Safety and efficacy of a biodegradable implant releasing tenofovir alafenamide for vaginal protection in a macaque model.

OBJECTIVES: To advance the initiative of ending the global epidemic, long-lasting HIV protection is needed through sustained release of antiretroviral drugs for months to years. We investigated in macaques the safety and efficacy of biodegradable polycaprolactone implants releasing tenofovir alafenamide for HIV pre-exposure prophylaxis (PrEP). METHODS: Implants were administered subcutaneously in the arm using a contraceptive trocar. Efficacy against vaginal simian-HIV (SHIV) infection was investigated in six pigtailed macaques that received two tenofovir alafenamide implants (0.35 mg/day), one in each arm, for a total release rate of tenofovir alafenamide at 0.7 mg/day. Macaques were exposed to SHIV twice weekly for 6 weeks. Statistical analyses were used to compare outcome with eight untreated controls. Histological assessments were performed on skin biopsies collected near implantation sites. RESULTS: Median (range) tenofovir diphosphate level in PBMCs was 1519 (1068-1898) fmol/106 cells. All macaques with tenofovir alafenamide implants were protected against vaginal SHIV infection. In contrast, 7/8 controls were infected after a median of 4 SHIV exposures (P = 0.0047). Histological assessment of tissues near tenofovir alafenamide implant sites showed inflammation and necrosis in 5/6 animals, which were not evident by visual inspection. CONCLUSIONS: We demonstrated complete protection against vaginal SHIV infection with two implants releasing a total of 0.7 mg of tenofovir alafenamide per day. We also identified tenofovir diphosphate concentrations in PBMCs associated with complete vaginal protection. Consistent with previous findings, we observed adverse local toxicity and necrosis near the tenofovir alafenamide implant site. Improved tenofovir alafenamide implants that are safe and maintain high efficacy have the potential to provide long-lasting protection against vaginal HIV infection.

Spatiotemporal interplay of severe acute respiratory syndrome coronavirus and respiratory mucosal cells drives viral dissemination in rhesus macaques.

Innate immune responses have a critical role in the control of early virus replication and dissemination. It remains unknown, however, how severe acute respiratory syndrome coronavirus (SARS-CoV) evades respiratory innate immunity to establish a systemic infection. Here we show in Chinese macaques that SARS-CoV traversed the mucosa through the respiratory tract within 2 days, resulting in extensive mucosal infiltration by T cells, MAC387(+), and CD163(+) monocytes/macrophages followed by limited viral replication in the lung but persistent viral shedding into the upper airway. Mucosal monocytes/macrophages sequestered virions in intracellular vesicles together with infected Langerhans cells and migrated into the tonsils and/or draining lymph nodes within 2 days. In lymphoid tissues, viral RNA and proteins were detected in infected monocytes upon differentiation into dendritic cells (DCs) within 3 days. Systemic viral dissemination was observed within 7 days. This study provides a comprehensive overview of the spatiotemporal interactions of SARS-CoV, monocytes/macrophages, and the DC network in mucosal tissues and highlights the fact that, while these innate cells contribute to viral clearance, they probably also serve as shelters and vehicles to provide a mechanism for the virus to escape host mucosal innate immunity and disseminate systemically.

Carboplatin chemotherapy in a pregnant patient with undifferentiated ovarian carcinoma: case report and review of the literature.

There are already 12 reports of women treated by chemotherapy for epithelial ovarian cancer during pregnancy. However, most cases received chemotherapy of single cisplatin or cisplatin-based regime, and only four cases received carboplatin-containing chemotherapy. We report the case of a woman treated with single-agent carboplatin during pregnancy. The patient underwent bilateral salpingo-oophorectomy at 18 weeks of gestation and was diagnosed as having stage IC undifferentiated ovarian carcinoma. She was treated with four courses of carboplatin (area under the curve = 6.0) chemotherapy during pregnancy without severe toxicity. At 33 weeks of gestation, cesarean section was performed, followed by total hysterectomy, omentectomy, and pelvic and para-aortic lymphadenectomy. No residual disease was histologically shown. The patient underwent additional chemotherapy with carboplatin and paclitaxel. After one year of follow-up, the baby shows normal growth and the patient has no evidence of disease. Postponing the termination of pregnancy by single-agent carboplatin chemotherapy during pregnancy might be considered as an option for therapy in selected women with ovarian malignancies.

