Clozapine-induced acute interstitial nephritis.

Acute interstitial nephritis is a common cause of acute kidney injury. Acute interstitial nephritis is most commonly induced by drug although the cause may also be infective, autoimmune, or idiopathic. Although eosinophilia and eosinophiluria may help identify this disease entity, the gold standard for diagnosis remains renal biopsy. Prompt diagnosis is important because discontinuation of the culprit drugs can reduce further kidney injury. We present a patient with an underlying psychiatric disorder who was subsequently diagnosed with clozapine-induced acute interstitial nephritis. Monitoring of renal function during clozapine therapy is recommended for early recognition of this rare side-effect.

Anti-müllerian hormone and ovarian reserve in systemic lupus erythematosus.

OBJECTIVE: To study the level of anti-müllerian hormone (AMH) and its relationship to age and previous exposure to cyclophosphamide (CYC) in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive female patients ages 18-52 years who had menses at least once during the preceding 12 months and fulfilled ≥4 American College of Rheumatology criteria for SLE were recruited. AMH was determined using an enzyme-linked immunosorbent assay (ELISA) kit. Serum AMH levels were compared in patients with and without previous use of immunosuppressive agents. The relationship of the AMH level to the patient's age and CYC exposure was studied by linear regression and receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 216 patients were studied (mean±SD age 35.1±10.1 years, mean±SD SLE duration 7.6±5.9 years). The mean±SD AMH level was significantly lower in patients previously exposed to CYC therapy than in those who had not been exposed after adjustment for age (1.58±2.92 versus 1.73±2.11 ng/ml; P=0.04). The median time interval between the AMH assay and the last dose of CYC administered was 6.7 years (interquartile range 3.4-8.5). AMH levels in users versus nonusers of other immunosuppressive agents, including mycophenolate mofetil, azathioprine, and the calcineurin inhibitors, were not statistically different. Linear regression revealed increasing age (beta -0.32, P=0.02) and each 5 gm of CYC exposure (beta -0.28, P=0.047) were independently associated with a lower AMH level. In patients ages 30 years and younger, a cumulative CYC dose cutoff of 5.9 gm yielded a sensitivity of 0.75 and a specificity of 0.80 for the prediction of undetectable AMH level on ROC curve analysis. CONCLUSION: AMH is a sensitive marker for ovarian damage due to previous CYC exposure in women with SLE.

Five Japanese cases of antidesmoglein 1 antibody-positive and antidesmoglein 3 antibody-negative pemphigus with oral lesions.

BACKGROUND: Oral mucosal lesions develop in pemphigus vulgaris, but not in pemphigus foliaceus. This clinical phenomenon is explained by the 'desmoglein (Dsg) compensation theory'. Dsg3 and Dsg1 are major autoantigens for pemphigus vulgaris and pemphigus foliaceus, respectively. Dsg3 is overexpressed and Dsg1 is weakly expressed on the oral mucosa. Thus, on the oral mucosa, suppression of Dsg3 function by anti-Dsg3 autoantibodies is not compensated by weakly expressed Dsg1 in pemphigus vulgaris, while suppression of Dsg1 function by anti-Dsg1 autoantibodies is perfectly compensated by richly expressed Dsg3 in pemphigus foliaceus. OBJECTIVES: We present five Japanese patients with pemphigus who deviate from this theory, i.e. all patients showed oral lesions (three also had cutaneous lesions) and reacted only with Dsg1, but not with Dsg3, by enzyme-linked immunosorbent assay. METHODS: To confirm whether the unique clinical phenotypes in our patients were due to a different immunological profile from that in classical pemphigus, we examined the reactivity of the patient sera by immunoprecipitation-immunoblotting analysis using five Dsg1/Dsg2 domain-swapped molecules. RESULTS: The sera of two patients who had only oral lesions tended to react with the extracellular (EC) 5 domain of Dsg1, the domain that is considered nonpathogenic in classical pemphigus foliaceus. Sera of three patients with mucocutaneous lesions reacted with EC1 domain or with both EC1 and EC2 domains of Dsg1, like classical pemphigus foliaceus. CONCLUSIONS: These results indicate that antigenic diversity of anti-Dsg1 antibodies in these patients may cause the unique oral mucosal and cutaneous lesions, although further studies are required to elucidate the pathomechanisms.

