Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission.

Although considerable evidence suggests that the chemical synapse is a lynchpin underlying affective disorders, how molecular insults differentially affect specific synaptic connections remains poorly understood. For instance, Neurexin 1a and 2 (NRXN1 and NRXN2) and CNTNAP2 (also known as CASPR2), all members of the neurexin superfamily of transmembrane molecules, have been implicated in neuropsychiatric disorders. However, their loss leads to deficits that have been best characterized with regard to their effect on excitatory cells. Notably, other disease-associated genes such as BDNF and ERBB4 implicate specific interneuron synapses in psychiatric disorders. Consistent with this, cortical interneuron dysfunction has been linked to epilepsy, schizophrenia and autism. Using a microarray screen that focused upon synapse-associated molecules, we identified Cntnap4 (contactin associated protein-like 4, also known as Caspr4) as highly enriched in developing murine interneurons. In this study we show that Cntnap4 is localized presynaptically and its loss leads to a reduction in the output of cortical parvalbumin (PV)-positive GABAergic (γ-aminobutyric acid producing) basket cells. Paradoxically, the loss of Cntnap4 augments midbrain dopaminergic release in the nucleus accumbens. In Cntnap4 mutant mice, synaptic defects in these disease-relevant neuronal populations are mirrored by sensory-motor gating and grooming endophenotypes; these symptoms could be pharmacologically reversed, providing promise for therapeutic intervention in psychiatric disorders.

Evaluation of a multiplex flow immunoassay versus conventional assays in detecting autoantibodies in systemic lupus erythematosus.

INTRODUCTION: Conventional diagnostic assays are being replaced with automated multiplex assays, but their performance needs to be evaluated. We compared a multiplex flow immunoassay with conventional techniques in the detection of antinuclear antibodies (ANAs) and antibodies to specific extractable nuclear antigens (ENAs) in serum samples from patients with systemic lupus erythematosus. METHODS: A total of 140 consecutive Chinese patients with systemic lupus erythematosus and 41 healthy controls were included. The automated BioPlex 2200 ANA Screen assay (Bio-Rad Laboratories, Hercules [CA], US) was compared with indirect immunofluorescence. In addition, use of BioPlex 2200 to detect anti-ENA antibodies was compared with in-house assays of countercurrent immunoelectrophoresis (CIEP), enzyme-linked immunosorbent assay (ELISA), and line blot. RESULTS: The sensitivity and specificity of BioPlex in detecting ANAs (91.4% and 95.1%, respectively) were comparable to those of indirect immunofluorescence (90.7% and 85.4%, respectively). Overall, BioPlex achieved the best agreement with ELISA in detecting anti-ENA antibodies: agreement was >90% for most antibody types (κ=0.79-0.94). In contrast, agreement was poorest with CIEP, ranging from 85.6% (κ=0.33) for anti-Sm antibodies to 93.9% (κ=0.88) for anti-Ro antibodies. Overall, BioPlex and ELISA had the highest sensitivity, whereas CIEP had the highest specificity. In terms of disease association, anti-Sm detected by CIEP had the best positive predictive value and specificity for lupus nephritis. CONCLUSIONS: In a local lupus cohort, BioPlex showed comparable sensitivity to indirect immunofluorescence in detecting ANAs and comparable performance to ELISA in detecting anti-ENA antibodies. However, CIEP was the best method in terms of disease specificity.

Breast Cancer and Transplantation.

Breast cancer is an important cancer among solid organ transplant recipients. While the incidence of breast cancer in solid organ transplant recipients is comparable to the age-matched general population, the outcomes are generally poor. Interventions such as cancer screening that preclude the development of late-stage disease through early detection are not well studied, and clinical practice guidelines for cancer screening rely solely on recommendations from the general population. Among patients with a prior breast cancer history, disease recurrence after transplantation is a rare but fearful event. Once disease recurs, the risk of death is high. The focus of this review is to present the epidemiology of breast cancer in solid organ transplant recipients, screening and preventive strategies for those who may be at risk, novel genomic profiling for determining tumor progression, and the newer targeted interventions for recipients who have developed breast cancers after solid organ transplantation.