What is the best method of detecting endometrial cancer in outpatients?-endometrial sampling, suction curettage, endometrial cytology.

OBJECTIVE: Office methods of endometrial sampling for outpatients with abnormal uterine bleeding should be minimally invasive. The purpose of this study was to determine the best method for detecting endometrial cancer in an outpatients setting. METHODS: In all, 114 symptomatic women who were suspected of having endometrial disease by their local gynaecologist were enrolled in this study. After pelvic examination and transvaginal ultrasonography, endometrial cytology, suction endometrial curettage, and four-site endometrial biopsy were performed, in this order without anaesthesia in each patient. After endometrial sampling, the patient was asked to comment on the intensity of any pain experienced during each procedure. Then the final histological diagnosis made from the surgical materials was compared with the results of the three pre-operative methods. RESULTS: Among the 114 consecutive patients, 56 had endometrial carcinoma, three had carcinosarcoma, six had endometrial hyperplasia, and 49 had benign conditions. The sensitivity of detecting malignancy was 88% (52/59) with endometrial cytology, 92% (54/59) with suction curettage, and 88% (52/59) with four-site biopsy. When endometrial cytology was combined with suction curettage, the sensitivity of detecting malignancy was increased from 92% to 98%, whereas the sensitivity was increased from 88% to 97%, when endometrial cytology was added to four-site biopsy. Suction curettage was significantly less painful than four-site biopsy. CONCLUSION: Our data indicated that suction curettage plus endometrial cytology was the best combination for pathological examination of outpatients with abnormal uterine bleeding.

Prognosis of patients with rounded atelectasis undergoing long-term hemodialysis.

We present 4 patients undergoing hemodialysis in whom thoracic computed tomography (CT) suggested a diagnosis of rounded atelectasis (RA) with pleural effusion. The clinical setting and follow-up CT of all 4 patients confirmed this diagnosis. The pleural fluid of each appeared serosanguineous or hemorrhagic and predominantly consisted of lymphocytes. Biochemical analysis of this fluid revealed high levels of total protein, lactate dehydrogenase and glucose. Bacterial culture and polymerase chain reaction for Mycobacterium tuberculosis DNA was negative. Pleural biopsy specimens from 2 of the 4 patients showed evidence of fibrinous change and mesothelial cell hyperplasia. Pleural effusion from all 4 patients did not respond to either fluid restriction or aggressive hemodialysis-induced dehydration. The subsequent clinical course and thoracentesis were repeated, and in 1 patient, this was followed by tetracycline pleurodesis. However, 2 patients died during pre-pleurodesis and 1 died during post-pleurodesis, all due to respiratory failure. We propose that the clinical setting and follow-up thoracic CT and thoracentesis of patients receiving long-term hemodialysis confirmed a diagnosis of rounded atelectasis with uremic pleural effusion. We also propose that the prognosis of patients with refractory pleural effusion receiving long-term hemodialysis would be improved by early pleurodesis.

Type II diabetes mellitus and primary Sjögren's syndrome complicated by pleural effusion.

A 73-year-old man was admitted to our hospital because of pleural effusion and nephrotic syndrome. Sjogren's syndrome (Sjs) was diagnosed based on a positive test for antibodies to Ro and La, and the result of labial salivary gland biopsy. The pleural effusion showed a high number of lymphocytes and high titers of antibodies to Ro and La. By immunohistochemistry, it was determined that infiltrating CD3+ cells predominated over infiltrating CD20+ cells in the pleura. Nephrotic syndrome was also present, which, as confirmed by renal biopsy was due to advanced diabetic nephropathy. Here, we report a case of Type II diabetes mellitus and primary Sjs complicated by pleural effusion, discuss the available treatment for pleural effusion.

