Dopamine agonists in the treatment of prolactinoma: are they still first choice?

Dopamine agonist therapy has been the cornerstone treatment for prolactinoma since the 1970s, replacing surgery in the primary management of this condition. These agents are effective in the management of prolactin excess, have a low side-effect profile, and in some cases may even be curative. However, recent studies of high dose dopamine agonists used in Parkinson's disease have raised the possibility that these drugs may be associated with cardiac valvulopathy. This paper discusses the modern use of dopamine agonists in a patient with prolactinoma.

Is karyotyping couples experiencing recurrent miscarriage worth the cost?

Karyotyping couples that have had recurrent miscarriages detects balanced rearrangements in carrier parents who can be offered prenatal cytogenetic analysis to prevent the birth of a subsequent child with an unbalanced rearrangement. In four UK centres, over periods of 5-30 years, balanced rearrangements were found in 406 out of 20,432 parents that had experienced miscarriage (1.9%), but only four unbalanced rearrangements were found after referral for prenatal diagnosis because of a balanced parental translocation ascertained for recurrent miscarriages. At an estimated cost of 3-4 million pounds, these data raise doubts about the cost effectiveness of current policies on the routine karyotyping of couples experiencing repeated miscarriages.

Selective parathyroid venous sampling in patients with complicated hyperparathyroidism.

OBJECTIVE: The role of preoperative localisation of abnormal parathyroid glands remains controversial but is particularly relevant to the management of patients with recurrent or persistent hyperparathyroidism and familial syndromes. We report our experience of the use of selective parathyroid venous sampling (PVS) in the localisation of parathyroid disease in such patients. DESIGN: We report a retrospective 10-year experience (n = 27) of the use of PVS in complicated primary hyperparathyroidism and contrast the use of PVS with neck ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and sestamibi imaging modalities. RESULTS: In 14 out of 25 patients who underwent surgery PVS results were completely concordant with surgical and histological findings and 88% of patients achieved post-operative cure. Out of 13 patients referred after previous failed surgery, 12 underwent further surgery which was curative in 9. In total PVS yielded useful positive (n = 13) and/or negative information (n = 6) in 19 out of 25 patients undergoing surgery. Using histology as the gold standard, 59% of PVS studies were entirely consistent with histology, as compared with 39% of ultrasound scans, 36% of sestamibi scans and 17% of MRI/CT scans. CONCLUSIONS: PVS is a valuable adjunct to MRI/CT and sestamibi scanning in selected patients with complicated hyperparathyroidism when performed in an experienced unit.

Cost Effectiveness of Using Array-CGH for Diagnosing Learning Disability.

OBJECTIVE: To undertake a cost-effectiveness analysis of using microarray comparative genomic hybridisation (array-CGH) as a first-line test versus as a second-line test for the diagnosis of causal chromosomal abnormalities in patients referred to a NHS clinical genetics service in the U.K. with idiopathic learning disability, developmental delay and/or congenital anomalies. METHODS: A cost-effectiveness study was conducted. The perspective is that of a U.K. NHS clinical genetics service provider (with respect to both costs and outcomes). A cohort of patients (n = 1590) referred for array-CGH testing of undiagnosed learning disability and developmental delay by a single NHS regional clinical genetics service (South East Thames Regional Genetics Service), were split into a before-and-after design where 742 patients had array-CGH as a second-line test (before group-comparator intervention) and 848 patients had array-CGH as a first-line test (after group-evaluated intervention). The mean costs were calculated from the clinical genetics testing pathway constructed for each patient including the costs of genetic testing undertaken and clinical appointments scheduled. The outcome was the number of diagnoses each intervention produced so that a mean cost-per-diagnosis could be calculated. The cost effectiveness of the two interventions was calculated as an incremental cost-effectiveness ratio to produce an incremental cost-per-diagnosis (in 2013 GBP). Sensitivity analyses were conducted by altering both costs and effects to check the validity of the outcome. RESULTS: The incremental mean cost of testing patients using the first-line testing strategy was -GBP241.56 (95% CIs -GBP256.93 to -GBP226.19) and the incremental mean gain in the percentage diagnoses was 0.39% (95% CIs -2.73 to 3.51%), which equates to an additional 1 diagnosis per 256 patients tested. This cost-effectiveness study comparing these two strategies estimates that array-CGH first-line testing dominates second-line testing because it was both less costly and as effective. The sensitivity analyses conducted (adjusting both costs and effects) supported the dominance of the first-line testing strategy (i.e. lower cost and as effective). CONCLUSIONS: The first-line testing strategy was estimated to dominate the second-line testing strategy because it was both less costly and as effective. These findings are relevant to the wider UK NHS clinical genetics service, with two key strengths of this study being the appropriateness of the comparator interventions and the direct applicability of the patient cohort within this study and the wider UK patient population.

