystal Quality Formed during Reactive Crystallization of l-Aspartic Acid.

The production of crystalline particles with a thick and low degree of agglomeration is required because the agglomerated crystals with thin primary particles, which are frequently formed during reactive crystallization, deteriorate the crystal size distribution (CSD) of the final product due to their fragile morphology. This study aimed to develop an operation strategy for improving the degree of agglomeration and thickness of crystalline particles in the reactive crystallization considering the effect of the solution pH using l-aspartic acid as an experimental system. The scanning electron microscopy observations showed that the thickness of primary particles which form agglomerated crystals could be increased by operating the crystallization under low solution pH conditions. In contrast, it was found that operating the crystallization under high solution pH led to a decrease in the nucleation rate of crystalline particles, which resulted in a decrease in the degree of agglomeration. Then, an operation method, that is, changing the addition method of feed solutions to overcome the trade-off between the thickness and degree of agglomeration, was proposed by considering the effect of solution pH. Consequently, crystalline particles with a narrow CSD could be successfully obtained using the proposed method due to the suppression of the agglomeration and increase of the thickness. Therefore, the development of the operation strategy based on the effect of the solution pH on the degree of agglomeration and thickness is important to produce crystalline particles with improved CSD in reactive crystallization.

Reduction in serum high mobility group box-1 level by polymyxin B-immobilized fiber column in patients with idiopathic pulmonary fibrosis with acute exacerbation.

BACKGROUND/AIM: Recent reports suggest that polymyxin B (PMX)-immobilized fiber may have beneficial effects in idiopathic pulmonary fibrosis (IPF) with acute exacerbation (AE). High mobility group box-1 (HMGB-1) is an important pro-inflammatory mediator that contributes to acute lung inflammation. This study was aimed to investigate whether PMX treatment affects serum HMGB-1 levels and oxygenation in IPF patients with AE. MATERIALS AND METHODS: Twenty IPF patients with AE were treated by PMX. PMX treatment was carried out once daily for 2 successive days. Serum HMGB-1 levels were measured before and after PMX treatment. We also monitored arterial oxygen tension (PaO(2))/inspiratory oxygen fraction (FiO(2)) (P/F) ratio. PMX fiber columns were analyzed to examine whether HMGB-1 was absorbed by PMX. RESULTS: PMX treatment significantly improved both the serum HMGB-1 level and P/F ratio. HMGB-1 was detected in washing medium from the PMX column. CONCLUSION: PMX treatment may reduce serum HMGB-1 and improve oxygenation in patients with IPF with AE.

[Nine-month observation of effects of SO2 on the respiratory system in child Miyakejima citizens].

BACKGROUND: Mt. Oyama on Miyakejima Island erupted in June 2000 and all Miyake village citizens were forced to evacuate the island in the September, due to continuous eruptions and emission of unsafe amounts of volcanic gas, mainly sulfur dioxide (SO2). Beginning in February 2005, residents returned to live on the island despite the fact that volcanic gas was still being emitted. OBJECTIVE: To examine changes in the respiratory systems of included children from February 2006 to November 2006. METHODS: The study population was 141 children who participated in health checkups in November 2006, including 33 SO2 hypersusceptible children who had a current or past history of asthma, obstructive lung function, current symptoms of whistling and wheezing, and/or deterioration of respiratory symptoms. Respiratory effects were evaluated by a questionnaire for respiratory symptoms and by spirometry. SO2 was monitored at 7 sampling points within inhabited areas, and the mean SO2 concentration from February 2005 to November 2006 was 0.031 ppm. The area was categorized into four areas by average SO2 concentration, namely, areas L, H-1, H-2, and H-3, where the average SO2 levels were 0.019, 0.026, 0.032, and 0.045 ppm, respectively. RESULTS: Compared to children in area L, the frequencies of "phlegm" and "irritation of the nose" were significantly greater in the children in areas H-2 and H-3. %FVC and %FEV1 in hypersusceptible children were significantly reduced in November 2006 as compared to February 2006 (P = 0.047, 0.027), though no reduction observed in normosusceptible children. CONCLUSION: Respiratory functions in hypersusceptible Miyakejima children may be affected by SO2 exposure, and further follow-up observation is necessary.

Off-line fractional exhaled nitric oxide measurement is useful to screen allergic airway inflammation in an adult population.