[Factors influencing clients' return home on discharge from geriatric intermediate care facilities in a metropolitan suburb].

The present study investigated factors influencing the destination following discharge from geriatric intermediate care facilities (GICF) located in a suburb of a metropolis. A set of questionnaires was prepared, and a survey was conducted involving 204 subjects (46 men, 158 women, average age 84 years) of three GICFs and their families. Seventy-two percent of clients were termed bedridden and 84% as having dementia. Furthermore, 63% of them were admitted to GICFs from hospitals, and about half used the GICFs more than twice. Most families cared for the subjects before admission into the GICFs, and were feeling the burden of daily care. The families desired them to stay in the GICFs for as long as possible. Forty-five percent of the families wanted the subject to go back home after discharge. About 30% of subjects returned home, 31% were admitted to a hospital and 40% were placed in GICFs. The following factors were related to discharge and return home: the family wanted the subject to return home, subjects admitted to GICFs from home could return home, good ability to walk, families consulted subjects about the destination following discharge, the cost of staying at the GICF was covered by the subjects' pension, and confirmed administration of drugs was not necessary. These findings suggest that in order for clients at GICFs to successfully return home, the facilities should consider where the family wants the clients to go.

[Characteristics of the clients in a geriatric intermediate care facility located in the suburbs of an urban area and factors related to the discharge destinations desired by family caregivers].

Among the clients in a geriatric intermediate care facility located in the suburbs of Osaka and their family caregivers (72 subjects), the characteristics of the clients and their caregivers, and the discharge destination desired by their family caregivers were investigated, and the associated factors were evaluated. 1. Characteristics of the clients. The clients were elderly females with a low degree of independence, and dementia was observed in about 60% of them. The clients had a relatively large number of children, but many of them lived alone before admission. The rate of admission from hospitals was high (54%), and that of discharge to hospitals was also high (50%). Sixty-seven percent of the clients stayed for a long duration of over 6 months. 2. Conditions of the family caregivers. Most of the family caregivers were daughters or daughters-in-law, and considered themselves to be healthy. Sixty-three percent of the caregivers had jobs. However, most of the caregivers did not have sub-caregiver. 3. Factors related to the discharge destination desired by family caregivers. Not many family caregivers (19.4%) wanted them to go back to their homes after discharge, but their preferred discharge destinations were home (19.4%), hospitals (55.5%), and nursing homes (25.1%). The caregivers of single household clients often desired a nursing home as the discharge destination, and those of the clients from a 2- or 3-generation household often desired a hospital. The factors related to the discharge destination desired by client's family caregivers were that the client not show dementia, the job of the caregiver was a part-time job, there was a sub-caregiver, and the client had the experience of home public health nursing visits. This study showed, the percentage of the clients discharged from the geriatric intermediate care facility to their homes was low, and that of the family caregivers who desired their home as the discharge destination was also low. However, the results suggested that leading the discharge destination to the client's home is possible if social resources are provided such as the use of public health nursing services.

[The effects of number of pre-target items and order of conditions on attention in rapid serial visual presentation].

Using rapid serial visual presentation, the present study attempted to show that an attentional control error in integrating the target-definition dimension into the response-definition dimension caused a target intrusion error. It also examined the temporal relation between such attentional control and monitoring. Forty-eight undergraduate and graduate students participated. Two conditions, consistent or varied timing of target presentation, were used to manipulate attentional control in the dimension integration. Each series of stimuli consisted of 7 (consistent timing) or from 7 to 15 (varied timing) pre-target items, followed by target and 8 post-target items. Results showed that timing had an effect on mean probability of report, but not on confidence rating. In addition, average position of reported items came later for consistent than varied timing. These results suggested that average position of reported items was delayed because a portion of attentional resources was allocated to processing of timing. Further, average position of confident items was earlier than that of reported items. It was suggested that monitoring seemed to precede attentional control.

[Allocation of attentional resource and monitoring processes under rapid serial visual presentation].