Life expectancy, standardized mortality ratios, and causes of death in six rheumatic diseases in Hong Kong, China.

OBJECTIVE: To examine the life expectancy, standardized mortality ratios (SMRs), and causes of death in 6 groups of patients from Hong Kong with different rheumatic diseases. METHODS: Patients with a diagnosis of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic vasculitis (SV), or systemic sclerosis (SSc) registered in 37 public hospitals between 1999 and 2008 were identified in the hospital registry. SMRs were calculated by comparing the mortality rate in patients with each disease with that in the general population. Life expectancy was calculated by abridged life-table analysis, and the causes of death were compared. RESULTS: In 2008, data on 8,367 RA, 5,243 SLE, 2,154 AS, 1,636 SV, 778 PsA, and 449 SSc patients were available in our registry. The age- and sex-adjusted SMRs were highest for SLE (5.25 [95% confidence interval 4.79-5.70]), SSc (3.94 [95% confidence interval 3.20-4.68]), and SV (2.64 [95% confidence interval 2.36-2.93]). In female patients, the loss in life expectancy was greatest for SSc (34.1 years), SV (19.3 years), and SLE (19.7 years). In male patients, the loss in life expectancy was highest for SV (28.3 years), SLE (27 years), and SSc (16 years). There were 2,486 deaths during the study period (1999-2008), and the principal causes were infections (28%), cardiovascular complications (18%), cancer (16%), and disease activity (7%). Infection was the leading cause of death in SLE, RA, AS, and PsA, whereas deaths from disease-related activity and cardiovascular complications were most frequent in SSc. Cancer was the most common cause of death in SV. CONCLUSION: Our findings indicate that patients with SLE, RA, AS, PsA, SV, and SSc have increased mortality rates and reduced life expectancy. SLE has the highest adjusted SMR, and female SSc patients have the greatest loss in life expectancy. Infection is the leading cause of death, followed by cardiovascular complications and malignancies.

Immune response towards the amino-terminus of desmoglein 1 prevails across different activity stages in nonendemic pemphigus foliaceus.

BACKGROUND: Pemphigus foliaceus (PF) is a blistering skin disease mediated by antibodies to desmoglein (Dsg) 1. The two major subtypes are nonendemic and endemic PF. A previous study in endemic PF demonstrated that changes in antibody epitope could modulate disease relapse and remission. OBJECTIVES: To characterize the frequency of immunoreactivity to various Dsg1 extracellular (EC) domains in nonendemic PF and to study if there is any change in epitope profile across various activity stages. METHODS: Sera from 34 patients with nonendemic PF were selected. To map the conformational epitopes by immunoprecipitation-immunoblotting, we constructed five Dsg1/Dsg2 domain-swapped molecules, with each molecule representing one EC domain of Dsg1 on a backbone of Dsg2. RESULTS: Dsg1 EC1, EC2, EC3, EC4 and EC5 domains were recognized by 88%, 50%, 13%, 22% and 0% of active PF sera, respectively. Immunoreactivity to EC3 or EC4 often cosegregated with that to either EC1 or EC2. Longitudinal follow-up of 21 patients with PF for a median of 16 months revealed that, in most cases, immunoreactivity to the amino-terminus of Dsg1 persisted across various activity stages; only two patients lost their EC1 reactivity upon remission and changed their major epitope(s) to EC2 ± EC3. CONCLUSIONS: Most of the anti-Dsg1 antibodies in nonendemic PF bind to the amino-terminus of Dsg1, a region critical for intercellular adhesion of cadherins, and this skewed amino-terminal immunoreactivity prevails across various activity stages in most patients, even upon remission. These findings are valuable for understanding the biology of Dsg-mediated cellular adhesion as well as for the development of epitope-based monitoring and therapeutic strategies.