To determine whether off-line fractional exhaled nitric oxide (FeNO) measurement is applicable to screen allergic airway inflammation for epidemiologic studies, we examined 280 adults, measuring off-line FeNO samplings, pulmonary function, and serum immunoglobulin E (IgE). Subjects with recurrent wheeze (recurrent wheezers) had significantly higher FeNO and IgE levels and significantly lower forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) than non-wheezers. Statistical analysis showed that FeNO and FEV1/FVC were significant predictors for recurrent wheezers, independent of smoking. The cut-off FeNO level for screening allergic airway inflammation was 38 ppb in non-smokers and 32.9 ppb in smokers. Thus, off-line FeNO can be used as a good marker to screen allergic airway inflammation, regardless of smoking.

[A case of polymyositis with concomitant diffuse alveolar damage following interstitial pneumonia].

A 68-year-old woman had been given a diagnosis of interstitial pneumonia (NSIP pattern) and followed up at our hospital for 3 years. She was admitted to our hospital because of dyspnea, lower limb edema and myalgia. On admission, serum CPK and CRP levels were elevated and an electromyogram suggested inflammatory myopathy. We diagnosed polymyositis (PM) with progressive interstitial pneumonia (IP). Although methylprednisolone pulse therapy and immunosuppressive agents were administered, pulmonary lesions became aggravated. The patient died due to respiratory failure as a result of the progress of IP. The autopsy lung revealed diffuse alveolar damage (DAD) at the both acute and fibrotic phases, suggesting that DAD could coincide with PM. We report here a rare case of polymyositis with diffuse alveolar damage (DAD).

An exploratory trial of intravenous immunoglobulin therapy for idiopathic pulmonary fibrosis: a preliminary multicenter report.

BACKGROUND AND AIMS: Idiopathic pulmonary fibrosis (IPF) is a fatal disorder without specific treatments. Although the efficacy of intravenous immunoglobulin (IVIG) therapy for autoimmune diseases has been reported, that for IPF remains unknown. This study aims to determine the efficacy and safety of IVIG for IPF. METHODS: In an exploratory, multicenter, non-randomized and prospective trial, patients with progressive IPF were enrolled. Patients were treated with IVIG for five consecutive days (5-day IVIG) or once monthly for five consecutive months (5-month IVIG). Changes in the vital capacity (VC), diffusion capacity of the lung for carbon monoxide (DLCO), 6-min walk test (6MWT) and high-resolution computed tomography (HRCT) findings were evaluated. RESULTS: A total of 10 patients with IPF were treated with IVIG: 6 were in 5-day IVIG and 4 were in 5-month IVIG group. In 5-day IVIG group, the treatment effects were temporal, and physiological and HRCT findings deteriorated in three of six patients. In 5-month IVIG group, changes in %VC, %DLCO and walk distance in 6MWT at 6 months were -0.9 ± 5.3%, 6.9 ± 12.6% and 79 ± 58 m (mean ± standard deviation), respectively, and the treatment effects were long lasting. The change in VC 6 months after starting IVIG was smaller than that of 6-12 months after starting IVIG (after cessation of IVIG) (-0.02 ± 0.15 vs -0.33 ± 0.14 L, P = 0.022). Ground glass opacities were diminished in two of four patients. Adverse events were mild and tolerable. CONCLUSION: This preliminary study shows that once-monthly IVIG treatment may be effective and tolerable in patients with IPF.

[Effects of volcanic sulfur dioxide on reconstruction workers and residents returning to Miyake Island].

Four and half years have passed since Mt. Oyama in Miyake Island erupted. Ambient sulfur dioxide (SO2) is still above the environmental air standard in parts of the island, even though emission of the volcanic gas has diminished. Reconstruction of life-support infrastructure in the island and safety measures started in July 2002, and a short-term trial stay project for former residents was completed in April 2003 for the total rehabilitation of the island. We conducted health examinations, and questionnaires on clinical symptoms among the reconstruction workers in January 2003, as well as questionnaires on respiratory symptoms among former residents who joined the trial stay, in late fall of 2003. The peak expiratory flow rate and symptoms of the workers and the symptoms of the short-term residents were not correlated to SO2 concentrations. In addition, we investigated the medical histories of outpatients at Miyake-mura National Insurance Center Clinic. We could not recognize any cases directly connected with higher ambient SO2 concentration in the area of the island, but there was a male worker, in his thirties, who suffered an initial attack of bronchial asthma, which required intensive care and treatment. As a general rule, all the workers and the residents are asked to wear gas masks for SO2 when its concentration is above 2.0 ppm and to stay in the house with desulfuration facilities as a precautionary measure at night. The residents are now well informed about the risks of volcanic gas and preventive measures for adverse health effects. We could not evaluate correlations between SO2 exposure indices and health effects sufficiently due to the limitation of the field study, but this study presents useful pieces of information as a risk communication for reconstruction workers and former inhabitants to the island.