Feasibility of direct venous inoculation of the radiation-attenuated Plasmodium falciparum whole sporozoite vaccine in children and infants in Siaya, western Kenya.

PfSPZ Vaccine, composed of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites, is administered by direct venous inoculation (DVI) for maximal efficacy against malaria. A critical issue for advancing vaccines that are administered intravenously is the ability to efficiently administer them across multiple age groups. As part of a pediatric safety, immunogenicity, and efficacy trial in western Kenya, we evaluated the feasibility and tolerability of DVI, including ease of venous access, injection time, and crying during the procedure across age groups. Part 1 was an age de-escalation, dose escalation trial in children aged 13 months-5 years and infants aged 5-12 months; part 2 was a vaccine efficacy trial including only infants, using the most skilled injectors from part 1. Injectors could use a vein viewer, if needed. A total of 1222 injections (target 0.5 mL) were initiated by DVI in 511 participants (36 were 5-9-year-olds, 65 were 13-59-month-olds, and 410 infants). The complete volume was injected in 1185/1222 (97.0%) vaccinations, 1083/1185 (91.4%) achieved with the first DVI. 474/511 (92.8%) participants received only complete injections, 27/511 (5.3%) received at least one partial injection (<0.5 mL), and in 10/511 (2.0%) venous access was not obtained. The rate of complete injections by single DVI for infants improved from 77.1% in part 1 to 92.8% in part 2. No crying occurred in 51/59 (86.4%) vaccinations in 5-9-year-olds, 25/86 (29.1%) vaccinations in 13-59-month-olds and 172/1067 (16.1%) vaccinations in infants. Mean administration time ranged from 2.6 to 4.6 minutes and was longer for younger age groups. These data show that vaccination by DVI was feasible and well tolerated in infants and children in this rural hospital in western Kenya, when performed by skilled injectors. We also report that shipping and storage in liquid nitrogen vapor phase was simple and efficient. (Clinicaltrials.gov NCT02687373).

The reporting of needlestick injuries sustained in theatre by surgeons: are we under-reporting?

Surgeons frequently sustain needlestick injuries when operating. The aim of this study was to evaluate the incidence and reporting rate of needlestick injuries at one institution. A questionnaire was distributed anonymously to 69 surgeons of all grades and specialties in a district general hospital in the UK. The questionnaire was returned by 42 surgeons (60.9%). There were 840 needlestick injuries over two years, of which 126 caused bleeding. Senior surgeons who spent more hours operating per week had a higher rate of needlestick injuries compared with junior surgeons (29.1 vs 6.59 injuries per surgeon over two years). Of the total number of injuries, 19 (2.26%) were reported to Occupational Health according to the surgeons questioned, but only six reported incidents were found in the Occupational Health records. Junior surgeons were significantly more likely to report needlestick injuries than senior surgeons (9.82% vs 1.10% of injuries reported, P=0.0000045). The main reasons for failure to report needlestick injuries were due to the lack of time and excessive paperwork. Seventy-three percent of surgeons did not routinely use double gloves when operating, mainly because of decreased hand sensation. The rate of needlestick injury reporting by surgeons at this institution is extremely low. Previous studies have shown a higher reporting rate suggesting that, despite awareness of blood-borne infections, surgeons are still not following recommended protocols.

Regular use of a verbal pain scale improves the understanding of oncology inpatient pain intensity.

PURPOSE: This study was undertaken to determine if the daily use of a verbal pain scale could improve the correlation of pain perception between hospitalized oncology patients and their caregivers. PATIENTS AND METHODS: Hospitalized oncology patients were asked to rate verbally their average pain over the past 24 hours on a scale ranging from 0 to 10. The patients' primary-care physicians and nurses were asked the same question on the same morning after they had evaluated their patients. RESULTS: During a baseline study, only 64% of caregivers' pain scores were within two points of the respective patient's score. Caregivers tended to underestimate patients' pain scores. Caregivers were alerted to these poor results and then requested to ask each patient daily for the average pain score and record this score on the patient's medical record. Nonetheless, correlation between patients' and caregivers' pain scores remained poor (68% within two points of each other) during a second study. The major reason for the poor results appeared to be because caregivers did not routinely ask patients for pain scores. Subsequently, a renewed, more intensive educational effort was undertaken and a third study was conducted. During the third study, 85% of caregivers' and patients' pain scores were within two points of each other (P = .001 when compared with baseline). CONCLUSION: The enforced use of a simple verbal pain assessment tool appears to improve caregiver's understanding of the pain status of hospitalized oncology patients.

