Israel Medical Association Journal

Melanoma is the leading cause of death from skin tumors worldwide, with an annual increase in incidence over the past decade. The molecular mechanisms involved in melanoma pathogenesis are beginning to be unraveled. While a family history of melanoma and exposure to ultraviolet irradiation have been known for years as risk factors in melanoma development, the precise genes involved in inherited predisposition were defined only in the past decade. Germline mutations in two genes that play a pivotal role in controlling cell cycle and division – CDKN2A and cyclin-dependent kinase 4 (CDK4) – have been detected in autosomal, dominant, high penetrance familial melanoma cases. In addition to these two highly penetrant genes, germline mutations and polymorphisms in a few low penetrance genes have been reported in familial melanoma cases: melanocortin-1 receptor, epidermal growth factor, glutathione s-transferase M1, cytochrome p450 debrisoquine hydroxylase locus (CYP2D6) and vitamin D receptor.

Background: Primary pulmonary hypertension is a rare disorder, characterized by progressive pulmonary hypertension and right heart failure. It may be familial or sporadic. Mutations in bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor-beta receptor superfamily of receptors, underlie many cases of the disorder.

Objectives: To perform molecular analysis of a patient with familial PPH[1] and provide her and her family with suitable genetic counseling.

Methods: DNA was extracted from 10 ml whole blood, and the BMPR2 gene was screened for mutations. Individual exons were amplified by polymerase chain reaction and sequenced. Mutation confirmation and molecular characterization of additional family members was performed using restriction enzyme analysis followed by appropriate genetic counseling.

Results: We identified a novel T to C missense mutation expected to result in substitution of arginine for a conserved cysteine in the ligand-binding domain of BMPR2. Screening of family members demonstrated the presence of the mutation in the father and a younger asymptomatic sister of the index patient.

Conclusions: Molecular diagnosis in PPH allows for identification of at-risk family members and raises the option of earlier diagnosis and possibly instituting earlier treatment in affected individuals. However, molecular screening of asymptomatic family members raises difficult ethical questions that can only be resolved by conducting large multicenter prospective studies in BMPR2 carriers.

Background: The chronic progressive course of peripheral arterial occlusive disease with its limb-threatening and life-threatening potential is associated with physical, psychological and social distress for elderly patients and their families.

Objective: To evaluate the influence of infra-inguinal bypass surgery for limb salvage, and social support, on quality of life in elderly patients (over 60 years old).

Methods: Sixty patients aged 60 years and above diagnosed with limb-threatening ischemia were evaluated using the SF-36 generic questionnaire for quality of life, and the MOS-SS questionnaire for social support. Thirty patients (group I) were evaluated in the hospital prior to reconstructive surgery and 30 postoperative patients (group II) were evaluated at home at least 6 months after infra-inguinal bypass operations. Both groups were comparable in terms of age, gender, prevalence of ischemic heart disease, diabetes, and other atherosclerosis risk factors.

Results: All quality of life parameters were higher among patients who underwent limb salvage surgery (group II) as compared to preoperative patients (group I), yet the obtained values were lower than those in the general population. Patients in the surgical intervention group had higher levels of function, lower pain levels, and higher emotional and social well-being and, in addition, were spared limb amputation. The findings also indicate that the social support dimensions (emotional support, receipt of information, affection and positive social interaction), as measured in terms of perceived availability, do not operate as one entity. Different types of social support were more beneficial along different stages of the disease.

Conclusion: Peripheral arterial occlusive disease causes severe impairment of the quality of life in elderly patients. Arterial reconstructive surgery improves the quality of life though it still remains low compared to the general population. Social support is beneficial in the treatment of these patients, and the social worker in the vascular surgery department has a key role in identifying the various needs of the patients along the path of their chronic illness.
 

Objective: To reexamine the impact of prolonged nasogastric tube feeding on the oral microbiota and to explore the salivary flow and composition in elderly patients in long-term care.

Methods: We compared a group of elderly patients fed by nasogastric tube with a control group of elderly patients in long-term care who are fed orally. Bacteriologic studies were performed by culturing samples from the oropharynx. Saliva studies included quantitative and biochemical analysis of basal and stimulated salivary flow.

Results: Bacteriologic studies performed in 90 patients revealed a significantly higher prevalence of gram-negative bacteria in nasogastric tube-fed patients (73% vs. 13%, P < 0.001). It is emphasized that Pseudomonas aeruginosa and Klebsiella pneumoniae were commonly and exclusively isolated from the oral flora of the nasogastric tube-fed patients (P < 0.001, P < 0.05). In the saliva studies performed on 23 nasogastric tube-fed and 21 control patients, basal and stimulated salivary flow was not significantly different in the two groups, however the ratio of stimulated to basal flow was reduced in the nasogastric tube-fed group (P < 0.05). Significant differences were also found in the concentrations of sodium, amylase, phosphor and magnesium. Noteworthy was the concentration of uric acid, the main non-enzymatic antioxidant of saliva, which was significantly lower in nasogastric-tube fed patients (P < 0.002).