Detection of submicroscopic subtelomeric chromosome translocations: a new case study.

Two sisters presented with multiple congenital abnormalities and developmental delay; abnormalities elsewhere in their extended family suggested that their father carried a balanced translocation. G-banded chromosome analysis showed apparently normal karyotypes. Fluorescence in situ hybridisation (FISH) with whole chromosome paints revealed no apparent abnormality in the father. However, further FISH studies, using multiple subtelomeric probes, demonstrated a derivative chromosome 16 in one sister. Subsequent studies showed that her sister also had a derivative 16 which had been inherited in an unbalanced form from their father, who carried a balanced reciprocal translocation between chromosomes 1 and 16. This report describes the detection of this submicroscopic translocation and the clinical findings in the two sisters.

Chromosome 22q11 deletions are not found in autistic patients identified using strict diagnostic criteria. IMGSAC. International Molecular Genetics Study of Autism Consortium.

A group of 103 subjects with a strict diagnosis of autism were tested for deletion of band q11.2 on the long arm of chromosome 22. No deletions were found, indicating that when a patient has been diagnosed with autism using strict and consistent criteria, in the absence of other indications, it is unlikely that this individual will have a 22q11 deletion. Testing for 22q11 deletions is therefore unlikely to be necessary in these patients. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:15-17, 2000.

Clinical expression of Menkes disease in a girl with X;13 translocation.

Menkes disease is a rare X-linked recessive disorder of copper metabolism, characterised by progressive neurological degeneration, abnormal hair and connective tissue manifestations. We report on a girl with classic Menkes disease, carrying a de novo balanced translocation 46,X,t(X;13)(q13.3; q14.3). The translocation breakpoints at Xq13.3 and 13q14.3 coincide with the Menkes disease and Wilson disease loci, respectively.

Results of diaphragmatic plication for unilateral diaphragmatic paralysis.

Seven adult patients with dyspnea resulting from nonmalignant unilateral diaphragmatic paralysis underwent plication of the affected hemidiaphragm. Preoperatively, the patients complained of exertional dyspnea and orthopnea and had a reduced arterial oxygen tension, total lung capacity, vital capacity, expiratory reserve volume, and functional residual capacity. Plication was performed by imbricating the diaphragm in layers through a thoracotomy. After plication there was a significant increase in arterial oxygen tension and all lung volumes except residual volume. The patients' symptoms were improved with plication and a significant decrease was recorded in breathlessness on a visual analogue scale. There were no postoperative complications and mean hospital stay was 12 days.

Characterization of a chromosomally complex lung cancer cell line using multiwell fluorescence in situ hybridization.

The chromosomal characterization of a non-small cell lung cancer cell line (NCIH358) is described. This characterization was achieved using a simple, cheap and technically straightforward multiwell fluorescence in situ hybridization (FISH) method. The many and complex chromosome rearrangements identified by this method could not be defined using conventional G-banded chromosome analysis, and have not been previously described. For the detailed characterization of complex cell lines, multiwell FISH has many advantages over more technically demanding and expensive FISH techniques, and opens up the possibility of screening for consistent rearrangements, leading to the identification of unique fusion genes.

Tumor osteolysis in osteopetrotic mice.

Details of the cellular and biochemical mechanisms involved in focal destruction of bone at sites of tumor osteolysis are unknown. It has been shown that tumors from sarcoma (2472) cell lines induce focal osteolysis in mice by stimulating formation and activation of osteoclasts. In this report, the influence of 2472 tumors on the skeletons of osteoclast-deficient animals (op/op) was studied. After op/op femora had been inoculated with 2472 cells, tumors developed and focal osteolysis occurred. There were more osteoclasts per histologic section in sham-injected femora (19 +/- 5) than in tumor-bearing femora (412 +/- 129) (p < 0.05). The size of the osteoclasts also increased from 304 +/- 81 microns 2 in sham-injected limbs to 407 +/- 62 microns 2 in tumor-bearing limbs (p < 0.001). Conditioned media from 2472 op/op tumor explants contained macrophage colony-stimulating factor. A deficiency of osteoclasts in op/op mice is the result of the absence of this factor; therefore, these data introduce the possibility that macrophage colony-stimulating factor derived from 2472 tumor may be responsible for directing osteoclast-mediated osteolysis at sites of the tumor.