A phase II trial of etoposide, leucovorin and 5-fluorouracil (ELF) in patients with advanced gastric cancer.

Etoposide, leucovorin and 5-fluorouracil (ELF) chemotherapy has been reported to be less toxic yet effective (response rates of 50%) in patients with advanced gastric cancer. A phase II study of ELF in 25 patients (11 males, 14 females, median age 53 years) with advanced adenocarcinoma of the stomach is reported. Patients received outpatient intravenous etoposide 120mg/m2 over 2 hours, folinic acid 300 mg/m2 over 2 hours, 5-fluorouracil 500 mg/m2 boluses daily for 3 days every 21 days. Of 17 measurable patients, there was one complete response (CR), 4 partial responses (PR) for a total response rate of 29.4%. Non-hematologic toxicity was modest (grade 0 vomiting 11/21, stomatitis 16/21, diarrhea 17/21). Grade 3/4 neutropenia was seen in 14/23, thrombocytopenia in 2/23, anemia in 5/23 patients. Median progression-free and overall survival was 4.1 and 7.1 months, respectively. In conclusion, ELF chemotherapy shows only modest activity in patients with advanced gastric cancer and is associated with severe hematologic toxicity.

Adult parameningeal rhabdomyosarcoma--a case report and literature review.

Although rhabdomyosarcoma is predominantly a malignant disease of children, it is also seen in adults. Since adults account for only 15% of rhabdomyosarcomas, the experience gathered for the treatment of the malignancy has been derived from treating children. The treatment of a case of adult extensive parameningeal rhabdomyosarcoma with CyVADlC chemotherapy and radiotherapy is described, together with a review of the literature.

Management of chemotherapy-induced neutropenic sepsis--combination of cephalosporin and aminoglycoside.

In cancer patients undergoing combination chemotherapy, neutropenic febrile episode (NFE) is a life-threatening condition. Prompt initiation of empirical antibiotics is essential to limit morbidity and mortality. To understand the effectiveness of combination antibiotics consisting of a third-generation cephalosporin and an aminoglycoside, a retrospective review of all patients admitted for NFEs was conducted. Between August 1990 and December 1991, there were 34 NFEs in 26 cancer patients which were treated with a combination of aminoglycoside (gentamicin or amikacin) and a cephalosporin (ceftriaxone or ceftazidime). Initial antibiotic therapy included aminoglycoside plus ceftriaxone in 23 NFEs and ceftazidime in 11 NFEs. A change of antibiotics was required in 11 NFEs because of deteriorating clinical status or culture-proven drug resistance. Bacteria were isolated in 12 (35%) NFEs (blood 7, respiratory tract 2, skin 2, urine 1). Of these, eight (62%) were gram-negative bacteria and five were gram-positive bacteria. One blood specimen grew both gram-positive and gram-negative organisms. Broad spectrum antibiotics were effective in almost all NFEs. Thirty-one (91%) NFEs resolved with antibiotics. Three patients succumbed to their infection despite combination antibiotics. Aminoglycoside and cephalosporin is an effective antibiotic combination in the management of fever in neutropenic hosts. Randomised trials comparing this combination with newer antibiotics like monobactams and quinolones are needed in the search for more effective therapy.

Ophthalmia neonatorum--the Middle Road Hospital perspective.

In a retrospective study of ophthalmia neonatorum seen in Middle Road Hospital between 1983 and 1986, 68% were caused by Neisseria gonorrhoeae. 40% of the Neisseria gonorrhoeae isolates were PPNG strains. For therapy of gonococcal ophthalmia neonatorum, 1% kanamycin eyedrops combined with a single intramuscular injection of kanamycin or a third generation Cephalosporin (Ceftriaxone or Cefotaxime) were all effective regimens. The use of intramuscular kanamycin was stopped because of concern for ototoxicity. Chlamydia trachomatis remains an uncommon cause of ophthalmia neonatorum in Singapore, in only 2 cases was this agent identified.