With the use of rapid serial visual presentation (RSVP), the present study investigated the cause of target intrusion errors and functioning of monitoring processes. Eighteen students participated in Experiment 1, and 24 in Experiment 2. In Experiment 1, different target intrusion errors were found depending on different kinds of letters --romaji, hiragana, and kanji. In Experiment 2, stimulus set size and context information were manipulated in an attempt to explore the cause of post-target intrusion errors. Results showed that as stimulus set size increased, the post-target intrusion errors also increased, but contextual information did not affect the errors. Results concerning mean report probability indicated that increased allocation of attentional resource to response-defining dimension was the cause of the errors. In addition, results concerning confidence rating showed that monitoring of temporal and contextual information was extremely accurate, but it was not so for stimulus information. These results suggest that attentional resource is different from monitoring resource.

Urinary biomarkers monitoring for experimental fluoride nephrotoxicity.

An excess of sodium fluoride (135 mg F/kg body weight) was given in a single oral dose to male Wistar rats. Effects were investigated of fluoride-induced acute kidney intoxication on the time-dependent variations of urine volume. Also, of urinary fluoride ion (F-), alpha-glutathione-S-transferase (alpha-GST), N-acetyl-beta-D-glucosaminidase (NAG), and creatinine (CR) concentrations. Fluoride administration strongly affects these urinary biochemical indices. Of the several biomarkers studied, alpha-GST is particularly useful as marker of S3 proximal tubule damage. We found that alpha-GST shows the strongest and more durable changes as a result of the large dose of F- given to the experimental animals. Our results suggest that the toxic effect of F- on the kidney may be more pronounced in the proximal tubule than the glomeruli region, and that the disorder of the proximal tubule is more serious in the S3 segment than S1 or S2 segment. Alpha-GST proved to be a useful marker for the early detection and long-term observation of proximal renal tubular injury resulting from F- intoxication. The animal model should help to establish guidelines for the treatment of industrial workers suffering from acute renal failure resulting from accidental exposure to fluoride.

Boron diffusion across the dialysis membrane during hemodialysis.

To investigate the movement of boron across the dialysis membrane, serum and dialysate boron levels of long-term hemodialysis (HD) patients (n = 17) were determined using inductively coupled plasma emission spectrometry in both the inlet and the outlet side of the dialyzer. Results revealed that 77.8% of the serum boron in the inlet side of the dialyzer was filterable and 94.4% of filterable boron was actually filtered during HD. Boron dialysance was found to be 138.6 +/- 16.1 ml/min, and this value was higher than the clearance value of blood urea nitrogen (not significant), phosphorus and creatinine (p < 0.001). It is concluded that HD is effective in eliminating serum boron even at low concentrations, and boron can be classified as an element that is easily diffusible across the dialysis membrane. There seems to be relatively little relation of boron to serum constituents of macromolecules that are reported to have a major impact on the diffusion of trace elements across the HD membrane.

Hemodialysis effect on serum boron level in the patients with long term hemodialysis.

Serum and dialysate boron levels in 17 patients with long term hemodialysis (HD) were determined by inductively coupled plasma emission spectrometry (ICPES). Serum boron level was compared with the value of age matched 467 healthy controls and the relationship between serum and dialysate boron level was analyzed. The results showed that serum boron level was significantly higher at the beginning of HD, and lower at the completion of HD in comparison with controls. Although the dialysate was contaminated with trace boron, HD resulted in an excessive decrease of serum boron, rather than boron exposure from the dialysate. Boron hemodialyzability was almost proportional to the gradient of the boron level at the beginning of HD and it could be controlled by the adjustment of the gradient. In conclusion, the serum boron level was very much disturbed in long term HD patients. If boron excess in serum at the beginning of HD, or deficiency at the completion of HD may contribute to the complications of HD patients, fine adjustment and close surveillance of the gradient should be taken into account.

Familial occurrence of Behçet's disease.