Conclusions: These findings suggest that prolonged nasogastric tube feeding is associated with pathologic colonization of the oropharynx and with alterations in the saliva that are related to the risk of aspiration pneumonia. Further research is called for, as well as a thorough revision of the existing oral cleansing procedures in these patients.

Vasopressin is a potent endogenous vasoconstrictor that increases blood pressure and systemic vascular resistance. The administration of exogenous vasopressin during closed and open cardiopulmonary resuscitation in humans was shown to be more effective than optimal doses of epinephrine in several clinical studies. We summarize here the recent experimental and clinical data on the use of vasopressin in cardiopulmonary resuscitation and septic shock. As the use of vasopressin in human resuscitation is now in its early stages, it is expected that accumulated future experience will shed more light regarding the risk-benefit aspects of its use.

Background: Low density lipoprotein apheresis is used as a complementary method for treating hypercholesterolemic patients who cannot reach target LDL[1]-cholesterol levels on conventional dietary and drug treatment. The DALI system (direct absorption of lipoproteins) is the only extracorporeal LDL-removing system compatible with whole blood.

Objective: To describe our one year experience using the DALI[2] system.

Methods: LDL apheresis was used in 13 patients due to inability to reach target LDL-C levels on conventional treatment. They included seven patients with familial hypercholesterolemia, three who had adverse reactions to statins, and three patients with ischemic heart disease who did not reach LDL-C target level on medical treatment.

Results: The average triglyceride, total cholesterol, high density lipoprotein-C and LDL-C levels before and after treatment in all patients were: 170 ± 113 vs. 124 ± 91, 269 ± 74 vs. 132 ± 48, 42 ± 8 vs. 37 ± 7.9, and 196 ± 77 vs. 80 ± 52 mg/dl, respectively. Comparing the results of a subgroup of seven patients who had previously been treated with plasma exchange, it is noteworthy that while the reduction in triglyceride, total cholesterol and LDL-C are comparable, the effect on HDL[3]-C concentration was less apparent: from an average of 39.7 ± 8.7 and 23 ± 5.7 mg/dl before and after plasma exchange to an average of 43.9 ± 8.1 and 38.4 ± 7 mg/dl before and after LDL apheresis, respectively. Five patients developed treatment-related adverse events: three experienced allergic reactions manifested as shortness of breath, urticaria and facial flushing; one patient developed rhabdomyolysis, an adverse reaction that was not reported previously as a result of LDL apheresis; and one patient had myopathy with back pain. All untoward effects occurred during the first few treatment sessions.

Conclusions: LDL apheresis using the DALI system is highly efficacious for the treatment of hypercholesterolemia. It is associated with a significant number of side effects occurring during the first treatment sessions. In patients not experiencing adverse effects in the early treatment period, it is well tolerated, and can provide remarkable clinical benefit even after short-term therapy.

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Background: The most frequent cause of defect in the mandible is tumor-related surgery. Larger defects or anterior arch defects cause severe morbidity due to disturbances in function and aesthetics.

Objectives: To assess the outcome of free tissue transfer for mandible reconstruction.

Methods: Since 1998 we operated on 11 patients with mandible defects using the fibula flap as the reconstruction method. We performed immediate reconstruction in eight patients after ablative surgery, and late reconstruction due to radiation-induced complications in three.

Results: All patients achieved good functional and aesthetic outcome. During the follow-up period two patients died of their malignant disease and one patient died from a non-related cause. Although two patients underwent reoperation in the first 3 months after their primary operation due to fixation failure, there were no other major complications.

Conclusions: According to the literature and our limited experience, the fibula flap is a safe and reliable option for mandible reconstruction.
 

Background: Superantigens produced by Staphylococcus aureus and Streptococcus pyogenes are among the most lethal of toxins. Toxins in this family trigger an excessive cellular immune response leading to toxic shock.

Objectives: To design an antagonist that is effective in vivo against a broad spectrum of superantigen toxins.

Methods: Short peptide antagonists were selected for their ability to inhibit superantigen-induced expression of human genes for cytokines that mediate shock. The ability of these peptides to protect mice against lethal toxin challenge was examined.

Results: Antagonist peptide protected mice against lethal challenge with staphylococcal enterotoxin B and toxic shock syndrome toxin-1, superantigens that share only 6% overall amino acid homology. Moreover, it rescued mice undergoing toxic shock. Antagonist peptides show homology to a β-strand/hinge/a-helix domain that is structurally conserved among superantigens, yet remote from known binding sites for the major histocompatibility class II molecule and T cell receptor that function in toxic T cell hyperactivation.

Conclusions: The lethal effect of superantigens can be blocked with a peptide antagonist that inhibits their action at the top of the toxicity cascade, before activation of T cells occurs. Superantigenic toxin antagonists may serve not only as countermeasures to biologic warfare but may be useful in the treatment of staphylococcal and streptococcal toxic shock, as well as in some cases of septic shock.