Localized, tumor-associated osteolysis involves the recruitment and activation of osteoclasts.

The cellular and biochemical mechanisms that direct destruction of bone at the site of tumor osteolysis are unknown. In order to understand this process better, a murine model designed for the study of tumor osteolysis was developed and the influence of osteolytic and nonosteolytic tumors on bone was investigated. Tumors developed following femoral intramedullary injection of sarcoma (2472) and melanoma (G3.26) cell lines; however, only tumors from the 2472 cell line caused osteolysis. It was determined that 2472 tumor-induced osteolysis commenced 6 days after the femora had been inoculated with 2472 cells. There were more osteoclasts per millimeter of bone surface in 2472 tumor-bearing limbs (16.7 +/- 5.0) than in sham-injected limbs (3.8 +/- 0.9) (p < 0.015). In addition, an increase in the osteoclast size (area) was detected in 2472 tumor-bearing limbs: 412 +/- 65 micron2 compared with 187 +/- 17 micron2 (p < 0.01). In vitro bone resorption experiments indicated that 2472 tumor cells had a limited ability to destroy bone in comparison with macrophages and osteoclasts. Taken in total, these findings define a model that is useful for the study of tumor osteolysis, and the data from analyses of the model demonstrate that the cellular mechanisms responsible for 2472 tumor-induced osteolysis include both an increase in the number of osteoclasts and activation of mature osteoclasts.

Necrotizing soft-tissue infections.

Necrotizing fasciitis is a rare and often fatal soft-tissue infection involving the superficial fascial layers of the extremities, abdomen, or perineum. Necrotizing fasciitis typically begins with trauma; however, the inciting event may be as seemingly innocuous as a simple contusion, minor burn, or insect bite. Differentiating necrotizing infections from common soft-tissue infections, such as cellulitis and impetigo, is both challenging and critically important. A high degree of suspicion may be the most important aid in early diagnosis. Prompt diagnosis is imperative because necrotizing infections typically spread rapidly and can result in multiple-organ failure, adult respiratory distress syndrome, and death. Although group A Streptococcus is the most common bacterial isolate, a polymicrobial infection with a variety of Gram-positive, Gram-negative, aerobic, and anaerobic bacteria is more common. Orthopaedic surgeons are often the first physicians to evaluate patients with such infections and therefore need to be familiar with this potentially devastating disease and its management. Prompt diagnosis, immediate administration of broad-spectrum antibiotic coverage, and emergent aggressive surgical debridement of all compromised tissues are critical to reduce the morbidity and mortality of these rapidly progressing infections.

Successful pregnancy outcomes after preimplantation genetic diagnosis (PGD) for carriers of chromosome translocations.

Reciprocal translocations are found in about 1 in 500 people, whereas Robertsonian translocations occur with a prevalence of 1 in 1000. Balanced carriers of these rearrangements, although phenotypically normal, may present with infertility, recurrent miscarriage, or offspring with an abnormal phenotype after segregation of the translocation at meiosis. Once the translocation has been identified, prenatal diagnosis can be offered, followed by termination of pregnancies with chromosome imbalance. Couples who have suffered repeated miscarriage or those who have undergone termination of pregnancy as a result of the translocation carrier status of one partner are looking increasingly to preimplantation genetic diagnosis (PGD) as a way of achieving a normal pregnancy. Similarly, infertile couples in which one partner is a translocation carrier may request PGD to ensure transfer of normal embryos after in vitro fertilization. Translocation PGD has been applied successfully in several centres worldwide and should now be considered as a realistic treatment option for translocation carriers who do not wish to trust to luck for a successful natural outcome.

PEComa of the Upper Extremity: A Unique Case and Description of an Initial Response to Neoadjuvant Chemotherapy.

Purpose. Tumors of the perivascular epithelial cell tumor (PEComa), first described in 1992, represent a rare soft tissue neoplasm of varying malignant potential. Cases of PEComa have been previously described in a few somatic and visceral sites, most notably in the gastrointestinal tract, genitourinary tract, and one extremity case in the thigh. To date, most malignant cases of PEComa have been resistant to chemotherapy, and as such, an appropriate therapy is not known. Case report. Here we describe the first case of PEComa of the upper extremity. Open biopsy revealed a high-grade malignant lesion, and the patient subsequently underwent both neoadjuvant therapy with doxorubicin, ifosfamide and mensa, and radiation therapy prior to wide surgical resection. After six cycles of chemotherapy, the tumor underwent an 80% reduction in size. Subsequent neoadjuvant radiation therapy of 5000 cGy did not further reduce the size of the tumor. Following limb sparing radical resection, pathology showed 20% necrosis within a high-grade malignant lesion. Twenty one months after beginning treatment, the patient shows no sign of local recurrence, but metastatic disease was confirmed after resection of a lung nodule. Conclusion. Given the favorable albeit partial response seen in this patient, the course of therapy outlined here may represent a good starting point for neoadjuvant treatment in a tumor with a historically bleak prognosis. In addition, the diagnosis of PEComa must now be entertained in the differential diagnosis of upper extremity soft tissue sarcoma.