Randomised study comparing imipenem/cilastatin to ceftriaxone plus gentamicin in cancer chemotherapy-induced neutropenic fever.

Prompt initiation of empiric antibiotic therapy is the cornerstone in the therapy of chemotherapy-induced neutropenic sepsis in cancer patients. Ceftriaxone plus gentamicin (ceftriaxone/gentamicin) is the most widely used combination of empiric antibiotics in the Department of Medical Oncology, Singapore General Hospital. However, imipenem/cilastatin has been shown to be a practical alternative. To compare the efficacy and cost effectiveness of monotherapy with our usual combination antibiotic therapy, 50 evaluable neutropenic cancer patients admitted for fever were randomised to empiric imipenem/cilastatin or ceftriaxone/gentamicin. Ceftriaxone/gentamicin was started in 24 patients. The initial clinical response rate to ceftriaxone/gentamicin was 62.5% and 84.6% to imipenem/cilastatin (P = 0.075). The average cost of antibiotics per patient started on ceftriaxone/gentamicin including cost of change of antibiotics was S$63 per day of antibiotic use and for imipenem/cilastatin it was S$252 (P < 0.02). In conclusion, although more patients receiving imipenem/cilastatin had an initial clinical response than those receiving ceftriaxone/gentamicin, this difference was not statistically significant. It would appear that imipenem/cilastatin is equivalent to ceftriaxone/gentamicin for the treatment of neutropenic sepsis. However, ceftriaxone/gentamicin was more cost effective.

Use of oral and intravenous ondansetron in patients treated with cisplatin.

Ondansetron, a selective 5-HT3 antagonist, has been shown to be effective in preventing chemotherapy-induced nausea and vomiting. From July and August 1991, 25 patients were accrued in a phase II study to assess the efficacy of ondansetron in patients receiving cisplatin-containing chemotherapy. Patients received intravenous cisplatin 100 mg/m2, given either as a 24-hour infusion on day 1 or in divided doses as eight-hour infusions daily on days 1 to 3. Each patient received 24 mg of ondansetron per day for six days. Intravenous dexamethasone 24 mg was given daily on the days of cisplatin infusion. The emetic episodes and degree of nausea were evaluated daily. "Good" control of emesis (0-2 episodes of vomiting) and nausea (mild or no nausea) ranged from 64-100% and 88-100% respectively. Failure in emesis control occurred most frequently on days 3 and 4. Ondansetron was generally well tolerated with only minimal side-effects. One patient developed unexplained encephalopathy which resolved completely. Our results suggest that ondansetron is an effective anti-emetic agent with minimal toxicities. Randomised studies comparing ondansetron against "standard" anti-emetics should be conducted.

Continuous infusion 5-fluorouracil as salvage chemotherapy in patients with advanced colorectal cancer.

For almost 40 years, 5-fluorouracil (5-FU) has been the only useful drug with clinically meaningful activity in metastatic colorectal carcinoma. When the disease progresses or recurs despite bolus 5-FU treatment, the options are limited. Our study shows that 5-FU given by continuous infusion is a viable alternative. Fifty-three patients received continuous infusion 5-FU. The overall response was 9%. Median survival of the entire cohort was 5 months. Patients with partial response and stable disease had median survival duration of 8 and 9 months, respectively. A dose-response relationship was observed. The commonest toxicities were mucositis (34%) and palmar-plantar syndrome (24%). There was no central line-related complication. Continuous infusion 5-FU is an effective "second-line" treatment. Further work is needed to ascertain its role, in comparison with newer agents like irinotecan (CPT-11), and oxaliplatin.

Efficacy and tolerability of irinotecan in patients with advanced colorectal cancer in Singapore.