[Diagnosis of ocular sarcoidosis by diagnostic criteria for systemic sarcoidosis].

PURPOSE: To evaluate the diagnostic criteria for systemic sarcoidosis in diagnosis of ocular sarcoidosis. SUBJECTS AND METHODS: Subjects were 105 ocular sarcoidosis suspects and 37 patients with other uveitis. We diagnosed ocular sarcoidosis suspects using the diagnostic criteria for systemic sarcoidosis proposed by the Japanese Committee for Diffuse Lung Diseases. The criteria included histological and clinical diagnosis, and the clinical diagnosis required 5 systemic tests: 1) tuberculin skin test, 2) serum gamma-globulin(gamma-gl), 3) serum angiotensin converting enzyme(ACE), 4) serum lysozyme, and 5) 67Ga scintigraphy. Three positive findings including either 1) or 3) fulfilled the clinical diagnosis. RESULTS: Sixty-two patients were histologically and/or clinically diagnosed, and 43 patients remained undiagnosed. The histological and clinical diagnosis did not produce the same diagnostic yields. The sensitivity of ACE and gamma-gl was low. The percentage of patients showing increased lymphocytosis and/or CD 4/8 in bronchoalveolar lavage was similarly high in the diagnosed and undiagnosed, suggesting the presence of definitive ocular sarcoidosis in the undiagnosed. CONCLUSIONS: The diagnostic criteria for systemic sarcoidosis yielded false negative results in diagnosing ocular sarcoidosis. The selection and combination of systemic tests for clinical diagnosis should be further studied.

[Relationship between sleep disordered breathing and body weight loss in patients with chronic obstructive pulmonary disease].

We evaluated body weight loss and growth hormone secretion in patients with sleep-disordered breathing associated with chronic obstructive pulmonary disease. Of 11 patients hospitalized for pulmonary rehabilitation, five (WL group) had a history of body weight loss within two years before their interviews, while the other 6 patients (NWL group) had no changes in body weight. All patients underwent body index measurements, pulmonary function tests, blood gas analyses, assessments of nutritional status, and full night polysomnography for two consecutive days. Growth hormone levels were measured in the first 3-hour period following falling asleep. There were no significant inter-group differences between the results of pulmonary function tests, blood gas analyses, or nutritional status assessment. The WL group had a significantly higher percentage loss of body weight than the NWL group (mean +/- S.D. 11.5 +/- 4.7% in the WL group versus 2.7 +/- 1.8% in the NWL group, p < 0.01). The WL group had a significantly higher sleep apnea/hypopnea index than the NWL group (42.4 +/- 9.5/hr in the WL group versus 7.8 +/- 2.9/hr in the NWL group, p < 0.01). The WL group showed a higher rate of stage I + II sleep than the NWL group (84.9 +/- 7.0% versus 64.5 +/- 8.7%), with lower rates of slow wave sleep (2.2 +/- 2.1% versus 15.0 +/- 8.7%) and rapid eye movement sleep (12.9 +/- 6.3% versus 20.6 +/- 1.0%). The WL group showed a low level of growth hormone secretion with no peak in the sequential curve, but had a higher level of insulin growth factor-1 than the NWL group (148 +/- 36 ng/ml versus 90 +/- 22 ng/ml, p < 0.01). These results suggest that chronic obstructive pulmonary disease patients undergoing weight loss are likely to have an increase of growth hormone secretions in the daytime, possibly induced by underlying psychiatric disorders such as depression. Patients with chronic obstructive pulmonary disease may lose weight regardless of nutritional status because of a disturbance of growth hormone secretion resulting of sleep-disordered breathing.

[A case of secondary pulmonary cryptococcosis showing various radiographic changes during its natural course without antifungal treatment].

A 58-year-old man who had been prescribed corticosteroids for rheumatoid arthritis in another hospital was admitted to our hospital for examination of an abnormal chest shadow. We obtained a positive result for cryptococcal antigen in the serum, in a measurement done as a screening test for abnormal chest shadows. We diagnosed secondary pulmonary cryptococcosis through a transbronchial biopsy. He showed various radiographic changes, including multiple nodular shadows, cavities and partial resolution during the natural course without antifungal treatment. This case taught us that secondary pulmonary cryptococcosis causes a more varied range of radiographic changes than its primary form, that measurement of cryptococcal antigen in serum is useful as a screening test of pulmonary cryptococcosis, and that it is important to consider whether a particular patient should be treated or not.