Regional lung function in asymptomatic cigarette smokers.

Regional pulmonary ventilation and perfusion were studied in the supine posture using xenon-133 in 10 asymptomatic cigarette smokers with normal chest radiographs and no evidence of large airway obstruction. The results were compared with those obtained in age-matched control subjects who were lifelong nonsmokers. The ventilation of the upper zones of the lungs was significantly less than that of the lower zones in smokers but not in control subjects, and perfusion of the upper zones of the lungs was significantly greater than that of the mid-zones in control subjects but not in smokers. It is suggested that the upper zone abnormalities found in the group of smokers were consistent with the development of early emphysema.

Screening oocytes and preimplantation embryos for aneuploidy.

Pregnancy and live birth rates following in-vitro fertilization decline rapidly with advancing maternal age partly because of an increase in age-related aneuploidies occurring in female meiosis. Screening oocytes or preimplantation embryos for common aneuploidies is now possible by polar body or cleavage stage biopsy and multicolour fluorescence in-situ hybridization.

Velopharyngeal incompetence and chromosome 22q11 deletion.

Chromosome 22q11 deletion gives rise to various phenotypes, including cardiac malformations, velopharyngeal abnormalities, absent thymus, and neurological defects. We assessed, in a prospective study, chromosome 22q11 deletion in 50 of 144 patients with velopharyngeal incompetence in the absence of overt clefting. 18 (12.5% of the whole cohort and 36% of patients tested for the deletion) had the 22q11 deletion. This frequency differs from an estimated population prevalence of 0.025% and suggests a need for screening for the 22q11 deletion in these patients.

Chromosomal mosaicism in cleavage-stage human embryos and the accuracy of single-cell genetic analysis.

PURPOSE: Our purpose was to assess the effect of chromosomal mosaicism in cleavage-stage human embryos on the accuracy of single-cell analysis for preimplantation genetic diagnosis. METHODS: Multicolor fluorescence in situ hybridization with X, Y, and 7 or X, Y, 7, and 18 chromosome-specific probes was used to detect aneuploidy in cleavage-stage human embryos. RESULTS: Most nuclei were diploid for the chromosomes tested but there was extensive mosaicism including monosomic, double-monosomic, nullisomic, chaotic, and haploid nuclei. CONCLUSIONS: Identification of sex by analysis of a single cleavage-stage nucleus is accurate but 7% of females are not identified. One or both parental chromosomes 7 were absent in at least 6.5% of the nuclei. With autosomal recessive conditions such as cystic fibrosis, carriers would be misdiagnosed as normal or affected. With autosomal dominant conditions, failure to analyze the affected parents allele (1.6-2.5%) would cause a serious misdiagnosis and analysis of at least two nuclei is necessary to reduce errors.

Chromosome translocations: segregation modes and strategies for preimplantation genetic diagnosis.

Preimplantation genetic diagnosis (PGD) offers polymerase chain reaction tests for an increasing range of single gene defects, and fluorescence in situ hybridization tests for sex determination (for X-linked conditions) and for aneuploidy detection. Patients carrying chromosome translocations with a high reproductive risk are increasingly seeking to increase their chances of a normal pregnancy with the help of PGD, for which they present a special challenge. This paper describes the behaviour of reciprocal translocations at meiosis, discusses current methods of detecting meiotic outcomes at the preimplantation stage and outlines ways forward for preimplantation diagnosis of these common rearrangements. We also propose a more general strategy using recently developed chromosome-specific sub-telomeric probes, combined, if possible, with proximal probes, to form a strong diagnostic tool.

The future of preimplantation genetic diagnosis.

This paper reviews the current status of preimplantation genetic diagnosis (PGD), outlining the methods currently in use for the diagnosis of sex and single-gene defects. New approaches under development are described, e.g. fluorescent polymerase chain reaction (PCR), the use of sub-telomeric probes for patients with balanced reciprocal translocations, the analysis of first and second polar bodies, the use of lasers to facilitate the biopsy of embryos, and ways forward for infertile patients.