INTRODUCTION: Colorectal cancer is the commonest malignancy encountered in Singapore. The long-term outcome of patients with advanced diseases is poor. For many decades, 5-fluorouracil was the only effective cytotoxic drug against colorectal cancers. Randomised trials have documented the efficacy of irinotecan in patients with metastatic colorectal cancer. We investigated the efficacy and safety profile of irinotecan (CPT-11), as a second-line treatment for an Asian population who had failed 5-fluorouracil-based chemotherapy. MATERIALS AND METHODS: A total of 33 patients were enrolled in the study between October 1996 and May 1999. This was an open label phase II study. All patients who had received at least one dose of CPT-11 were evaluated for toxicity. Thirty patients were evaluated for response. RESULTS: Six patients (20%) had partial responses and 1 (3%) experienced minor response. Fourteen patients (47%) progressed. Nine patients (30%) had stable disease. The range of time to progression was 5.8 months to 21 months. The median survival was 9.5 months. There was no treatment-related death. Seven patients (23%) who received treatment had diarrhoea. Only 2 of the 7 patients had grade 3-4 diarrhoea. Eleven patients (37%) suffered from haematological toxicity, of whom 2 patients had grade 3-4 neutropenia. CONCLUSION: We demonstrated efficacy and tolerability of CPT-11 in Singaporean patients with advanced colorectal cancer.

Adjuvant chemotherapy for patients with resected Dukes' C and high-risk B2 colon cancer with fluorouracil and levamisole.

Carcinoma of the large bowel is the second leading cause of cancer mortality in Singapore. Although the great majority of patients are discovered at a stage where resection with curative intent is possible, almost half of the patients afflicted will die of it. The combination of 5-fluorouracil + levamisole used in patients with curatively resected high risk Dukes B2 and all Dukes' C colon cancers has been shown to reduce cancer recurrence rate and improve overall survival. Since 1990 adjuvant chemotherapy has been recommended for this group of patients. This report describes patients treated in Singapore, their toxicities and their outcome. A total of 341 patients were treated between 1990 and 1996. Treatment compliance was 71.8%. Toxicity was moderate with mainly grade 1-2 nausea and vomiting, diarrhoea, stomatitis, alopecia, and neutropenia. There was 1 treatment-related death. Median recurrence-free interval was 81 months and median survival was not reached at 90 months. This regimen is tolerable. Until further randomised reports comparing 5-fluorouracil + levamisole to other combinations are available, this combination chemotherapy is recommended to patients after surgical resection of the high risk Dukes' B2 and Dukes' C colon cancer to reduce cancer recurrence and improve overall survival.

Gastrointestinal lymphoma--a review of 54 patients in Singapore.

Primary gastrointestinal (GI) lymphoma accounts for 2% to 5% of all GI malignancies. Primary therapy in uncomplicated GI lymphoma remains controversial. Fifty-four patients (male to female ratio of 4:3, median age 56 years) with GI lymphoma were studied to evaluate complications and results of therapy. The sites involved were the stomach (31), small bowel (12), large bowel (4), gallbladder (1) and multifocal (6). Distribution by stage and grade (Working Formulation or Kiel) were: IE-30%, IIE-43%, IIIE-6%, IV-20% and unknown-1%; low grade-33%, intermediate grade-59% and high grade-8%. Majority (54%) had diffuse large cell lymphoma. Twenty-three patients (43%) underwent primary resection of the tumour followed by chemotherapy in 14 or radiotherapy in 3. Seventeen patients (31%) had primary chemotherapy and 3 (6%) had primary radiotherapy. Of the 48 patients who underwent therapy, 52% had complete response. At the last follow-up (median 21 months), 25 patients were disease-free. Overall survival was 67% at two years. Treatment strategies employing surgery, radiotherapy and chemotherapy, alone or in combination, do not appear to influence outcome. Surgical resection plus chemotherapy appear to be effective in the control of local and distant disease.

Clinical update of gemcitabine in pancreas cancer.

Pancreatic cancer constitutes less than 2% of all cancers diagnosed in Singapore, consistent with the proportion described worldwide. About 40% of patients are diagnosed when the disease is locally advanced but without metastases. Another 40% are diagnosed with distant metastases. Only 20% are diagnosed when resectable. Most are adenocarcinomas arising from the head of the pancreas. Systemic chemotherapy is used for advanced metastatic pancreatic cancer but has met with limited success. Gemcitabine is a new fluorine-substituted cytarabine compound. In a randomised study it appears to confer statistically significant, although modest, improvement in quality of life and survival of patients with metastatic pancreas cancer. Evaluation of the drug in combination chemotherapy regimens and with radiation continues.