COVID-19: Initial experience of an international group of hand surgeons.

The emergence of the COVID-19 pandemic has severely affected medical treatment protocols throughout the world. While the pandemic does not affect hand surgeons at first glance, they have a role to play. The purpose of this study was to describe the different measures that have been put in place in response to the COVID-19 pandemic by hand surgeons throughout the world. The survey comprised 47 surgeons working in 34 countries who responded to an online questionnaire. We found that the protocols varied in terms of visitors, health professionals in the operating room, patient waiting areas, wards and emergency rooms. Based on these preliminary findings, an international consensus on hand surgery practices for the current viral pandemic, and future ones, needs to be built rapidly.

The cytoplasmic droplet of rat epididymal spermatozoa contains saccular elements with Golgi characteristics.

The cytoplasmic droplet of epididymal spermatozoa is a small localized outpouching of cytoplasm of the tail of unknown significance. EM revealed flattened saccular elements as the near exclusive membranous component of the droplet. Light and electron microscopic immunolabeling for Golgi/TGN markers showed these saccules to be reactive for antibodies to TGN38, protein affinity-purified alpha 2,6 sialyltransferase, and anti-human beta 1,4 galactosyltransferase. The saccules were isolated by subcellular fractionation and antibodies raised against this fraction immunolabeled the saccules of the droplet in situ as well as the Golgi region of somatic epithelial cells lining the epididymis. The isolated droplet fraction was enriched in galactosyltransferase and sialyltransferase activities, and endogenous glycosylation assays identified the modification of several endogenous glycopeptides. EM lectin staining in situ demonstrated galactose and N-acetyl galactosamine constituents in the saccules. Endocytic studies with cationic and anionic ferritin as well as HRP failed to identify the saccules as components of the endocytic apparatus. Epididymal spermatozoa were devoid of markers for the ER as well as the Golgi-associated coatamer protein beta-COP. It is therefore unlikely that the saccular elements of the droplet participate in vesicular protein transport. However, the identification of Golgi/TGN glycosylating activities in the saccules may be related to plasma membrane modifications which occur during epididymal sperm maturation.

Cutaneous pemphigus vulgaris with skin features similar to the classic mucocutaneous type: a case report and review of the literature.

Pemphigus vulgaris (PV) is a life-threatening autoimmune blistering skin disease that specifically involves oral mucosa. It was recently shown that a very small number of patients with PV show no mucous membrane involvement although they have circulating autoantibodies directed against both desmoglein (Dsg)1 and Dsg3 that are associated with histopathological suprabasal acantholysis. These cases are classed as cutaneous-type PV. We report here a case of cutaneous-type PV that occurred in a 50-year-old man. Clinical examination revealed numerous tense and spreading blisters and erosions over the patient's entire body, similar to the classic mucocutaneous-type PV. Interestingly, none of the previously reported patients with cutaneous PV had shown skin features like those of mucocutaneous PV, whereas the present case clearly demonstrated very typical clinical features similar to those in mucocutaneous PV.

Effects of different cryopreservation methods on DNA integrity and sperm chromatin quality in men.