The familial occurrence of Behçet's disease in the 564 Behçet's patients treated in the Uveitis Survey Clinic of the Hokkaido University Hospital between 1967 and 1992 was investigated. Familial occurrence of Behçet's disease was found in 18 patients from 9 families. The male-to-female ratio was 3.5 in the familial cases, which was significantly higher than in the sporadic cases. Familial occurrence was most frequently seen among siblings. Most patients, including all female patients, had the complete type. They had typical ocular lesions, and exhibited bilateral uveoretinitis with poor visual prognosis, particularly the female patients. Frequency of HLA-B5 was 92% in the familial patients, which was much higher than in both the controls and the sporadic cases. It seems probable that patients with familial occurrence of this disease have a poorer prognosis with more susceptible immunogenetic backgrounds.

Increased met-enkephalin plasma levels in hemodialysis patients with or without pruritus.

Met-enkephalin plasma levels were measured in 21 hemodialysis patients with or without pruritus. The mean value was significantly increased in the total of the patients compared with that in ten healthy subjects. There was, however no correlation between met-enkephalin levels and the degree of pruritus. The findings suggest that the opioid system may be activated in this condition, although the relevance of this endogenous opioid peptide to pruritus remains to be determined.

Effect of exercise on hemodynamics and urinary protein excretion in patients with early-stage diabetic nephropathy.

We investigated the effects of exercise on hemodynamics and urinary protein excretion in 15 patients with early-stage diabetic nephropathy (DN) as compared the findings with these of 16 healthy volunteers. Patients were divided into two groups according to their renal histopathologic findings; Group D0 consisted of 8 patients in whom light microscopy showed minor glomerular abnormalities and Group DI consisted of 7 patients with early stage diffuse lesions. The subjects exercised on a treadmill at a workload of 4.7 METS for 20 minutes. Systolic blood pressure, heart rate and the pressure rate product were significantly higher in the DI group than in the D0 and control groups during exercise. Diastolic blood pressure was similar among the three groups. Creatinine clearance was unchanged during exercise. Urinary albumin excretion, urinary acid soluble protein excretion and urinary alpha 1-microglobulin excretion were all significantly increased in group DI compared with the D0 and control groups. Excretion of beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase activity were unchanged during exercise. Our findings suggest that this provocative exercise test is useful for diagnosing early-stage diabetic nephropathy.

[Familial occurrence of Behçet's disease].

Familial occurrence of Behçet's disease was studied in the Uveitis Survey Clinic of Hokkaido University Hospital. Eighteen patients in the nine families had familial occurrence of this disease. Male to female ratio was 0.28 in the familial cases, which was significantly higher than in the sporadic cases. Familial occurrence was most frequently seen among siblings. Most patients, including all of the females, belonged to the complete type. They had typical ocular lesions and exhibited bilateral uveoretinitis with poor visual prognosis, particularly in the females. The frequency of HLA-B5 was 92% in the familial patients, which was significantly higher than in the normal controls and the sporadic cases. It is probable that patients with familial occurrence of this disease have poorer prognosis with stronger immunogenetic backgrounds.

Glomerular lesions in patients with non-insulin-dependent diabetes mellitus and microalbuminuria.

To evaluate the renal structural changes in non-insulin-dependent diabetes mellitus (NIDDM), we studied the renal histological findings and urinary albumin excretion in 75 patients with NIDDM. They were divided into two groups according to excretion of urinary albumin: 40 cases of normoalbuminuria and 35 cases of microalbuminuria. Renal biopsy specimens were evaluated by light microscopy. Diffuse glomerular lesions were graded on a scale of D0 through DIV (Gellman's criteria). The incidence of microalbuminuria was 19.2% in D0, 53.3% in DI, 61.5% in DII and 100% in DIII. Grade IV lesions were not present in either group. Creatinine clearance differed significantly between the groups with and without microalbuminuria. There was no difference between the groups with normoalbuminuria and microalbuminuria in the incidence of retinopathy and hypertension, or in the urinary excretion of beta 2MG and NAG. We conclude that microalbuminuria in NIDDM indicates the early morphological changes of glomerular lesions.