BACKGROUND: Cryopreserved human sperm are used in assisted reproductive technology. However, the effect of cryopreservation on sperm DNA integrity is unclear. OBJECTIVES: The objectives of this study were to: (i) determine the impact of semen cryopreservation on human sperm DNA integrity and chromatin structure; (ii) test if parameters obtained from TUNEL and SCSA® correlate; and (iii) verify correlation between sperm motility, morphology and viability with TUNEL and SCSA® parameters. MATERIALS AND METHODS: Men attending a fertility clinic were recruited and grouped according to their sperm parameters (n = 9/group): normozoospermia, oligoasthenoteratozoospermia and teratozoospermia. Each semen sample was processed as follow: (i) directly frozen at -80 °C; (ii) diluted in Sperm Maintenance Medium, cooled for 30 min at 4 °C and frozen at -80 °C; (iii) diluted in Sperm Maintenance Medium; or (iv) in SpermFreeze. Each mixture from method (iii) and (iv) was then suspended for 30 min in liquid nitrogen vapor and plunged into liquid nitrogen. After at least two months of storage, samples were thawed at room temperature and analyzed for motility and viability, TUNEL and SCSA® assays. RESULTS: Progressive motility and viability decreased after freeze-thawing. TUNEL scores increased significantly in all samples after freezing-thawing while no significant change in the DNA fragmentation index (DFI) from SCSA® was observed. No change in the percentage high DNA stainability (HDS) was observed in normozoospermic samples; however it was significantly increased in all the methods in oligoasthenoteratozoospermic and in the methods (ii)-(iv) in teratozoospermic samples. The DFI and TUNEL scores correlated significantly with each other and inversely with sperm motility, viability and morphology. DISCUSSION AND CONCLUSION: Cryopreservation seems to be deleterious for the integrity of human sperm DNA and compaction. However, the sperm DFI was not affected during cryopreservation under the various methods of storage tested. Clinicians and investigators should take this information into consideration when using cryopreserved sperm for assisted reproduction.

Primary non-Hodgkin's lymphoma of the nose and nasopharynx: clinical features, tumor immunophenotype, and treatment outcome in 113 patients.

PURPOSE: To study the clinical features and outcome for primary non-Hodgkin's lymphomas of the nose/nasopharynx (NNP-NHLs) according to immunophenotype. PATIENTS AND METHODS: One hundred thirteen Chinese patients with primary NNP-NHLs that belonged to the categories E, F, G, or H according to the Working Formulation (WF), with full immunophenotypic data and complete clinical follow-up data, were analyzed in this retrospective study. RESULTS: Ninety (79.6%) patients had localized (stage I or II) disease, while 23 (20.4%) had stage III or IV disease. The lymphomas in 51 (45.1%), 24 (21.3%), and 38 (33.6%) patients showed natural killer (NK)/T- (CD56-positive), T-cell, and B-cell immunophenotype, respectively. Seventy-three patients (65.8%) achieved a complete remission, of whom 34 (46.6%) subsequently relapsed. The median follow-up time for those alive was 88 months. The 5-year actuarial disease-free and overall survival rates were 34.4% and 37.9%, respectively. Multivariate analysis showed that only stage and immunophenotype were significant for survival. NK/T lymphomas were distinctive among the three immunophenotypes in the following aspects: the highest male-to-female ratio, more frequent involvement of the nasal cavity alone, higher risk of dissemination to the skin, more frequent development of hemophagocytic syndrome, and the worst prognosis (overall median survival, 12.5 months). CONCLUSION: The three immunophenotypes studied are shown to exhibit different clinical patterns. Since the NK/T phenotype carries the worst prognosis, patients who present with NNP-NHL should have their tumors analyzed for CD56 expression.

The regulation and regulatory role of collagenase in bone.

Interstitial collagenase plays an important role in both the normal and pathological remodeling of collagenous extracellular matrices, including skeletal tissues. The enzyme is a member of the family of matrix metalloproteinases. Only one rodent interstitial collagenase has been found but there are two human enzymes, human collagenase-1 and -3, the latter being the homologue of the rat enzyme. In developing rat and mouse bone, collagenase is expressed by hypertrophic chondrocytes, osteoblasts, and osteocytes, a situation that is replicated in a fracture callus. Cultured osteoblasts derived from neonatal rat calvariae show greater amounts of collagenase transcripts late in differentiation. These levels can be regulated by parathyroid hormone (PTH), retinoic acid, and insulin-like growth factors, as well as the degree of matrix mineralization. Much of the work on collagenase in bone has been derived from studies on the rat osteosarcoma cell line, UMR 106-01. All bone-resorbing agents stimulate these cells to produce collagenase mRNA and protein, with PTH being the most potent stimulator. Determination of secreted levels of collagenase has been difficult because UMR cells, normal rat osteoblasts, and rat fibroblasts possess a scavenger receptor that removes the enzyme from the extracellular space, internalizes and degrades it, thus imposing another level of control. PTH can also regulate the abundance of the receptor as well as the expression and synthesis of the enzyme. Regulation of the collagenase gene by PTH appears to involve the cAMP pathway as well as a primary response gene, possibly Fos, which then contributes to induction of the collagenase gene. The rat collagenase gene contains an activator protein-1 sequence that is necessary for basal expression, but other promoter regions may also participate in PTH regulation. Thus, there are many levels of regulation of collagenase in bone perhaps constraining what would otherwise be a rampant enzyme.

7-Nitroindazole: a selective inhibitor of penile erection: an in vivo study in a rat animal model.

OBJECTIVES: The neuronal isoform of nitric oxide synthase (nNOS) has been localized in neurons innervating the penis and is believed to be an important mediator of erection. Using the selective inhibitor 7-nitroindazole (7-NI), we evaluated the possible role of nNOS in penile erection using a rat animal model. METHODS: Eighteen Sprague-Dawley rats were divided into three study groups. A sham group (n = 6) received the vehicle arachis oil, a low-dose group received 5 mg/kg (n = 6), and a high-dose group received 50 mg/kg (n = 6) of 7-NI prior to measurement of blood pressure and cavernous nerve stimulation-induced rise in intracavernous pressure. RESULTS: A dose-dependent inhibition of erection by 7-NI was seen. Control animals had an intracavernous pressure rise of 55.5 +/- 4.0 cm H2O, whereas the low-dose group had 26.5 +/- 2.8 cm H2O and the high-dose group had 6.2 +/- 2.1 cm H2O. A partial recovery of erection was seen in the low- and high-dose groups after 3 hours. Blood pressure was unaffected by 7-NI administration. CONCLUSIONS: 7-NI induced a reversible, dose-dependent inhibition of erection without affecting blood pressure. This in vivo study provides further evidence of the role played by nNOS in erection.

Antioxidant activity of natural flavonoids is governed by number and location of their aromatic hydroxyl groups.

We studied antioxidant activity of five natural flavonoids in canola oil, an emulsion, and rat red blood cell membrane. In the canola oil heated at 105 degrees C, myricetin most effectively attenuated lipid oxidation, followed by quercetin, morin and kaempferol in a decreasing order. When the emulsion containing canola oil was incubated at 54 degrees C, quercetin was most protective against lipid oxidation, followed by kaempferol, myricetin and morin in a decreasing rank. Apigenin demonstrated no antioxidant activity in either the canola oil or the emulsion. Of the flavonoids tested, quercetin was the best in quenching free radical chain reaction in rat red blood cell membrane. The antioxidative characteristics of these flavonoids was determined by multiple factors including the system used, the hydrophobicity, and the total number and the location of aromatic hydroxyl groups. We conclude that myricetin is an effective antioxidant in canola oil, while quercetin is an effective protector against lipid oxidation in the cell membrane.

FGF-2 immunoreactivity in adult rat ependyma and choroid plexus: responses to global forebrain ischemia and intraventricular FGF-2.

Fibroblast growth factor 2 (FGF-2) immunoreactivity (IR) was examined in the ependyma and choroid plexus (CP) of lateral and third ventricles in normal adult rats, as well as in response to transient forebrain ischemia (TFI) and exogenous FGF-2 delivered intraventricularly for several days by osmotic pump. Similar patterns of FGF-2 IR were seen in the CP epithelia of both lateral and third ventricles, as well as in ependymal cells of the third ventricle and along lateral sides of the lateral ventricles. Consistent staining was seen along the apical aspect of epithelial cells facing the cerebrospinal fluid (CSF). Cytoplasmic staining was seen in the absence of ischemia, and was dramatically reduced in response to TFI. FGF-2 treatment followed by TFI resulted in sustained FGF-2 IR within CP and ependymal cells, supporting the idea that these tissues are involved in synthesis and secretion of growth factors into the CSF. In contrast, along the medial sides of the lateral ventricles, adjacent to brain structures such as the hippocampus, consistent staining was seen along the basal aspect of the ependymal cells. We propose that at least some regions of ependyma may function to transport molecules such as FGF-2 directly into the underlying brain parenchyma.

The temporal profile and morphologic features of neuronal death in human stroke resemble those observed in experimental forebrain ischemia: the potential role of apoptosis.

Although neuronal death has been studied in experimental models of ischemia, the precise mechanisms regulating cell death remain unclear. Furthermore, the timing and pattern of neuronal death in human stroke has not been extensively studied. To further our understanding of ischemia-induced neuronal death, we examined the temporal profile of histochemical and morphologic characteristics of hippocampal neuronal death following experimental forebrain ischemia and compared these findings to human brain specimens obtained from subjects suffering cerebral infarction. Transient forebrain ischemia (TFI) was induced in normothermic adult rats by bilateral carotid artery occlusion combined with hypotension. Animals were sacrificed at 6, 12, 18, 24, 48, and 72 h and 7, 14, and 28 days following ischemia (n = 4 at each time point). Experimental tissue was analyzed using light and electron microscopy as well as TUNEL histochemistry. A total of 27 human brain specimens with neuropathological confirmation of ischemic damage and appropriate controls were also examined using light microscopy and TUNEL histochemistry. Dense TUNEL staining in hippocampal CA-1 neurons was present at 48 and 72 h following experimental ischemia. Prior to these times, little or no nuclear staining was noted and after 72 h nuclear staining diminished rapidly. Ultrastructural findings at these time points demonstrated many features similar to those seen in cells undergoing apoptosis, such as cell shrinkage with increased electron density, chromatin condensation with formation of heterochromatin, intact plasma membranes, and intact intracellular organelles. In a similar fashion, human stroke specimens during the subacute period showed dense nuclear TUNEL staining in penumbral neurons, whereas in the acute or chronic stages little or no staining was noted. Our results demonstrate that the timing of morphologic changes and TUNEL histochemistry following human stroke resembles that observed in experimental TFI. Furthermore, neuronal death in both experimental ischemia and human stroke share several features characteristic of apoptotic cell death.

Tarsal tunnel syndrome caused by talocalcaneal coalition.

Tarsal tunnel syndrome caused by talocalcaneal coalition is uncommon. We presented the ultrasonography (US) and magnetic resonance imaging findings of this disease. This is, to our knowledge, the first case report describing the US findings in tarsal tunnel syndrome caused by talocalcaneal coalition.

Attitudes of Hong Kong high school students towards the nursing profession.

The increased development of hospital services in Hong Kong over the last decade has given rise in the demand for more recruits to join the nursing profession. Despite the advancement in education and the improvement in the working conditions, the problems of attracting sufficient new recruits remain critical. This study aimed to examine high school students' attitudes towards the nursing profession and to identify the contributing factors affecting shortage of nurses within the context of Hong Kong. A convenience sample of 375 high school students was recruited. A questionnaire was used to measure their knowledge, attitudes and intention to study nursing. Descriptive and inferential statistics were used to describe their career preferences and to compare knowledge, attitudes and intention scales between gender and nursing exposure groups. Results indicated that the students were generally knowledgeable about nursing but were reluctant to pursue nursing as a career. However, students who were socially acquainted with a nurse demonstrated a slightly more positive attitude towards nursing and slightly higher intention to pursue nursing as a career compared with those having no social acquaintance with a nurse. Implications for promotion of nursing profession and limitations of the study were discussed.